Judith T Zelikoff, Ph.D.

Maternal allergy acts synergistically with cigarette smoke exposure during pregnancy to induce hepatic fibrosis in adult male offspring
Allina, Jorge; Grabowski, Jacquelin; Doherty-Lyons, Shannon; Fiel, M Isabel; Jackson, Christine E; Zelikoff, Judith T; Odin, Joseph A
2011 Oct;8(4):258-264, Journal of immunotoxicology
Maternal environmental exposures during pregnancy are known to affect disease onset in adult offspring. For example, maternal asthma exacerbations during pregnancy can worsen adult asthma in the offspring. Cigarette smoking during pregnancy is associated with future onset of cardiovascular disease, obesity and diabetes. However, little is known about the effect of maternal environmental exposures on offspring susceptibility to liver disease. This pilot study examined the long-term effect of maternal allergen challenge and/or cigarette smoking during pregnancy on hepatic inflammation and fibrosis in adult mouse offspring. Ovalbumin (OVA) or phosphate-buffered saline (PBS)-sensitized/challenged CD-1 dams were exposed to mainstream cigarette smoke (MCS) or filtered air from gestational day 4 until parturition. Eight weeks postnatally, offspring were sacrificed for comparison of hepatic histology and mRNA expression. Adult male offspring of OVA-sensitized/challenged dams exposed to MCS (OSM) displayed significantly increased liver fibrosis (9.2% collagen content vs. <4% for all other treatment groups). These mice also had 1.8-fold greater collagen 1A1 mRNA levels. From the results here, we concluded that maternal allergen challenge in combination with cigarette smoke exposure during pregnancy may be an important risk factor for liver disease in adult male offspring
— id: 140522, year: 2011, vol: 8, page: 258, stat: Journal Article,

Exposure of Pregnant Mice to Cadmium Oxide (CdO) Nanopartides (NP) Poses a Risk to the Developing Offspring
Blum, Jason L.; Hoffman, Carol; Xiong, Judy Q.; Zelikoff, Judith T.
2010 NOV 23 ;122(21):115-115, Biology of reproduction
— id: 120559, year: 2010, vol: 122, page: 115, stat: Journal Article,

Effects of metal compounds with distinct physicochemical properties on iron homeostasis and antibacterial activity in the lungs: chromium and vanadium
Cohen, Mitchell D; Sisco, Maureen; Prophete, Colette; Yoshida, Kotaro; Chen, Lung-chi; Zelikoff, Judith T; Smee, Jason; Holder, Alvin A; Stonehuerner, Jacqueline; Crans, Debbie C; Ghio, Andrew J
2010 Feb;22(2):169-178, Inhalation toxicology
In situ reactions of metal ions or their compounds are important mechanisms by which particles alter lung immune responses. The authors hypothesized that major determinants of the immunomodulatory effect of any metal include its redox behavior/properties, oxidation state, and/or solubility, and that the toxicities arising from differences in physicochemical parameters are manifest, in part, via differential shifts in lung iron (Fe) homeostasis. To test the hypotheses, immunomodulatory potentials for both pentavalent vanadium (V(V); as soluble metavanadate or insoluble vanadium pentoxide) and hexavalent chromium (Cr(VI); as soluble sodium chromate or insoluble calcium chromate) were quantified in rats after inhalation (5 h/day for 5 days) of each at 100 mug metal/m(3). Differences in effects on local bacterial resistance between the two V(V), and between each Cr(VI), agents suggested that solubility might be a determinant of in situ immunotoxicity. For the soluble forms, V(V) had a greater impact on resistance than Cr(VI), indicating that redox behavior/properties was likely also a determinant. The soluble V(V) agent was the strongest immunomodulant. Regarding Fe homeostasis, both V(V) agents had dramatic effects on airway Fe levels. Both also impacted local immune/airway epithelial cell Fe levels in that there were significant increases in production of select cytokines/chemokines whose genes are subject to regulation by HIF-1 (whose intracellular longevity is related to cell Fe status). Our findings contribute to a better understanding of the role that metal compound properties play in respiratory disease pathogenesis and provide a rationale for differing pulmonary immunotoxicities of commonly encountered ambient metal pollutants
— id: 105696, year: 2010, vol: 22, page: 169, stat: Journal Article,

Breaking patterns of environmentally influenced disease for health risk reduction: immune perspectives
Dietert, Rodney R; DeWitt, Jamie C; Germolec, Dori R; Zelikoff, Judith T
2010 Aug;118(8):1091-1099, Environmental health perspectives
BACKGROUND: Diseases rarely, if ever, occur in isolation. Instead, most represent part of a more complex web or 'pattern' of conditions that are connected via underlying biological mechanisms and processes, emerge across a lifetime, and have been identified with the aid of large medical databases. OBJECTIVE: We have described how an understanding of patterns of disease may be used to develop new strategies for reducing the prevalence and risk of major immune-based illnesses and diseases influenced by environmental stimuli. FINDINGS: Examples of recently defined patterns of diseases that begin in childhood include not only metabolic syndrome, with its characteristics of inflammatory dysregulation, but also allergic, autoimmune, recurrent infection, and other inflammatory patterns of disease. The recent identification of major immune-based disease patterns beginning in childhood suggests that the immune system may play an even more important role in determining health status and health care needs across a lifetime than was previously understood. CONCLUSIONS: Focusing on patterns of disease, as opposed to individual conditions, offers two important venues for environmental health risk reduction. First, prevention of developmental immunotoxicity and pediatric immune dysfunction can be used to act against multiple diseases. Second, pattern-based treatment of entryway diseases can be tailored with the aim of disrupting the entire disease pattern and reducing the risk of later-life illnesses connected to underlying immune dysfunction. Disease-pattern-based evaluation, prevention, and treatment will require a change from the current approach for both immune safety testing and pediatric disease management
— id: 134396, year: 2010, vol: 118, page: 1091, stat: Journal Article,

Identifying patterns of immune-related disease: use in disease prevention and management
Dietert, Rodney R; Zelikoff, Judith T
2010 May;6(2):111-118, World journal of pediatrics : WJP
BACKGROUND: Childhood susceptibility to diseases linked with immune dysfunction affects over a quarter of the pediatric population in some countries. While this alone is a significant health issue, the actual impact of immune-related diseases extends over a lifetime and involves additional secondary conditions. Some comorbidities are well known (e.g., allergic rhinitis and asthma). However, no systematic approach has been used to identify life-long patterns of immune-based disease where the primary condition arises in childhood. Such information is useful for both disease prevention and treatment approaches. DATA SOURCES: Recent primary research papers as well as review articles were obtained from PubMed, Chem Abstracts, Biosis and from the personal files of the authors. Search words used were: the diseases and conditions shown Figs. 1 and 2 in conjunction with comorbid, comorbidities, pediatric, childhood, adult, immune, immune dysfunction, allergy, autoimmune, inflammatory, infectious, health risks, environment, risk factors. RESULTS: Childhood diseases such as asthma, type-1 diabetes, inflammatory bowel disease, respiratory infections /rhinitis, recurrent otitis media, pediatric celiac, juvenile arthritis and Kawasaki disease are examples of significant childhood health problems where immune dysfunction plays a significant role. Each of these pediatric diseases is associated with increased risk of several secondary conditions, many of which appear only later in life. To illustrate, four prototypes of immune-related disease patterns (i.e., allergy, autoimmunity, inflammation and infectious disease) are shown as tools for: 1) enhanced disease prevention; 2) improved management of immune-based pediatric diseases; and 3) better recognition of underlying pediatric immune dysfunction. CONCLUSIONS: Identification of immune-related disease patterns beginning in childhood provides the framework for examining the underlying immune dysfunctions that can contribute to additional diseases in later life. Many pediatric diseases associated with dysfunctional immune responses have been linked with an elevated risk of other diseases or conditions as the child ages. Diseases within a pattern may be interlinked based on underlying immune dysfunctions and/or current therapeutic approaches for managing the entryway diseases. It may be beneficial to consider treatment options for the earliest presenting diseases that will concomitantly reduce the risk of immune-linked secondary conditions. Additionally, improved disease prevention is possible with more relevant and age-specific immune safety testing
— id: 134402, year: 2010, vol: 6, page: 111, stat: Journal Article,

Non-coplanar polychlorinated biphenyl (PCB)-induced immunotoxicity is coincident with alterations in the serotonergic system
Duffy-Whritenour, Jessica E; Kurtzman, Rebecca Z; Kennedy, Sarah; Zelikoff, Judith T
2010 Oct-Dec;7(4):318-326, Journal of immunotoxicology
Attention to non-coplanar polychlorinated biphenyl (PCB) congeners in immunotoxicological research is increasing. However, the exact mechanism by which these congeners may induce immune dysfunction is still undefined. Because the serotonergic nervous system has been shown to be involved in the regulation of some immune responses, and also serves as a sensitive target for PCBs, the relationship (if any) between non-coplanar PCB exposure, immune responsiveness and the neurotransmitter serotonin (5-HT) was examined. Using bluegill sunfish (Lepomis macrochirus) as a model, changes in brain 5-HT levels, 5-HT synthesis and metabolism, and innate and cell-mediated immune parameters were evaluated following a single intraperitoneal injection of PCB 153 (5.0 or 50 mug/g body weight). Results revealed that 3 d following administration, PCB exposure decreased brain 5-HT levels (in the absence of effects on some enzymes involved in 5-HT synthesis and metabolism), increased oxyradical production by kidney phagocytes, and reduced splenic T- and B-lymphocyte proliferation. In vivo treatment of PCB-exposed fish with 5-hydroxy-L-tryptophan (the immediate precursor to 5-HT) ameliorated the observed PCB-induced immunotoxicity; in vitro treatment of immune cells from PCB-exposed fish with 5-HT failed to reverse the effects. Taken together, results from this study could suggest a link between PCB-induced alterations of brain 5-HT levels and subsequent immune dysfunction. These studies highlight the importance of indirect mechanisms of immunotoxicity, and, specifically, suggest a role for the neuroimmune axis in non-coplanar PCB-induced immune alterations
— id: 114586, year: 2010, vol: 7, page: 318, stat: Journal Article,

Tumor challenges in immunotoxicity testing
Ng, Sheung; Yoshida, Kotaro; Zelikoff, Judith T
2010 ;598:143-155, Methods in molecular biology
Syngeneic murine tumor models have been widely used by researchers to assess changes in tumor susceptibility associated with exposure to toxicants. Two common tumor models used to define host resistance against transplanted tumors in vivo are EL4 mouse lymphoma cells (established from a lymphoma induced in a C57BL/6 mouse by 9,10-dimethyl-1,2-benzanthracene) and B16F10 mouse melanoma cells (derived through variant selection from a B16 melanoma arising spontaneously in C57BL/6 mice). While C57BL/6 mice are commonly used as the syngeneic host for these tumor models, other mouse strains such as B(6)C(3)F(1) (C57BL/6 x C3H) can also be used. Tumor challenge of the host can be done by subcutaneous (sc) or intravenous (iv) injection, depending upon whether the effects are to be examined on local tumor development or experimental/artificial metastasis. Materials and methodologies for injection of both tumor cell models are described in detail in the subsequent sections
— id: 105673, year: 2010, vol: 598, page: 143, stat: Journal Article,

FETAL STRESS IN UTERO PREDISPOSES TO HEPATIC FIBROSIS IN ADULT MALE B6C3F1 MICE
Allina, J; Fiel, MI; Doherty-Lyons, S; Grabowski, J; Zelikoff, JT; Odin, JA
2009 OCT ;50(4):1185A-1185A, Hepatology
— id: 105951, year: 2009, vol: 50, page: 1185A, stat: Journal Article,

Pediatric immune dysfunction and health risks following early-life immune insult
Dietert R.R.; Zelikoff J.T.
2009 ;5(1):36-51, Current Pediatric Reviews
Chronic pediatric diseases arising from early-life immune insult and postnatal immune dysfunction are among the most prevalent health challenges for children. Diseases such as childhood asthma and allergies, chronic otitis media, type 1 diabetes, childhood leukemia and pediatric celiac disease all feature dysfunctional immune responses and/ or inappropriately skewed immune capacities. Additionally, these disorders have been increasing in incidence in recent years with previously identified risk factors unable to fully account for the change. Still, some treatment approaches target the initial health complaint and its symptoms without fully addressing either the underlying immune dysfunction of the initial disease or the likelihood for additional associated health risks in later life. Therefore, it is useful to understand both the nature of the immune dysfunction as well as the reported associated health risks. This review characterizes those pediatric immune dysfunctions produced by well-studied immunotoxicants and provides a matrix of those health risks that appear to be linked together via the underlying pediatric immune dysfunction. This information could lead to: 1) improved identification and treatment of underlying immune dysfunction, 2) long-term approaches to health management, and 3) improved prenatal and neonatal prevention strategies to avoid environmentally-induced immune insult and developmental immunotoxicity. copyright 2009 Bentham Science Publishers Ltd
— id: 99334, year: 2009, vol: 5, page: 36, stat: Journal Article,

Early life insult from cigarette smoke may be predictive of chronic diseases later in life
Doherty, S P; Grabowski, J; Hoffman, C; Ng, S P; Zelikoff, J T
2009 Jul;14 Suppl 1:97-101, Biomarkers
Evidence is rapidly accumulating that links cigarette smoke (CS) exposure in utero with the development of a variety of disease pathologies in the older offspring including, type 2 diabetes, obesity, certain childhood cancers and respiratory disorders. The role that the fetal environment plays in these late-onset outcomes and the underlying cellular/molecular mechanisms by which these CS-induced effects may occur are currently unknown. Although we are becoming more aware of the fact that prenatal insult can underlie childhood/adult diseases, critical knowledge gaps still exist including gene-environment interactions, and how a CS-induced imbalance in immune dynamics (i.e. TH1/TH2) might affect asthma development and/or exacerbation later in life. In this mini-review we introduce the concept of sexual dimorphism in CS-induced late-onset disease outcomes, as well as explore the mechanisms by which CS exposure in utero can lead to cardiovascular, cancer and respiratory abnormalities in the exposed offspring. By addressing such questions using animal models, appropriate intervention strategies can be developed that will help to protect children's health and their long-term quality of life
— id: 104718, year: 2009, vol: 14 Suppl 1, page: 97, stat: Journal Article,

Prenatal exposure to cigarette smoke induces diet- and sex-dependent dyslipidemia and weight gain in adult murine offspring
Ng, Sheung P; Conklin, Daniel J; Bhatnagar, Aruni; Bolanowski, Duane D; Lyon, Jessica; Zelikoff, Judith T
2009 Jul;117(7):1042-1048, Environmental health perspectives
BACKGROUND: Cardiovascular disease (CVD) affects 71 million American adults and remains the leading cause of death in the United States and Europe. Despite studies that suggest that the development of CVD may be linked to intrauterine growth or early events in childhood, little direct experimental evidence supports the notion. OBJECTIVE: We investigated whether exposure to cigarette smoke in utero alters the risk of developing CVD later in life. METHODS: We exposed B(6)C(3)F(1) mice (via whole-body inhalation) to either filtered air or mainstream cigarette smoke (MCS, at a particle concentration of 15 mg/m(3)) from gestational day 4 to parturition. Adult offspring were fed a normal chow diet or switched to a high-fat diet 2 weeks before sacrifice. We measured dam and offspring body weight, plasma lipid parameters, lipoprotein subclass particle numbers and sizes, and total antioxidant capacities. RESULTS: Adult female mice prenatally exposed to MCS demonstrated significantly higher body weight and levels of plasma high-density lipoprotein (HDL) and low-density lipoprotein than did their air-exposed counterparts. When fed a high-fat diet for 2 weeks, males, but not females, exposed prenatally to MCS gained substantially more weight and exhibited dramatic alterations in total cholesterol and HDL levels compared with their air-exposed counterparts. CONCLUSIONS: These data provide, for the first time, direct experimental evidence supporting the notion that prenatal exposure to cigarette smoke affects offspring weight gain and induces a lipid profile that could alter the offspring's risk of developing CVD later in life
— id: 101334, year: 2009, vol: 117, page: 1042, stat: Journal Article,

The effects of pyridoxine deficiency and supplementation on hematological profiles, lymphocyte function, and hepatic cytochrome P450 in B6C3F1 mice
Tangjarukij, C; Navasumrit, P; Zelikoff, JT; Ruchirawat, M
2009 SEP 25 ;6(3):147-160, Journal of immunotoxicology
Pyridoxine, a B-6 vitamin, is a co-factor in a variety of enzymatic reactions involved in intermediary metabolism. The effects of pyridoxine deficiency and supplementation on hematological profiles, lymphocyte function, and hepatic CYP1A1 and CYP2E1 were investigated in B6C3F1 mice fed a diet containing either 0 (i.e., pyridoxine deficient diet, [PD]); or 7 mg pyridoxine-HCl/kg (i.e., control diet, [CD]) for 8 or 13 weeks followed by administration of 500 mu g pyridoxine-HCl (IP) daily for either 2 (PD-S2 and CD-S2) or 3 (PD-S3 and CD-S3) consecutive days. Results demonstrated that erythrocyte aspartate aminotransferase activity coefficient (EAST-AC) values, which reflect host pyridoxine status, were significantly higher in PD mice than in CD mice, and dropped to control levels after supplementation. PD mice had significantly reduced weight gains, mean corpuscular volume (MCV), hemoglobin (HGB), and hematocrit (HCT) levels compared to CD mice after 8 and 13 weeks on the prescribed diet. In addition, PD mice had significantly lower circulating levels of total white blood cells, but higher red blood cell numbers after 8 weeks (compared to CD mice). Pyridoxine supplementation for 3 days restored HGB levels in PD mice to that of the unsupplemented CD controls; HCT, MCV and MCH levels were also increased in PD-S3 mice compared to their unsupplemented PD counterparts, but failed to reach comparable levels to those seen in mice fed a control diet. The pyridoxine-deficient diet also resulted in decreased mitogen stimulated T-lymphocyte proliferation after a 13-week feeding regimen and increased hepatic CYP1A1 activity that was reversed by pyridoxine supplementation. These studies demonstrate in a murine model that pyridoxine deficiency can cause multiple alterations that, in many cases, can be reversed by supplementation
— id: 102961, year: 2009, vol: 6, page: 147, stat: Journal Article,

The role of parity status on cigarette smoke-induced modulation of anti-tumor immune mechanisms
Vancza, Elizabeth M; Ng, Sheung Pui; Harkema, Jack R; Zelikoff, Judith T
2009 Jun;6(2):94-103, Journal of immunotoxicology
Epidemiologic studies indicate that women who smoke cigarettes are more likely to experience adverse reproductive and immunological health effects. Despite these facts, 20-30% of American women still smoke during their reproductive years. As little is known of the relationship between smoking and the immune response during pregnancy, an investigation was conducted using parous and non-parous (virgin) B6C3F1 mice to investigate what role (if any) parity status had on cigarette smoke (CS) induced effects on immune functions important in surveillance against developing tumors. Pregnant mice were exposed to CS for 5 d/wk ( 4 hr/d) from gestational day 4 to parturition; virgin mice were exposed for an equivalent amount of time. Smoke- and parity-associated alterations in pulmonary histology and lung inflammation, along with tumor cell host resistance, and cytotoxic T-lymphocyte (CTL) activity were examined either 24- 48 hr or 5 wk post-exposure/parturition; in the parous mice, gestational parameters were also evaluated. Exposure to CS significantly increased tumor susceptibility in virgin mice first injected with EL4 lymphoma cells at the 5 wk post-exposure timepoint; tumor incidence began to increase in smoke-exposed virgin mice as early as 24- 48 hr post-exposure. Pregnancy itself increased tumor incidence in mice injected with EL4 cells 24- 48 hr after birth, but this effect then dissipated over 5 wk to levels seen in virgin mice. When EL4 injections were first performed at either timepoint in CS-exposed parous mice, the tumor incidence was not significantly different from that in the air-exposed parity-matched controls. CTL activity in CS-exposed parous mice was significantly increased from both nulliparous groups as well as from the parous air control mice examined 5 wk post-exposure. Results suggest that exposure to CS throughout gestation could act in combination with pregnancy-associated changes to up-regulate immune responses, potentially compromising fetal tolerance
— id: 100669, year: 2009, vol: 6, page: 94, stat: Journal Article,

Early-life environment, developmental immunotoxicology, and the risk of pediatric allergic disease including asthma
Dietert, Rodney R; Zelikoff, Judith T
2008 Dec;83(6):547-560, Birth defects research. Pt B. Developmental & reproductive toxicology
Incidence of childhood allergic disease including asthma (AD-A) has risen since the mid-20th century with much of the increase linked to changes in environment affecting the immune system. Childhood allergy is an early life disease where predisposing environmental exposures, sensitization, and onset of symptoms all occur before adulthood. Predisposition toward allergic disease (AD) is among the constellation of adverse outcomes following developmental immunotoxicity (DIT; problematic exposure of the developing immune system to xenobiotics and physical environmental factors). Because novel immune maturation events occur in early life, and the pregnancy state itself imposes certain restrictions on immune functional development, the period from mid-gestation until 2 years after birth is one of particular concern relative to DIT and AD-A. Several prenatal-perinatal risk factors have been identified as contributing to a DIT-mediated immune dysfunction and increased risk of AD. These include maternal smoking, environmental tobacco smoke, diesel exhaust and traffic-related particles, heavy metals, antibiotics, environmental estrogens and other endocrine disruptors, and alcohol. Diet and microbial exposure also significantly influence immune maturation and risk of allergy. This review considers (1) the critical developmental windows of vulnerability for the immune system that appear to be targets for risk of AD, (2) a model in which the immune system of the DIT-affected infant exhibits immune dysfunction skewed toward AD, and (3) the lack of allergy-relevant safety testing of drugs and chemicals that could identify DIT hazards and minimize problematic exposure of pregnant women and children
— id: 94112, year: 2008, vol: 83, page: 547, stat: Journal Article,

Relationship between serotonin and the immune system in a teleost model
Duffy-Whritenour, J E; Zelikoff, J T
2008 Feb;22(2):257-264, Brain, behavior & immunity
An immunomodulatory role for serotonin (5-HT) has been demonstrated in mammals and evidence for a similar role for 5-HT has recently emerged in fish. However, as limited studies are available, discrepancies often exist regarding the role of 5-HT in the teleost immune response. Therefore, studies were undertaken to help clarify this relationship. Lymphocyte proliferation and extracellular superoxide (O2.-) production were examined in cells from bluegill sunfish injected with either 5-HTP (the immediate precursor to 5-HT) or pCPA (an inhibitor of the rate-limiting enzyme in 5-HT synthesis), or, in vitro following exposure of immune cells to either 5-HT, the 5-HT(1A) receptor agonist, 8-OH-DPAT, or the receptor antagonist, NAN-190. Exposure of fish to 5-HTP increased whole brain 5-HT levels, while pCPA exposure decreased whole brain and splenic 5-HT. In vivo exposure of fish to pCPA depressed T- and B-lymphocyte proliferation; exposure to 5-HTP failed to alter either immune endpoint. In vitro exposure of bluegill splenocytes to 5-HT or 8-OH-DPAT inhibited lymphoproliferation; treatment with NAN-190 had no effect on immune function. Results suggest a link in bluegill between immune function and the serotonergic system. The disparity observed following in vivo- and in vitro-induced serotonergic alterations indicates the complexity of this neuro-immune relationship and emphasizes the need for further studies in this regard
— id: 75764, year: 2008, vol: 22, page: 257, stat: Journal Article,

The effects of prenatal exposure of mice to cigarette smoke on offspring immune parameters
Ng, Sheung P; Zelikoff, Judith T
2008 ;71(7):445-453, Journal of toxicology & environmental health. Pt. A
While direct exposure to cigarette smoke (CS) was shown in numerous human and animal studies to impair host immune responses, effects on the offspring following in utero CS exposure are relatively unknown. Thus, a toxicological study was performed that extended our previous investigations examining the effects of relatively low-dose CS exposure on immune tumor surveillance parameters of the prenatally exposed offspring. In the current study, pregnant B6C3F1 mice were exposed by inhalation to mainstream CS (at a concentration equivalent to smoking approximately 1 pack of cigarettes/d) for 5 d/wk, 4 h/d from gestational day 4 to parturition. Smoke-induced effects on a number of immune parameters were examined in 3- (and/or 5-), 10-, and 20-wk-old male and female offspring, including lymphoid organ weight/cellularity; blood and bronchopulmonary lavage cell numbers/profiles; splenic lymphocyte proliferation; mixed lymphocyte reactions; and, host resistance against transplanted melanoma cells. Exposure in utero to CS significantly increased circulating white blood cell and lymphocyte numbers in both sexes for up to 2.5 mo after birth (compared to their age-/sex-matched, air-exposed counterparts). In addition, 3-wk-old male and female offspring from smoke-exposed mothers had decreased mitogen-stimulated T-lymphocyte proliferation, while 5-wk-old male pups had increased mixed lymphocyte response compared to their sex-matched, air-exposed counterparts. Although effects of prenatal smoke exposure on overall offspring immunity were relatively modest, these findings could suggest that early toxic insult by CS may alter subsequent immune homeostasis in the offspring, leading, possibly, to changes in disease vulnerability
— id: 76347, year: 2008, vol: 71, page: 445, stat: Journal Article,

Pulmonary immunotoxic potentials of metals are governed by select physicochemical properties: vanadium agents
Cohen, Mitchell D; Sisco, Maureen; Prophete, Colette; Chen, Lung-Chi; Zelikoff, Judith T; Ghio, Andrew J; Stonehuerner, Jacqueline D; Smee, Jason J; Holder, Alvin A; Crans, Debbie C
2007 Jan;4(1):49-60, Journal of immunotoxicology
The in situ reactions of metal ions/complexes are important in understanding the mechanisms by which environmental and occupational metal particles alter lung immune responses. A better understanding of these reactions in situ will also allow for the improved specificity and controlled toxicity of novel metallocompounds to be used as inhaled diagnostics or therapeutics. Our previous work showed that inhalation of metals (e.g., chromium, vanadium, nickel) caused altered lung immune cell function and host resistance. The data also suggested that the degree of immunomodulation induced depended not only on the amount of metal deposited, but also the compound used. If specificity governs pulmonary immunomodulatory potential, it follows that physicochemical properties inherent to the metal have a role in the elicited effects. We hypothe-size that major determinants of any metal compound's potential are its redox behavior, valency (generally referred to as oxidation state and considered speciation in chemical literature), and/or solubility. In accord with the extensive work carried out with vanadium (chemical symbol V) compounds showing the importance of form used, differences in potential for a range of V agents (pentavalent [V(V)] insoluble vanadium pentoxide and soluble sodium metavanadate, tetravalent [V(IV)] vanadyl dipicolinate, and trivalent [V(III)] bis(dipicolinato)vanadium) were quantified based on induced changes in local bacterial resistance after host inhalation of each agent at 100 mu g V/m(3) (5 hr/d for 5 d). Differences in effect between V(V) forms indicated that solubility was a critical property in in situ pulmonary immunotoxicity. Among the soluble forms, oxidizing vanadate had the greatest impact on resistance; reducing V(III) altered resistance to a lesser extent. Both the V(IV) and insoluble V(V) had no effect. When data was analyzed in the context of pre-infection lung V burdens, soluble V agents with different oxidation states induced varying responses, supporting the hypothesis that differences in immunomodulatory potential might be attributed to redox behavior or valency. Our findings both provide a basis for understanding why some metals could be a greater health risk than others (when encountered in equal amounts) and will assist in the design of inhalable metallopharmaceuticals by allowing researchers to preempt selection of certain metal ions or complexes for use in such products
— id: 94113, year: 2007, vol: 4, page: 49, stat: Journal Article,

Detection of Changes in Alveolar Macrophage Iron Status Induced by Select PM(2.5)-Associated Components Using Iron-Response Protein Binding Activity
Doherty, S P; Prophete, C; Maciejczyk, P; Salnikow, K; Gould, T; Larson, T; Koenig, J; Jaques, P; Sioutas, C; Zelikoff, J T; Lippmann, M; Cohen, M D
2007 May;19(6):553-562, Inhalation toxicology
The extent of adverse health effects, including induction/exacerbation of infectious lung disease, arising from entrainment of equivalent amounts (or exposure to a fixed increment) of fine particulate matter (PM(2.5)) can vary from region to region or city to city in a region. To begin to explain how differing effects on host resistance might arise after exposure to PM(2.5) from various sites, we hypothesized that select metals (e.g., V, Al, and Mn) in each PM(2.5) caused changes in alveolar macrophage (AM) Fe status that, ultimately, would lead to altered antibacterial function. To test this, iron-response protein (IRP) binding activity in a rat AM cell line was assessed after exposure to Fe alone and in conjunction with V, Mn, and/or Al at ratios of V:Fe, Al:Fe, or Mn:Fe encountered in PM(2.5) samples from New York City, Los Angeles, and Seattle. Results indicated that V and Al each significantly altered IRP activity, though effects were not consistently ratio-(i.e., dose-) dependent; Mn had little impact on activity. We conclude that the reductions in Fe status detected here via the IRP assay arose, in part, from effects on transferrin-mediated Fe(3 +) delivery to the AM. Ongoing studies using this assay are allowing us to better determine: (1) whether mass (and/or molar) relationships between Fe and V, Al, and/or Mn in any PM(2.5) sample consistently govern the extent of change in AM Fe status; (2) how much any specified PM(2.5) constituent (metal or nonmetal) contributes to the overall disruption of Fe status found induced by an intact parent sample; and (3) whether induced changes in binding activity are relatable to other changes expected to occur in the AM, that is, in IRP-dependent mRNA/levels of ferritin/transferrin receptor and Fe-dependent functions. These studies demonstrate that pollutant-induced effects on lung cell Fe status can be assessed in a reproducible manner using an assay that can be readily performed by investigators who might otherwise have no access to other very costly analytical equipment, such as graphite atomic absorption or x-ray fluorescence spectro(photo)meters
— id: 72616, year: 2007, vol: 19, page: 553, stat: Journal Article,

Woodsmoke health effects: a review
Naeher, Luke P; Brauer, Michael; Lipsett, Michael; Zelikoff, Judith T; Simpson, Christopher D; Koenig, Jane Q; Smith, Kirk R
2007 Jan;19(1):67-106, Inhalation toxicology
The sentiment that woodsmoke, being a natural substance, must be benign to humans is still sometimes heard. It is now well established, however, that wood-burning stoves and fireplaces as well as wildland and agricultural fires emit significant quantities of known health-damaging pollutants, including several carcinogenic compounds. Two of the principal gaseous pollutants in woodsmoke, CO and NOx, add to the atmospheric levels of these regulated gases emitted by other combustion sources. Health impacts of exposures to these gases and some of the other woodsmoke constituents (e.g., benzene) are well characterized in thousands of publications. As these gases are indistinguishable no matter where they come from, there is no urgent need to examine their particular health implications in woodsmoke. With this as the backdrop, this review approaches the issue of why woodsmoke may be a special case requiring separate health evaluation through two questions. The first question we address is whether woodsmoke should be regulated and/or managed separately, even though some of its separate constituents are already regulated in many jurisdictions. The second question we address is whether woodsmoke particles pose different levels of risk than other ambient particles of similar size. To address these two key questions, we examine several topics: the chemical and physical nature of woodsmoke; the exposures and epidemiology of smoke from wildland fires and agricultural burning, and related controlled human laboratory exposures to biomass smoke; the epidemiology of outdoor and indoor woodsmoke exposures from residential woodburning in developed countries; and the toxicology of woodsmoke, based on animal exposures and laboratory tests. In addition, a short summary of the exposures and health effects of biomass smoke in developing countries is provided as an additional line of evidence. In the concluding section, we return to the two key issues above to summarize (1) what is currently known about the health effects of inhaled woodsmoke at exposure levels experienced in developed countries, and (2) whether there exists sufficient reason to believe that woodsmoke particles are sufficiently different to warrant separate treatment from other regulated particles. In addition, we provide recommendations for additional woodsmoke research
— id: 72084, year: 2007, vol: 19, page: 67, stat: Journal Article,

Smoking during pregnancy: Subsequent effects on offspring immune competence and disease vulnerability in later life
Ng, Sheung P; Zelikoff, Judith T
2007 Apr-May;23(3):428-437, Reproductive toxicology
About 1 million babies are born each year after prenatal cigarette smoke (CS) exposure from maternal smoking which does not include involuntary maternal exposure to passive smoke. While past emphasis has been on immediately obvious perinatal consequences (e.g., preterm delivery, and low birthweight), smoking during pregnancy has recently emerged as a possible risk factor for later onset disease outcomes in the prenatally exposed offspring. This review brings together those epidemiologic and toxicologic studies demonstrating a link between prenatal CS exposure and subsequent disease vulnerabilities in the progeny. While disorders such as obesity, and type 2 diabetes are included in this category, this paper focuses on two immunologically-related outcomes, cancer and asthma. The review defines the current state of knowledge in this understudied area of children's health, sheds light on the seriousness of such disease vulnerabilities, and reveals gaps that need to be filled to provide a better understanding of the extent and nature of the problem
— id: 72083, year: 2007, vol: 23, page: 428, stat: Journal Article,

Role of testosterone in gender-related enhanced tumor susceptibility of mice prenatally exposed to cigarette smoke
Steinetz, B; Ng, SP; Zelikoff, J
2007 APR ;25(3):215-215, Biology of reproduction
— id: 73248, year: 2007, vol: 25, page: 215, stat: Journal Article,

Pulmonary immunotoxic potentials of metals are governed by select physicochemical properties: chromium agents
Cohen, Mitchell D; Prophete, Colette; Sisco, Maureen; Chen, Lung-Chi; Zelikoff, Judith T; Smee, Jason J; Holder, Alvin A; Crans, Debbie C
2006 Jul 1;3(2):69-81, Journal of immunotoxicology
Increasing the understanding of how metal ions/complexes react in situ will allow for the improved specificity and controlled toxicity of novel synthetic metallocompounds that will be used as inhaled diagnostics or therapeutics. Our previous work showed that inhalation of select metals (e.g., chromium, vanadium, nickel, iron) caused alterations in lung immune cell function and in local bacterial resistance. The data also suggested that variations in the degree of immuno-modulation induced were not solely dependent on the amount of metal deposited in the lung, but also on the specific compound. If specificity governs immunomodulatory potential, it follows that physicochemical properties inherent to the metal may have a role in the elicited effects. We hypothesize that major determinants of any metal compound's immunomodulatory potential in situ are its redox behavior, valency, and/or solubility. Using changes in local bacterial resistance as an endpoint, differences in immunotoxic potential in the lungs were quantified for a range of chromium agents (insoluble calcium chromate(VI), and soluble sodium chromate(VI), potassium bis(dipicolinato)chromate(III) and sodium bis(dipicolinato)chromate(II)). Results indicated that among the latter three forms of Cr, strongly oxidizing hexavalent Cr (Cr[VI]) had the greatest impact on resistance, while reducing divalent and fairly unreactive trivalent forms of Cr had no effect at an equal exposure level (i.e., 100 mug Cr/m(3), 5 hr/d, for 5 d). Insoluble Cr(VI) had a greater effect than its soluble form. When data was analyzed in the context of pre-infection lung Cr burdens, it was seen that immunomodulatory potentials for both Cr(VI) agents did not differ significantly; however, complexes with different oxidation states did induce varying responses, suggesting that differences in potential might be attributed to redox behavior. From this it was concluded that for Cr, certain physicochemical properties are likely more important to any in situ pulmonary immunotoxicity than others (i.e., redox behavior is more critical than solubility). Our findings, in part, will help provide a basis for understanding why certain metals could be a greater health risk than others, even when encountered in equal amounts. This, in turn, will help researchers in the design of inhalable diagnostic/therapeutic metallopharmaceuticals by pre-empting the selection of certain metal ions/complexes for potential use in these products
— id: 94114, year: 2006, vol: 3, page: 69, stat: Journal Article,

The Relationship Between Noncoplanar PCB-Induced Immunotoxicity and Hepatic CYP1A Induction in a Fish Model
Duffy, Jessica E; Zelikoff, Judith T
2006 Jan 1;3(1):39-47, Journal of immunotoxicology
Abundant literature exists demonstrating the immunomodulating effects of polychlorinated biphenyls (PCBs). To date, most of the research has focused on dioxin-like coplanar PCB congeners because of their high affinity for the aryl hydrocarbon receptor (AhR) and cytochrome P450-inducing capability. For this study, the impact of two structurally different PCB congeners on the immune responsiveness of bluegill sunfish (Lepomis macrochirus) was examined to evaluate the immunotoxic potential of each congener (as separate entities) and to relate effects on immune function with hepatic CYP1A induction. Fish received a single intraperitoneal injection of the: coplanar congener, PCB 126 (0.01 or 1.0 mug/g BW); noncoplanar PCB 153 (5.0 or 50.0 mug/g BW); or, the corn oil vehicle. PCB-induced effects on innate and cell-mediated immune parameters, and on hepatic CYP1A protein induction were evaluated in fish sacrificed 1, 3, 7, 14 or 21 days post-injection. In the absence of CYP1A induction, PCB 153 increased kidney phagocyte-mediated superoxide production 3 d post-injection, and at the highest dose suppressed B- and T-lymphocyte proliferation after 3 and 7 days, respectively. Treatment of fish with PCB 126 had no effect on oxyradical production, but altered B-lymphocyte proliferation after 1 day, also in the absence of CYP1A induction. Hepatic CYP1A was only induced in fish exposed to the highest PCB 126 dose; protein induction appeared at 3 d post-injection and persisted for up to 21 days. Taken together, these results demonstrate that exposure to different PCB congeners can alter immune function in the absence of CYP1A induction, suggesting that mechanisms other than the AhR pathway may play a role in PCB-induced immunotoxicity, particularly for the noncoplanar congeners
— id: 94115, year: 2006, vol: 3, page: 39, stat: Journal Article,

Differential inducibility of rat pulmonary CYP1A1 by cigarette smoke and wood smoke
Iba, Michael M; Fung, Jacqueline; Chung, Le; Zhao, Jason; Winnik, Bozena; Buckley, Brian T; Chen, Lung Chi; Zelikoff, Judith T; Kou, Yu Ru
2006 Jul 14;606(1-2):1-11, Mutation research
Mainstream cigarette smoke (CS) and wood smoke (WS) were compared in terms of their pulmonary CYP1A1 inducibility. The inducibility was assessed in pulmonary microsomes from rats exposed to freshly generated CS or WS and in rat lung explants treated with extracts of CS or WS total particulate matter (TPM). Mutagenicity in Salmonella typhimurium TA98 and TA100, an effect established for CS and WS in previous studies, was also examined as a test of the biological activity of the smoke samples in the present study. Pulmonary microsomal CYP1A1 activity (as measured by ethoxyresorufin O-deethylase), was induced 4.4-fold and 8.3-fold following exposure of rats to smoke from a single cigarette and three cigarettes, respectively, relative to the activity in control rats. The induction was paralleled by elevated CYP1A1 mRNA level (by northern blot analysis). WS, in contrast to CS, induced neither pulmonary CYP1A1 activity nor mRNA in exposed rats. CYP1A1 protein (by western blot analysis) was induced in cultured rat lung explants by extracts of CS TPM or by a high concentration (496 nM) of benzo[a]pyrene (B[a]P) but not by extracts of WS TPM or a low concentration (0.110 nM) of B[a]P. The induction by high B[a]P concentration was inhibited by extracts of CS or WS TPM, with the inhibition by extracts of WS TPM (75%) being greater than that by extracts of CS TPM (31%). Extracts of CS TPM were as mutagenic as extracts of WS TPM to Salmonella typhimurium TA98 but were more mutagenic than extracts of WS TPM to Salmonella typhimurium TA100. The results show that CS and WS are mutagenic but that WS differs from CS in its inability to induce pulmonary CYP1A1
— id: 66149, year: 2006, vol: 606, page: 1, stat: Journal Article,

Effects of prenatal exposure to cigarette smoke on offspring tumor susceptibility and associated immune mechanisms
Ng, Sheung P; Silverstone, Allen E; Lai, Zhi-Wei; Zelikoff, Judith T
2006 Jan;89(1):135-144, Toxicological sciences
Epidemiologic evidence suggests that prenatal exposure to intact (unfractionated) cigarette smoke (CS) increases the incidence of cancer in the offspring. A toxicology study was carried out to examine the effects and underlying mechanisms of prenatal exposure to mainstream cigarette smoke (MCS) on offspring resistance to tumor challenge and surveillance mechanisms critical for the recognition and destruction of tumors. Pregnant B6C3F1 mice were exposed by inhalation to MCS for 5 days/week (4 h/day from gestational day 4 to parturition). Smoke-induced effects on offspring-host resistance to transplanted tumor cells; natural killer (NK) cell and cytotoxic T-lymphocyte (CTL) activity; cytokine levels; lymphoid organ immune cell subpopulations; and histology-were examined in 5-, 10- and 20-week-old male and female offspring. At a concentration of smoke roughly equivalent to smoking <1 pack of cigarettes/day, prenatally exposed male offspring challenged at 5 week of age with EL4 lymphoma cells demonstrated a greater than two-fold increase in tumor incidence (relative to age-/gender-matched air-exposed offspring); tumors in prenatally smoke-exposed pups also grew significantly faster. Cytotoxic T-lymphocyte activity in the smoke-exposed 5- and 10-week-old male pups was significantly less than that of the age- and gender-matched controls. No effects of prenatal CS exposure were observed on offspring NK activity, cytokine levels, lymphoid organ histology, or immune cell subpopulations. Results demonstrated that exposure of pregnant mice to a relevant dose of MCS decreased offspring resistance against transplanted tumor cells and persistently reduced CTL activity in prenatally exposed pups. This study provides biological plausibility for the epidemiologic data indicating that children of mothers who smoke during pregnancy have a greater risk of developing cancer in later life
— id: 62363, year: 2006, vol: 89, page: 135, stat: Journal Article,

Hormonal changes accompanying cigarette smoke-induced preterm births in a mouse model
Ng, Sheung P; Steinetz, Bernard G; Lasano, Salamia G; Zelikoff, Judith T
2006 Sep;231(8):1403-1409, Experimental biology & medicine
Epidemiologic evidence indicates that maternal smoking increases the risk of preterm birth. While a number of plausible mechanisms for early delivery have been offered, the role of gestational hormones in this smoke-induced outcome is uncertain. Thus, a toxicologic study was performed to examine the effects and underlying hormonal mechanisms of mainstream cigarette smoke (MCS) exposure on gestational duration. Pregnant B6C3F1 mice were exposed by inhalation to MCS for 5 days/week (4 hrs/day) from Gestational Day (GD) 4 to parturition. Smoke-induced effects on gestational length, interpubic ligament length, maternal hormone secretion patterns (estradiol-17beta, progesterone, prolactin, and relaxin), body weight gain, postimplantation loss, litter size, and offspring sex ratio were examined. Dams exposed to MCS at a concentration equivalent to smoking less than one pack of cigarettes/day (carbon monoxide = 25 parts per million, total suspended particulates = 16 mg/m3) demonstrated a significant (P < 0.05) shortening of gestational duration (compared with pregnant, air-exposed mice). In addition, MCS-exposed mice sacrificed on GD 18 had significantly (P < 0.05) increased interpubic ligament length, elevated serum estrogen levels, and a reduced progesterone to estradiol-17beta ratio (compared with air-exposed controls); levels of progesterone and prolactin were only modestly decreased and increased, respectively, in the MCS-exposed mice. Smoke exposure had no significant effects on maternal relaxin levels, body weight gain, postimplantation loss, litter size, or sex ratio. Results of this study demonstrate that inhalation exposure of pregnant mice to a low dose of MCS shortens gestation and alters hormone secretory patterns, which are important for maintaining pregnancy and inducing parturition. These findings support the view that pregnant women who smoke (even modestly) may be at increased risk for preterm birth, and that early delivery may be related (at least partly) to MCS-induced
— id: 68987, year: 2006, vol: 231, page: 1403, stat: Journal Article,

Effects of elevated temperature and nickel pollution on the immune status of Japanese medaka
Prophete, C; Carlson, E A; Li, Y; Duffy, J; Steinetz, B; Lasano, S; Zelikoff, J T
2006 Sep;21(3):325-334, Fish & shellfish immunology
Changes in a host's environment (i.e. physical or chemical) can alter normal immune function. In aquatic organisms, exposure to stress can result in significant changes in innate immunity. In the natural environment, fish are exposed to multiple stressors simultaneously. Temperature change and/or chemical exposure as individual environmental stressors have been shown in various fish species to alter all aspects of the immune response. These same stressors have also been shown to alter plasma steroid levels in exposed fish. For this study, the effects of elevated temperature and nickel pollution on specific immune parameters of Japanese medaka (Oryzias latipes) were determined. Fish were exposed for 1, 7 or 14d to either: waterborne nickel (Ni) at the nominal concentration of 125ppb; a 5 degrees C (+/-0.5 degrees C) rapid increase in water temperature; or, both potential stressors in combination. Medaka maintained at room temperature (25 degrees C+/-1 degrees C) served as the controls. Altered function of the innate and adaptive arms of the immune response was evaluated by assessing kidney macrophage-mediated superoxide (O(2)(-)) production and splenic T-cell proliferation, respectively. Plasma cortisol levels were analysed in the same fish as a marker of the physiological stress response. While kidney cell number was unaffected by exposure of fish to either stressor alone or both factors in combination, spleen cellularity was decreased (compared to control fish) in medaka exposed for 1d to thermal stress in combination with Ni, and to a lesser extent to thermal stress alone. T-lymphocyte proliferation by medaka splenocytes was not affected by any exposure paradigm. Unstimulated intracellular O(2)(-) production by kidney phagocytes was significantly elevated (compared to control) in medaka exposed for 1d to either thermal stress alone or temperature change in combination with Ni; by 7d, only the stressor combination significantly increased baseline O(2)(-) production. Resting levels of extracellular O(2)(-) production was significantly reduced in fish maintained for 1d at the elevated temperature. Effects on phorbol 12-myristate 13 acetate (PMA)-stimulated intracellular and extracellular O(2)(-) production were less dramatic than those observed for resting phagocytes. Exposure of medaka to elevated temperature for 14d tended (p<0.06) to reduce PMA-stimulated intracellular O(2)(-) production (compared to the time-matched control). Although exposure of fish for 14d to elevated temperature only slightly reduced stimulated extracellular O(2)(-) production, exposure for the same duration to Ni alone significantly depressed oxyradical production by kidney phagocytes (compared to the time-matched controls). Decreased plasma cortisol levels were observed in fish exposed for 7d to either an elevated water temperature or Ni (compared to the time-matched control); by 14d of exposure, no significant treatment-induced effects on cortisol levels were observed. These findings add to the growing body of literature seeking to determine what effects, if any, exposure to multiple aquatic pollution-induced effects have upon fish health and the health of impacted ecosystems
— id: 66150, year: 2006, vol: 21, page: 325, stat: Journal Article,

The parity-related protection against breast cancer is compromised by cigarette smoke during rat pregnancy: observations on tumorigenesis and immunological defenses of the neonate
Steinetz, Bernard G; Gordon, Terry; Lasano, Salamia; Horton, Lori; Ng, Sheung Pui; Zelikoff, Judith T; Nadas, Arthur; Bosland, Maarten C
2006 Jun;27(6):1146-1152, Carcinogenesis
Early pregnancy is a powerful negative risk factor for breast cancer (BCa) in women. Pregnancy also protects rats against induction of BCa by carcinogens such as N-methyl-N-nitrosourea (MNU), making the parous rat a useful model for studying this phenomenon. Smoking during early pregnancy may lead to an increased risk of BCa in later life, possibly attributable to carcinogens in cigarette smoke (CS), or to reversal of the parity-related protection against BCa. To investigate these possibilities, 50-day-old timed first-pregnancy rats were exposed to standardized mainstream CS (particle concentration = 50 mg/m3) or to filtered air (FA) 4 h/day, Day 2-20 of gestation. Age-matched virgin rats were similarly exposed to CS or FA. At age 100 days, the CS or FA-exposed, parous and virgin rats were injected s.c. with MNU (50 mg/kg body wt), or with MNU vehicle. Mammary tumors (MTs) first appeared in virgin rats 9 weeks post-MNU injection. While no MTs were detected in FA-exposed parous rats until 18 weeks post-MNU, MTs appeared in the CS-exposed parous rats as early as 10 wks (P < 0.02). As no MTs developed in CS-exposed rats not injected with MNU, CS did not act as a direct mammary carcinogen. Serum prolactin concentration on Day 19 of pregnancy in CS-exposed dams was reduced by 50% compared with FA-exposed dams (P < 0.005). CS exposure during a pregnancy may thus 'deprotect' rats, enhancing their vulnerability to MNU-induced BCa. Prenatal CS exposure had no detectable effect on the immune responses of the pups examined at 3, 8 or 19 weeks of age. However, prolactin concentration in stomach contents (milk) of 3-day-old pups suckled by CS-exposed dams was decreased when compared with that of FA-exposed dams (P < 0.032). As milk-borne prolactin modulates development of the central nervous and immune systems of neonatal rats, CS exposure of the dams could adversely affect later maturation of these systems by reducing milk prolactin
— id: 66151, year: 2006, vol: 27, page: 1146, stat: Journal Article,

PCB-induced hepatic Cyp1A induction is associated with innate immune dysfunction in a feral teleost fish
Duffy, J E; Li, Y; Zelikoff, J T
2005 Jan;74(1):107-113, Bulletin of environmental contamination & toxicology
— id: 66152, year: 2005, vol: 74, page: 107, stat: Journal Article,

Benzo[a]pyrene-induced immunotoxicity in Japanese medaka (Oryzias latipes): relationship between lymphoid CYP1A activity and humoral immune suppression
Carlson, E A; Li, Y; Zelikoff, J T
2004 Nov 15;201(1):40-52, Toxicology & applied pharmacology
Exposure to the environmental contaminant benzo[a]pyrene (BaP) results in suppression of immune function in both mammalian and fish species. This laboratory has previously demonstrated that a single intraperitoneal (IP) injection of BaP reduced lymphocyte proliferation, phagocyte-mediated superoxide generation, and antibody-forming cell (AFC) numbers in Japanese medaka (Oryzias latipes). The objective of the current study was to determine the role of BaP metabolism in the observed immunosuppression. Results from rodent studies have suggested that BaP elicits its immunotoxic effects via upregulation of cytochrome P4501A1 (CYP1A1) and the subsequent production of immunosuppressive BaP metabolites. In this study, exposure of medaka to 200 microg BaP/g BW significantly induced CYP1A expression or activity within lymphoid tissue 48 h post-IP injection; induction was observed specifically within distinct subpopulations of kidney mononuclear cells. Concurrent injection of fish with BaP and the CYP1A1 inhibitors alpha-naphthoflavone (ANF) or dehydroepiandrosterone (DHEA) resulted in inhibition of renal EROD activity and amelioration of BaP-induced suppression of medaka AFC numbers. Results of this study suggest that (1) BaP-induced suppression of medaka humoral immunity relies upon the CYP1A-catalyzed production of immunotoxic BaP metabolites and (2) BaP metabolites may be created in situ, directly by specific cells within kidney lymphoid tissue. Thus, apparently, mechanisms involved in BaP-induced immunosuppression have been phylogenetically conserved from fish to mammals
— id: 47798, year: 2004, vol: 201, page: 40, stat: Journal Article,

Suppressive effects of benzo[a]pyrene upon fish immune function: evolutionarily conserved cellular mechanisms of immunotoxicity
Carlson, E A; Li, Y; Zelikoff, J T
2004 Aug-Dec;58(2-5):731-734, Marine environmental research
Knowledge gained through the use of alternative animal models has significantly enhanced our understanding of life at all levels of biological organization. The discipline of toxicology is under considerable pressure to develop such models due to increasing public concern regarding the experimental use of mammals. Studies in this laboratory have focused on the utility of a small laboratory fish model, the Japanese medaka (Oryzias latipes), to investigate immunotoxicological effects of benzo[a]pyrene (BaP). BaP is a ubiquitous environmental contaminant and known mammalian immunotoxicant. This laboratory has demonstrated that in vivo exposure of medaka to BaP (2-200 microg/g BW) significantly depresses both innate and humoral immunity. Further studies have indicated that BaP activates its own biotransformation pathway within medaka immune cells following both in vivo and in vitro exposure. In addition, reduction of BaP metabolism with alpha-naphthoflavone results in the reversal of BaP-induced suppression of antibody production in vitro. Inhibition of CYPlA-mediated metabolism within medaka immune cells also alleviates the immunotoxicity induced by benzo[a]pyrene-7,8-dihydrodiol, but not benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). This suggests that BPDE may be an ultimate immunotoxicant. Results from this study in medaka are in agreement with previously conducted rodent studies that indicated a role for immunotoxic BaP metabolites in BaP-induced suppression of humoral immunity
— id: 45976, year: 2004, vol: 58, page: 731, stat: Journal Article,

Application of multiple sublethal stress indicators to assess the health of fish in Pamlico Sound following extensive flooding
Adams, SM; Greeley, MS; Law, JM; Noga, EJ; Zelikoff, JT
2003 OCT ;26(5):1365-1382, Estuaries
Multiple indicators of sublethal stress (bioindicators) were used to assess the health and condition of two important estuarine fish species in the Pamlico Sound estuary following extensive flooding from three sequential hurricanes that occurred during early fall 1999. Bioindicators ranging from the biochemical to the reproductive and organism-level were used to assess the health of southern flounder and spot in Pamlico Sound compared to the health of these same species sampled from a relatively unaffected reference site in lower Core Sound. Many of the physiological, reproductive, immunological, histopathological, and general condition indices suggested that both species, and particularly spot, in Pamlico Sound were sublethally stressed and in poorer condition than fish sampled from Core Sound. The major environmental stressors causing these sublethal stress responses in Pamlico Sound fish appears to be those related to episodic hypoxic exposure or a combination of effects associated with hypoxic conditions such as alterations in preferred habitat and food availability. Although fish populations in Pamlico Sound do not appear to be severely damaged or impaired at this time, organisms that are sublethally stressed can incur increased vulnerability to additional or future stressors such as modified physicochemical regimes, changes in food and habitat availability, and increases in infectious pathogens. Because of the low flushing rate (similar to1 yr) of Pamlico Sound, recovery rate may be exceptionally slow, prolonging any adverse effects of altered nutrient regimes (such as hypoxia) on the health and fitness of resident fish populations. Flooding from the 1999 hurricanes may have contributed to the short-term health and condition of finfish species in Pamlico Sound and also influenced longer-term recovery and ecological status of this system. Longer-term manifestation of effects from flooding may be of particular concern as the frequency of hurricanes is expected to increase over the next few years and the accelerated uses of the coastal zone places further stress on estuarine resources
— id: 42546, year: 2003, vol: 26, page: 1365, stat: Journal Article,

Biochemical and toxicopathic biomarkers assessed in smallmouth bass recovered from a polychlorinated biphenyl-contaminated river
Anderson, M J; Cacela, D; Beltman, D; Teh, S J; Okihiro, M S; Hinton, D E; Denslow, N; Zelikoff, J T
2003 Sep-Oct;8(5):371-393, Biomarkers
Smallmouth bass (Micropterus dolomieu) were collected to quantify the nature and prevalence of biomarker responses, including biochemical indices, toxicopathic lesions and general health indices, among fish collected from polychlorinated biphenyl (PCB)-contaminated and nearby uncontaminated reaches of the Kalamazoo River, Michigan, USA. Blood and tissue samples (gill, liver, spleen, head kidney, trunk kidney, thyroid and gonads) were collected and preserved at necropsy for biochemical and histological analyses. The body condition factor and liver somatic index were significantly lower in fish collected from the downstream, contaminated site. Plasma vitellogenin was not detected in male fish collected from either site. Liver ethoxyresorufin-O-deethylase activity and liver and spleen superoxide dismutase activity were significantly depressed in fish collected from the downstream site. Significant toxicopathic lesions such as glycogen depletion, enhanced macrophage aggregates, hepatic foci of cellular alteration (i.e. preneoplastic lesions) and neoplasia were also detected in the liver of fish collected from the downstream site. This study indicates that many of the biochemical and histopathological biomarker responses were associated with liver and body tissue PCB concentrations. Taken together, the biomarkers of exposure and effect strongly suggest that fish within the downstream site are adversely affected by PCBs and other chemical stressors
— id: 66153, year: 2003, vol: 8, page: 371, stat: Journal Article,

The role of metabolism in benzo(a)pyrene-induced immunosuppression in a fish model
Carlson, E; Li, Y; Zelikoff, JT
2003 MAR ;72(1):174-174, Toxicological sciences
— id: 38495, year: 2003, vol: 72, page: 174, stat: Journal Article,

The U.S. Environmental Protection Agency Particulate Matter Health Effects Research Centers Program: a midcourse report of status, progress, and plans
Lippmann, Morton; Frampton, Mark; Schwartz, Joel; Dockery, Douglas; Schlesinger, Richard; Koutrakis, Petros; Froines, John; Nel, Andre; Finkelstein, Jack; Godleski, John; Kaufman, Joel; Koenig, Jane; Larson, Tim; Luchtel, Dan; Liu, L-J Sally; Oberdorster, Gunter; Peters, Annette; Sarnat, Jeremy; Sioutas, Constantinos; Suh, Helen; Sullivan, Jeff; Utell, Mark; Wichmann, Erich; Zelikoff, Judith
2003 Jun;111(8):1074-1092, Environmental health perspectives
In 1998 Congress mandated expanded U.S. Environmental Protection Agency (U.S. EPA) health effects research on ambient air particulate matter (PM) and a National Research Council (NRC) committee to provide research oversight. The U.S. EPA currently supports intramural and extramural PM research, including five academically based PM centers. The PM centers in their first 2.5 years have initiated research directed at critical issues identified by the NRC committee, including collaborative activities, and sponsored scientific workshops in key research areas. Through these activities, there is a better understanding of PM health effects and scientific uncertainties. Future PM centers research will focus on long-term effects associated with chronic PM exposures. This report provides a synopsis of accomplishments to date, short-term goals (during the next 2.5 years) and longer-term goals. It consists of six sections: biological mechanisms, acute effects, chronic effects, dosimetry, exposure assessment, and the specific attributes of a coordinated PM centers program
— id: 39177, year: 2003, vol: 111, page: 1074, stat: Journal Article,

Inhalation of cadmium at a concentration associated with sidestream cigarette smoke alters antimicrobial host defense
Zelikoff, JT; Chee, G; Schermerhorn, K; Prophete, C; Cohen, MD
2003 MAR ;72(1):293-293, Toxicological sciences
— id: 38506, year: 2003, vol: 72, page: 293, stat: Journal Article,

Effects of inhaled ambient particulate matter on pulmonary antimicrobial immune defense
Zelikoff, Judith T; Chen, Lung Chi; Cohen, Mitchell D; Fang, Kaijie; Gordon, Terry; Li, Yun; Nadziejko, Christine; Schlesinger, Richard B
2003 Feb;15(2):131-150, Inhalation toxicology
Respiratory-tract infection, specifically pneumonia, contributes substantially to the increased morbidity and mortality among elderly individuals exposed to airborne particulate matter of <10 micro m diameter (PM(10)). These epidemiological findings suggest that PM(10) may act as an immunosuppressive factor that can undermine normal pulmonary antimicrobial defense mechanisms. To investigate whether, and how, compromised pulmonary immunocompetence might contribute to increased mortality, two sets of laboratory studies were performed. The first examined the effects of a single inhalation exposure to concentrated ambient PM(2.5) (CAPS) from New York City air on pulmonary/systemic immunity and on the susceptibility of exposed aged rats to subsequent infection with Streptococcus pneumoniae. The second set of studies determined whether CAPS exposure, at a concentration approximating or somewhat greater than the promulgated 24-h NAAQS of 65 micro g/m(3), could exacerbate an ongoing infection. Taken together, results demonstrated that a single exposure of healthy animals to CAPS had little effect on pulmonary immune function or bacterial clearance during subsequent challenge with S. pneumoniae. Alterna-tively, CAPS exposure of previously infected rats significantly increased bacterial burdens and decreased percentages of lavageable neutrophils and proinflammatory cytokine levels compared to those in infected filtered-air-exposed controls. These studies demonstrate that a single exposure to ambient PM(2.5) compromises a host's ability to handle ongoing pneumococcal infections and support the epidemiological findings of increased pneumonia-related deaths in ambient PM-exposed elderly individuals
— id: 34379, year: 2003, vol: 15, page: 131, stat: Journal Article,

Exposure of Japanese medaka (Oryzias latipes) to benzo[a]pyrene suppresses immune function and host resistance against bacterial challenge
Carlson, E A; Li, Y; Zelikoff, J T
2002 Mar;56(4):289-301, Aquatic toxicology
Besides being a potent chemical carcinogen, benzo[a]pyrene (BaP) has also been shown to suppress the immune response of mammals. However, even though BaP is a ubiquitous environmental contaminant to which aquatic species may be directly exposed, information regarding the effects of BaP on the immune system of fish is still lacking. Therefore, laboratory studies were conducted using Japanese medaka (Oryzias latipes) to examine the effects of BaP on host immune status. A single IP injection of BaP at 2, 20 or 200 microg/g BW had no effect upon medaka survival or condition factors for up to 7 days post-injection. Forty-eight hours after injection of either BaP or the vehicle control, fish were sacrificed and the appropriate organs/cells used to assess effects upon: splenic lymphocyte proliferation; kidney phagocyte intracellular superoxide (*O(2)(-)) production; and, CYP1A protein level/activity. In separate experiments, fish were injected with either sheep red blood cells or the bacterial pathogen Yersinia ruckeri at 48 h post-BaP exposure for later determination of antibody-forming cell (AFC) numbers and bacterial host resistance, respectively. Results demonstrated that in the absence of effects upon host survival or condition factors, a single exposure to a relatively low dose of BaP (2 microg/g BW) significantly suppressed mitogen-stimulated T- and B-lymphocyte proliferation (in the absence of elevated hepatic CYP1A expression/activity). At higher concentrations, BaP also reduced AFC numbers, phagocyte-mediated *O(2)(-) production, and host resistance against bacterial infection. These results clearly demonstrate the ability of BaP to compromise the immune response of fish and indicate the utility of the fish immune response to serve as an early indicator of BaP exposure/effects in exposed feral populations
— id: 39701, year: 2002, vol: 56, page: 289, stat: Journal Article,

The Japanese medaka (Oryzias latipes) model: applicability for investigating the immunosuppressive effects of the aquatic pollutant benzo[a]pyrene (BaP)
Carlson, E A; Li, Y; Zelikoff, J T
2002 Sep-Dec;54(3-5):565-568, Marine environmental research
Despite the fact that BaP is a carcinogen, mammalian immunosuppressant, and ubiquitous aquatic pollutant, knowledge regarding the effects of BaP on the immune system of fish is still lacking. To begin to fill this gap, studies were conducted in medaka to examine the effects and mechanisms by which BaP exposure might alter host immunocompetence. Fish, exposed by IP injection of BaP (2-600 microg/g BW), were examined after 48 h for effects upon immune function and CYP1A expression/activity. Benzo[a]pyrene, at a concentration below that which increased levels of CYPIA expression/activity (2 microg BaP/g BW) suppressed lymphocyte proliferation. Concentrations of BaP at 20 and 200 microg/g BW. suppressed antibody-forming cell (AFC) numbers, superoxide production, and host resistance against bacteria. In contrast, exposure to the low affinity aryl hydrocarbon receptor (AhR) agonist, benzo[e]pyrene (BeP), neither induced CYP1A expression nor altered immune function. Given the lack of immunosuppressive effects produced by BeP, and the fact that exposure to the AhR antagonist (and CYP1A inhibitor) alpha-naphthoflavone (ANF) ameliorated the suppressive effects of BaP upon AFC numbers, the AhR pathway (including CYP1A-mediated production of reactive BaP metabolites) appears important in mediating BaP-induced immunotoxicity in fish, as in mammals. In the past, the medaka has proven a successful model for assessing carcinogenic agents. These studies have demonstrated its utility for also determining the immunosuppressive effects of an important aquatic contaminant
— id: 39571, year: 2002, vol: 54, page: 565, stat: Journal Article,

Effects of inhaled ozone on pulmonary immune cells critical to antibacterial responses in situ
Cohen, Mitchell D; Sisco, Maureen; Baker, Kathy; Li, Yun; Lawrence, David; van Loveren, Henk; Zelikoff, Judith T; Schlesinger, Richard B
2002 Jun;14(6):599-619, Inhalation toxicology
The goal of this study was to examine effects from repeated exposure to ozone (O3) on immune cells involved in cell-mediated antibacterial responses in the lungs. Rats exposed to 0.1 or 0.3 ppm O3 for 4 h/day, 5 days/wk, for 1 or 3 wk were analyzed for the ability to clear an intrapulmonary challenge with Listeria monocytogenes or had their lungs processed to obtain pulmonary alveolar macrophages (PAM) and lung-associated lymphocytes for analyses of select cell functions and surface marker expression. The results indicate that repeated inhalation exposure to O3 affected local cell-mediated immunity (CMI) responses as evidenced by effects on clearance of Listeria. However, this modulation was not consistently dependent on exposure concentration or duration. Short-term repeat exposures had more effect on host resistance than did the more prolonged regimen, with rats exposed to 0.1 ppm O3 most adversely impacted. Clearance patterns suggest modifications in innate resistance following 1 wk of exposure to 0.1 ppm O3, but no similar effect following a 3-wk regimen. Exposure to 0.3 ppm O3 appeared to affect both innate and acquired resistance after a 1-wk regimen, but mainly the former after an additional 2 wk of exposure. We conclude that these two mechanisms of resistance are differentially affected by O3 and that distinct time- and O3 concentration-dependent adaptation phenomena evolve for each; that is, in situ adaptation to higher levels of O3 may occur more readily with acquired than with innate/PAM-dependent resistance. A similar pattern of inconsistent effect on PAM and lung-associated lymphocytes was also evident. For example, while 3-wk exposures had a greater effect on PAM reactive oxygen intermediate ROI production, evidence for a significant effect on antibacterial activity was only notable among PAM from rats exposed for 1 wk. Among lung lymphocytes, while 3-wk exposure to 0.1 ppm O3 led to a significant increase in CD25 expression, there was no corresponding increase in responsivity to concanavalin A (ConA); only among cells from 1-wk-exposed rats did lymphoproliferative responses increase. Though investigations of altered immune cell cytokine receptor expression/binding activity are ongoing, results herein provide further evidence to support our longstanding hypothesis that some well-documented effects of O3 exposure on human health are quite likely linked to changes in local immune cell (i.e., PAM and lung-associated lymphocytes) functions, with the latter being related to changes in the capacities of these cells to interact with immunoregulatory cytokines
— id: 32458, year: 2002, vol: 14, page: 599, stat: Journal Article,

Impact of polychlorinated biphenyls (PCBs) on the immune function of fish: age as a variable in determining adverse outcome
Duffy, J E; Carlson, E; Li, Y; Prophete, C; Zelikoff, J T
2002 Sep-Dec;54(3-5):559-563, Marine environmental research
Polychlorinated biphenyls (PCBs) are a major contaminant of global extent in water resources and aquatic biota. Due to its high lipid solubility, PCBs fail to be degraded and, therefore, continue to bioaccumulate throughout the environment and food chain. To determine the impact of PCBs on the immune system of aged and juvenile Japanese medaka (Oryzias latipes), fish were injected with the coplanar PCB congener 126 and examined after 3 and 14 days. PCB 126 produced oxidative stress in both age groups of fish 14 days post-injection; however, juvenile medaka appeared more susceptible than aged fish. Humoral immunity, as determined by antibody forming cell (AFC) numbers, was significantly depressed for up to 14 days post-injection in both age groups. These results demonstrate the sensitivity of the fish immune response for predicting PCB-induced immunotoxicity and identify age as a variable in determining adverse outcome
— id: 39572, year: 2002, vol: 54, page: 559, stat: Journal Article,

Ozone differentially modulates airway responsiveness in atopic versus nonatopic guinea pigs
Schlesinger, Richard B; Cohen, Mitchell D; Gordon, Terry; Nadziejko, Christine; Zelikoff, Judith T; Sisco, Maureen; Regal, Jean F; Menache, Margaret G
2002 May;14(5):431-457, Inhalation toxicology
While acute exposures to ozone (O(3)) can alter airway responsiveness, effects from long-term exposures at low concentrations are less clear. This study assessed whether such exposures could induce nonspecific hyperresponsiveness in nonatopic (nonsensitized) guinea pigs and/or could exacerbate the pre-existing hyperresponsive state in atopic (sensitized) animals, and whether gender was a factor modulating any effect of O(3). Responsiveness was measured during and following exposures to 0.1 and 0.3 ppm O(3) for 4 h/day, 4 days/wk for 24 wk in male and female nonsensitized animals, those sensitized to allergen (ovalbumin) prior to initiation of O(3) exposures, and those sensitized concurrently with exposures. Ozone did not produce hyperresponsiveness in nonsensitized animals, but did exacerbate hyperresponsiveness to both specific and nonspecific bronchoprovocation challenges in sensitized animals, an effect that persisted through at least 4 wk after exposures ended. Gender was not a factor modulating response to O(3). Induced effects on responsiveness were not associated with numbers of eosinophils in the lungs nor with any chronic pulmonary inflammatory response, but were correlated with antigen-specific antibodies in blood. This study supports a role for chronic O(3) exposure in the exacerbation of airways dysfunction in a certain segment of the general population, namely, those demonstrating atopy
— id: 34505, year: 2002, vol: 14, page: 431, stat: Journal Article,

Ozone-induced modulation of airway hyperresponsiveness in guinea pigs
Schlesinger, Richard B; Cohen, Mitchell; Gordon, Terry; Nadziejko, Christine; Zelikoff, Judith T; Sisco, Maureen; Regal, Jean F; Menache, Margaret G
2002 Jun;49(109):1-40, Research report (Health Effects Institute)
Although acute exposure to ozone (03*) has been shown to influence the severity and prevalence of airway hyperresponsiveness, information has been lacking on effects due to long-term exposure at relatively low exposure concentrations. The goals of this study were to determine whether long-term repeated ozone exposures could induce nonspecific hyperresponsiveness in normal, nonatopic (nonsensitized) animals, whether such exposure could exacerbate the preexisting hyperresponsive state in atopic (sensitized) animals, or both. The study was also designed to determine whether gender modulated airway responsiveness related to ozone exposure. Airway responsiveness was measured during and after exposure to 0.1 and 0.3 ppm ozone for 4 hours/day, 4 days/week for 24 weeks in normal, nonsensitized guinea pigs, in guinea pigs sensitized to an allergen (ovalbumin) prior to initiation of ozone exposures, and in animals sensitized concurrently with ozone exposures. Both male and female animals were studied. Ozone exposure did not produce airway hyperresponsiveness in nonsensitized animals. Ozone exposure did exacerbate airway hyperresponsiveness to specific and nonspecific bronchoprovocation in both groups of sensitized animals, and this effect persisted at least 4 weeks after the end of the exposures. Although the overall degree of airway responsiveness did differ between genders (males had more responsive airways than did females), the airway response to ozone exposure did not differ between the two groups. Ozone-induced effects upon airway responsiveness were not associated with the number of pulmonary eosinophils or with any chronic pulmonary inflammatory response. Levels of antigen-specific antibodies increased in sensitized animals, and a significant correlation was observed between airway responsiveness and antibody levels. The results of this study provide support for a role of ambient ozone exposure in exacerbation of airway dysfunction in persons with atopy
— id: 34490, year: 2002, vol: 49, page: 1, stat: Journal Article,

Immunotoxicity biomarkers in fish: Development, validation and application for field studies and risk assessment
Zelikoff, JT; Carlson, E; Li, Y; Raymond, A; Duffy, J; Beaman, JR; Anderson, M
2002 Feb;8(2):253-263, Human & ecological risk assessment
Imunocompetence is usually monitored using a tiered approach that is based upon several parameters including immunopathology, immune function, and host resistance. Through the efforts of numerous investigations, well-characterized immune assays validated in rodents for their sensitivity and reproducibility in assessing xenobiotic-induced immunotoxicity are currently available. Recently, many of these same endpoints have been utilized in non-mammalian species as indicators to predict chemical-induced immunotoxicity. In this laboratory, immune assays that measure immunopathology, antibody-forming cell response to T-dependent antigens, lymphocyte proliferation, macrophage function, antioxidant activity, and host resistance against infectious bacteria have been employed successfully to assess metal-, pesticide-, aromatic hydrocarbon-, and mixture-induced immunotoxicity in laboratory- reared Japanese medaka (Oryzias latipes). These same assays have also proven successful in feral fish populations for predicting risk(s) associated with habitation in contaminated aquatic environments. For example, smallmouth bass (Micropterus dolomieu) collected from a polychlorinated biphenyl- contaminated site had reduced phagocyte function, oxyradical production, and antioxidant levels (compared to reference fish), while circulating leukocyte profiles and lymphocyte proliferation by splenic T-cells were altered in organochlorine-exposed walleye (Stizostedium vitreum vitreum). Results of the aforementioned studies demonstrate that immune assays developed and validated in a laboratory fish model can be successfully applied to feral fish populations to predict the toxicological hazards associated with exposure to immunomodulating aquatic pollutants
— id: 27522, year: 2002, vol: 8, page: 253, stat: Journal Article,

The toxicology of inhaled woodsmoke
Zelikoff, Judith T; Chen, Lung Chi; Cohen, Mitchell D; Schlesinger, Richard B
2002 Jul-Sep;5(3):269-282, Journal of toxicology & environmental health. Pt. B. Critical reviews
In addition to developing nations relying almost exclusively upon biomass fuels, such as wood for cooking and home heating, North Americans, particularly in Canada and the northwestern and northeastern sections of the United States, have increasingly turned to woodburning as an alternate method for domestic heating because of increasing energy costs. As a result, the number of households using woodburning devices has increased dramatically. This has resulted in an increase in public exposure to indoor and outdoor woodsmoke-associated pollutants, which has prompted widespread concern about the adverse human health consequences that may be associated with prolonged woodsmoke exposure. This mini-review article brings together many of the human and animal studies performed over the last three decades in an attempt to better define the toxicological impact of inhaled woodsmoke on exposed children and adults; particular attention is given to effects upon the immune system. General information regarding occurrence and woodsmoke chemistry is provided so as to set the stage for a better understanding of the toxicological impact. It can be concluded from this review that exposure to woodsmoke, particularly for children, represents a potential health hazard. However, despite its widespread occurrence and apparent human health risks, relatively few studies have focused upon this particular area of research. More laboratory studies aimed at understanding the effects and underlying mechanisms of woodsmoke exposure, particularly on those individuals deemed to be at greatest risk, are badly needed, so that precise human health risks can be defined, appropriate regulatory standards can be set, and accurate decisions can be made concerning the use of current and new woodburning devices
— id: 34503, year: 2002, vol: 5, page: 269, stat: Journal Article,

A role for associated transition metals in the immunotoxicity of inhaled ambient particulate matter
Zelikoff, Judith T; Schermerhorn, Kimberly R; Fang, Kaijie; Cohen, Mitchell D; Schlesinger, Richard B
2002 Oct;110 Suppl 5(2):871-875, Environmental health perspectives
Epidemiologic studies demonstrate that infection, specifically pneumonia, contributes substantially to the increased morbidity and mortality among elderly individuals following exposure to ambient particulate matter (PM). This laboratory has previously demonstrated that a single inhalation exposure of Streptococcus pneumoniae-infected rats to concentrated ambient PM(2.5) (particulate matter with aerodynamic diameter < or =2.5 microm) from New York City (NYC) air exacerbates the infection process and alters pulmonary and systemic immunity. Although these results provide some basis for explaining the epidemiologic findings, the identity of specific PM constituents that might have been responsible for the worsening pneumonia in exposed hosts remains unclear. Thus, studies were performed to correlate the physicochemical attributes of ambient PM(2.5) with its in vivo immunotoxicity to identify and characterize the role of constitutive transition metals in exacerbating an ongoing streptococcal infection. Uninfected or previously infected rats were exposed in the laboratory to soluble divalent Fe, Mn, or Ni chloride salts. After exposure, uninfected rats were sacrificed and their lungs were lavaged. Lungs from infected hosts were used to evaluate changes in bacterial clearance and effects of exposure on the extent/severity of infection. Results demonstrated that inhalation of Fe altered innate and adaptive immunity in uninfected hosts, and both Fe and Ni reduced pulmonary bacterial clearance in previously infected rats. The effects on clearance produced in infected Fe-exposed rats were similar to those seen in infected rats exposed to ambient NYC PM. Taken together, these studies demonstrate that inhaled ambient PM can worsen the outcome of an ongoing pulmonary infection and that associated Fe may play some role in the immunotoxicity
— id: 34502, year: 2002, vol: 110 Suppl 5, page: 871, stat: Journal Article,

Ozone-induced modulation of cell-mediated immune responses in the lungs
Cohen MD; Sisco M; Li Y; Zelikoff JT; Schlesinger RB
2001 Mar 1;171(2):71-84, Toxicology & applied pharmacology
Most pulmonary immunotoxicology studies of ambient pollutants have been broadly designed to discern if overall humoral or cell-mediated immunity (CMI) was altered; few have assessed effects on particular aspects of immune function. We hypothesized that effects from ozone (O3) exposure on pulmonary CMI are linked in part to changes in local immune cell capacities to form and/or to interact with immunoregulatory cytokines. Rats exposed to 0.1 or 0.3 ppm O3 4 h/day 5 days/week, for 1 or 3 weeks were assessed for resistance to, and pulmonary clearance of, a subsequent Listeria monocytogenes challenge. In situ cytokine release and immune cell profiles were also analyzed at different stages of the antilisterial response. Although O3 exposure modulated CMI, effects were not consistently concentration- or duration-dependent. Exposure did not effect cumulative mortality from infection, but induced concentration-related effects upon morbidity onset and persistence. All 1-week exposed rats had listeric burdens trending higher than controls; 0.3 ppm rats displayed continual burden increases rather than any onset of resolution. Rats exposed for 3 weeks had no O3-related changes in clearance. No exposure-related effect on neutrophil or pulmonary macrophage (PAM) numbers or percentages was noted. Bacterial burden analyses with respect to cell type showed that Listeria:PAM ratios in 0.3 ppm rats ultimately became greatest compared to all other rats. In situ IL-1alpha and TNFalpha levels were consistently higher in O3-exposed rats. All rats displayed increasing in situ IFNgamma levels as infection progressed, but no constant relationship was evident between IFNgamma and initial IL-1alpha/TNFalpha levels in O3-exposed hosts. It seems that short-term (i.e., 1 week) repeated O3 exposures imparted more effects upon CMI than a more prolonged (i.e., 3 week) regimen, with effects manifesting at the level of the PAM and in the cytokine network responsible for immunoactivation
— id: 26782, year: 2001, vol: 171, page: 71, stat: Journal Article,

Cytotoxic and cytoprotective effects of selenium on bluegill sunfish (Lepomis macrochirus) phagocytic cells in vitro
Palchaudhuri S; Raymond A; Carlson EA; Li Y; Zelikoff JT
2001 Nov;67(5):672-679, Bulletin of environmental contamination & toxicology
— id: 66154, year: 2001, vol: 67, page: 672, stat: Journal Article,

Toxicology and immunotoxicology of mercury: a comparative review in fish and humans
Sweet LI; Zelikoff JT
2001 Apr-Jun;4(2):161-205, Journal of toxicology & environmental health. Pt. B. Critical reviews
This review addresses an important area of environmental and mammalian toxicology by evaluating and comparing mercury-induced effects upon the immune responses of two evolutionarily divergent yet immunologically-related species. The mechanisms of mercury toxicology and immunotoxicology are described herein, including supporting data from the following: sources of exposure; bioavailability and biodistribution; metabolism; and laboratory and field investigations. Based upon the studies presented, the relative sensitivities of fish and human immune cells to mercury exposure are compared and contrasted with regard to mercury's ability to stimulate and/or suppress host immunocompetence. In addition, results from immune assays are compared to mercury tissue burdens, as well as to toxicological threshold level estimates. Such comparisons may help to resolve gaps in our knowledge regarding sensitivity of immunological assays, standardization of immunotoxicological techniques between species, and the extent to which the vertebrate immune system possesses functional reserve and redundancy in response to xenobiotics. A review of this type begins to provide support for the potential usefulness of fish immune cells to serve as indicators for human immunotoxicology risk assessment. Analysis of the reviewed studies supports the following conclusions in both lower and higher vertebrates: a threshold for mercury-induced immunotoxicological effects is likely; multiple exposure scenarios involving high and/or chronic exposures leading to increased body burdens are linked to increased risk of immunomodulation; and highly exposed and/or susceptible subpopulations are at greater risk of toxicological impact
— id: 66155, year: 2001, vol: 4, page: 161, stat: Journal Article,

PCBs, liver lesions, and biomarker responses in adult walleye (Stizostedium vitreum vitreum) collected from Green Bay, Wisconsin
Barron, MG; Anderson, MJ; Cacela, D; Lipton, J; Teh, SJ; Hinton, DE; Zelikoff, JT; Dikkeboom, AL; Tillitt, DE; Holey, M; Denslow, N
2000 OCT 1 ;26(3):250-271, Journal of Great Lakes research
Adult walleye were collected from several locations in the Lower Fox River and Green Bay, Wisconsin (the assessment area) and two relatively uncontaminated reference locations (Lake Winnebago and Fatten Lake, Wisconsin) between July and October in 1996 and 1997 Whole body and liver samples collected in 1996 were analyzed for total PCBs, PCB congeners, and liver histological lesions. Follow-up sampling in 1997 included examination of liver histopathology, PCBs in liver samples, measurement of ethoxyresorufin-O-deethylase (EROD) activity, immunological evaluation of kidney and blood samples, measurement of plasma vitellogenin, and examination of tissues for parasites as well as bacterial and viral infections. Mean PCB concentrations in whole body and liver samples were elevated in assessment area walleye (4.6 to 8.6 and 3.6 to 6.4 mg/kg wet weight, respectively) compared to PCB concentrations in reference areas (0.04 mg/kg in walleye fillets from Lake Winnebago). A significant (p < 0.01) elevation was observed in the prevalence (26%) of hepatic preneoplastic foci of cellular alteration (FCA) and neoplasms in 5 to 8 year old walleye collected from the assessment area, compared to reference area fish (6% prevalence). Walleye from the assessment area also contained multiple FCA and hepatic tumors per liver sample, whereas no tumors and a reduced prevalence of FCA were observed in reference area walleye. Both tumors and FCA were more prevalent in female fish than in male fish within the 5 to 8 year age classes. There were no remarkable effects on immunological parameters in assessment area walleye, although hematocrit was elevated and blood monocyte counts were 40% lower than those of reference area fish. The data did not show any clear distinctions in the prevalence of disease between reference and assessment area walleye. EROD activity was similar in assessment area and reference area walleye. Plasma vitellogenin was elevated in female walleye from eastern. Green Bay, but was not detected in male fish from this location. The results of this investigation demonstrate significant elevation in hepatic preneoplastic lesions and hepatocellular adenomas and carcinomas in assessment area walleye exposed to elevated concentrations of PCBs. These histopathological lesions are consistent with long-term exposure to tumor promoters such as PCBs, although quantitative association between tumors and PCBs was not observed at the level of the individual fish. Additional research would be needed to elucidate the causal mechanisms underlying tumorigenesis
— id: 54515, year: 2000, vol: 26, page: 250, stat: Journal Article,

Pulmonary immunotoxicology
Cohen, Mitchell D.; Schlesinger, Richard B.; Zelikoff, Judith T.
Boston, Mass. ; London : Kluwer, c2000,
— id: 710, year: 2000, vol: , page: , stat: ,

Biomarkers of immunotoxicity in fish: from the lab to the ocean
Zelikoff JT; Raymond A; Carlson E; Li Y; Beaman JR; Anderson M
2000 Mar 15;112-113:325-331, Toxicology letters
Historically, host immunocompetence has been monitored using a battery of immune parameters. Recently, many of these same assays have been employed as biomarkers for predicting chemical-induced immunotoxicity in wildlife species. In this laboratory, assays measuring immunopathology, immune cell function, and host resistance against bacteria have been used successfully to assess immunotoxicity in laboratory-reared Japanese medaka (Oryzias latipes) and in feral fish populations. As an example of the latter, smallmouth bass collected from a PCB-contaminated site demonstrated significantly reduced phagocyte function and antioxidant activity compared to reference site fish. Taken together, these studies along with those from other investigators demonstrate the usefulness of immune assays as indicators to predict the toxicological risk associated with 'real-world' polluted aquatic environments
— id: 10350, year: 2000, vol: 112-113, page: 325, stat: Journal Article,

Mammalian immunoassays for predicting the toxicity of malathion in a laboratory fish model
Beaman JR; Finch R; Gardner H; Hoffmann F; Rosencrance A; Zelikoff JT
1999 Apr 23;56(8):523-542, Journal of toxicology & environmental health. Pt. A
This study describes the use of a panel of immune assays, originally developed by the National Toxicology Program for assessing xenobiotic-induced immunotoxicity in mice, to quantify the effects of sublethal malathion exposure on the immune responses of fish. For this study, Japanese medaka (Oryzias latipes) were exposed subchronically to the organophosphate pesticide malathion in a series of two experiments. In the first set of studies, fish were exposed for 7 or 14 d to untreated well water (i.e., controls) or to waterborne malathion at 0.2 or 0.8 mg/L. Following exposure, fish from each group were sacrificed and their kidneys (primary organ of leukopoiesis in fish and equivalent to mammalian bone marrow) were used to provide cells for assessing any malathion-induced effects upon nonspecific and acquired immune defense mechanisms. Effects upon humoral-mediated immunity were determined by enumerating antibody plaque-forming cell (PFC) numbers from a subset of fish exposed to malathion for 14 d and then injected intraperitoneally (ip) with sheep erythrocytes (sRBC). Results of these studies demonstrated that while malathion exposure had no significant effect upon hematocrit/leukocrit values or upon mitogen-stimulated T-cell lymphoproliferation, PFC numbers in the kidney of exposed fish were significantly reduced (compared to control fish) in a dose-dependent manner. In addition, total recoverable kidney cell numbers and viability, as well as superoxide anion production by kidney phagocytes, were reduced slightly (compared to control values) in fish exposed for 14 d to the highest malathion concentration tested. In the second set of experiments, medaka exposed for up to 21 d to either 0.1 or 0.3 mg malathion/L were challenged ip with an LD50 dose of the bacterial fish pathogen Yersinia ruckeri. Results from these infectivity studies demonstrated that exposure to either malathion concentration, for 14 or 21 d reduced host resistance against Yersinia infection. Taken together, these findings demonstrate the applicability of mammalian immune assays for predicting malathion-induced immunosuppression in a teleost fish, as well as the potential utility of a small laboratory fish to serve as an alternate model for mammals in immunotoxicological studies
— id: 57544, year: 1999, vol: 56, page: 523, stat: Journal Article,

Immunotoxicity biomarkers in fish: Development, validation, and application to field settings
Zelikoff, J T; Carlson, E; Li, Y; Raymond, A; Beaman, J R; Anderson, M
1999 Oct 04-06;(2293):23-23, Canadian technical report of fisheries & aquatic sciences
— id: 15826, year: 1999, vol: , page: 23, stat: Journal Article,

Profiling immunotoxicology: Chairpersons summary
Zelikoff, J T; Thomas, P T
1999 Oct 04-06;(2293):20-21, Canadian technical report of fisheries & aquatic sciences
— id: 15827, year: 1999, vol: , page: 20, stat: Journal Article,

Immunotoxicologic effects of inhaled chromium: role of particle solubility and co-exposure to ozone
Cohen MD; Zelikoff JT; Chen LC; Schlesinger RB
1998 Sep;152(1):30-40, Toxicology & applied pharmacology
Soluble and insoluble hexavalent chromium (Cr6+) agents are concomitantly released with ozone (O3) during welding. Although pulmonary/immunologic implications from exposure to each agent individually have been investigated, the effects from simultaneous exposure, as occurs under actual working conditions, are unclear. To investigate immunomodulatory effects of inhaled Cr6+, F-344 rats were exposed for 5 h/day, 5 days/week for 2 or 4 weeks to atmospheres containing soluble potassium chromate (K2CrO4) or insoluble barium chromate (BaCrO4), each alone at 360 micrograms Cr/m3 or in combination with 0.3 ppm O3. One day after the final exposure, rats were euthanized, their lungs were lavaged, and pulmonary macrophages (PAM) were recovered for assessment of basal and inducible functions. Rats inhaling K2CrO4-containing atmospheres had greater levels of total recoverable cells, neutrophils, and monocytes in bronchopulmonary lavage compared to rats exposed to insoluble Cr6+ atmospheres, O3 alone, or air; these rats also had a reduced percentage of PAM, although total PAM levels remained unaffected. Although Cr exposure-related changes in PAM functionality were evident, any dependence upon Cr solubility was variable. K2CrO4-containing atmospheres modulated PAM-inducible interleukins-1 and -6, and tumor necrosis factor-alpha production to a greater degree than those containing BaCrO4. Conversely, BaCrO4-containing atmospheres affected PAM basal nitric oxide production and interferon-gamma-primed/zymosan-stimulated reactive oxygen intermediate production to a greater extent than did those containing K2CrO4. In none of the PAM assays did co-inhalation of O3 result in a modulation of the effects obtained with either Cr6+ compound itself. The results indicate that, while immunomodulatory effects of inhaled Cr6+ upon PAM are related to particle solubility, the co-inhalation of O3 apparently does not cause further modifications of the metal-induced effects.
— id: 7314, year: 1998, vol: 152, page: 30, stat: Journal Article,

Biomarkers of immunotoxicity in fish and other non-mammalian sentinel species: predictive value for mammals?
Zelikoff JT
1998 Aug 7;129(1):63-71, Toxicology
Through the efforts of different laboratories, a battery of immunological assays is available to predict the immunotoxicity of xenobiotics. These assays, originally developed in rodents, have been adapted for use in a variety of animal species and are now used routinely in these models to assess the immunotoxicity of different chemical classes. For example, our laboratory has employed assays that measure antibody-forming cell response to T-dependent antigens, T- and B-cell lymphoproliferation, macrophage function, and host resistance against infectious bacteria to assess metal-induced immunotoxicity in laboratory-reared Japanese medaka (Oryzias latipes); immunologically-related assays measuring antioxidant activity have also been used in this capacity. Results of the aforementioned investigations have shown the usefulness of these endpoints to reliably demonstrate chemical-mediated immunotoxicity in teleost systems. Many of these same endpoints have also proved successful for predicting the immunotoxic effects of contaminated aquatic environments in feral fish populations. For example, smallmouth bass collected from a chlorinated hydrocarbon-contaminated site demonstrated significant changes in blood cell profiles and kidney phagocyte function compared to fish collected from a 'clean water' reference site. Some of these same immune parameters have also been used successfully to predict the immunotoxicity of polluted aquatic environments in feral populations of fish-eating birds and harbor seals. While interspecies extrapolation is difficult and should be approached with caution due to variables such as metabolism and pharmacokinetics, results from these studies demonstrate the usefulness of these immune assays to predict the immunomodulating effects of xenobiotics in fish and other wildlife species, as well as the applicability of fish to serve as additional/alternate animal models for mammalian species in immunotoxicological studies
— id: 12065, year: 1998, vol: 129, page: 63, stat: Journal Article,

Immunotoxicology of environmental and occupational metals
Zelikoff, Judith T; Thomas, Peter T
London : Taylor & Francis, 1998,
— id: 1223, year: 1998, vol: , page: , stat: ,

Effects of vanadium upon polyl:C-induced responses in rat lung and alveolar macrophages
Cohen MD; Becker S; Devlin R; Schlesinger RB; Zelikoff JT
1997 Aug 29;51(6):591-608, Journal of toxicology & environmental health
Hosts exposed to vanadium (V) display a subsequent decrease in their resistance to infectious microorganisms. Our earlier studies with rats inhaling occupationally relevant levels of V (as, ammonium metavanadate, NH4VO3) indicated that several nascent/inducible functions of pulmonary macrophages (PAM) were reduced. In the present study, V-exposed rats were examined to determine whether some of the same effects might also occur in situ. Rats were exposed nose-only to air or 2 mg V/m3 (as NH4VO3) for 8 h/d for 4 d, followed, 24 h later, by intratracheal (it) instillation of polyinosinic:polycytidilic acid (polyl:C) or saline. Analysis of lavaged lung cells/fluids after polyl:C instillation indicated that total lavageable cell/neutrophil numbers and protein levels, while significantly elevated in both exposure groups (as well as in saline-treated V-exposed rats), were always greater in V-exposed hosts. Exposure to V also affected the inducible production of interleukin 6 (IL-6) and interferon gamma (IFN gamma), but apparently not that of tumor necrosis factor-alpha (TNF alpha) or IL-1. Although polyl:C induced significant increases in lavage fluid IL-6 and IFN gamma levels in both exposure groups, levels were greater in V-exposed rats. If calculated with respect to total lavaged protein, however, V-exposed rats produced significantly less cytokine. Following polyl:C instillation, there were no marked exposure-related differences in basal or stimulated superoxide anion production by pooled lavaged cells or PAM specifically. With V-exposed rats, pooled cells recovered 24 h after saline instillation displayed reduced production (in both cases) compared to the air control cells; PAM-specific production was affected only after stimulation. In both exposure groups, polyl:C caused decreased superoxide production in recovered cells. Though less apparent with pooled cells, there was a time post polyl:C instillation-dependent decrease in stimulated PAM-specific superoxide production; this effect was greater in PAM from V-exposed rats than in PAM from air controls. Phagocytic activity of PAM from rats in both exposure groups was significantly increased by polyl:C instillation, although total activity in cells obtained from V-exposed rats was always significantly lower compared to air control cells. Our results indicate that short-term, repeated inhalation of occupationally relevant levels of V by rats modulates pulmonary immunocompetence. Modified cytokine production and PAM functionality in response to biological response modifiers (such as lipopolysaccharide, IFN gamma, or polyl:C) may be, at least in part, responsible for the increases in bronchopulmonary disease in humans occupationally exposed to V
— id: 7133, year: 1997, vol: 51, page: 591, stat: Journal Article,

Pulmonary retention and distribution of inhaled chromium: Effects of particle solubility and coexposure to ozone
Cohen, MD; Zelikoff, JT; Chen, LC; Schlesinger, RB
1997 DEC ;9(9):843-865, Inhalation toxicology
Soluble and insoluble chromium (Cr) agents are concomitantly released with ozone (O-3) during welding. Although pulmonary implications from exposure to each agent individually have been investigated, the effects from simultaneous exposure, as occurs under actual working conditions, are unclear. To investigate the retention/distribution of inhaled Cr, male F-344 rats were exposed nose-only to atmospheres containing soluble potassium chromate (K2CrO4) or O-3, either alone or in combination, at 360 mu g Cr/m(3) and 0.3 ppm O-3. In a second phase of the study, insoluble barium chromate (BaCrO4) was used in place of K2CrO4. Rats were exposed for 5 h/day, 5 days/wk for 2 or 4 wk. One day after the final exposure, rats were euthanized and their lungs either removed intact or lavaged for quantitation of tissue-, lavaged cell-, and acellular lavage fluid-associated Cr. In general, rats inhaling insoluble Cr had greater total lung Cr burdens than did rats exposed to soluble Cr. Simultaneous inhalation of O-3 and K2CrO4 led to reduced lung Cr levels compared to those in rats receiving K2CrO4 only; with BaCrO4 coexposure to O-3 resulted in increased lung BaCrO, levels compared to BaCrO3 alone. Particle solubility also affected Cr levels in lavageable cells, with those from rats inhaling BaCrO, alone or BaCrO4 + O-3 consistently having greater burdens than their K2CrO4 counterparts; the presence of O-3 itself had no effect upon cell Cr levels when either compound was used. Solubility-dependent differences were also apparent in acellular lavage fluid, with Cr levels initially being greater in fluids from rats inhaling K2CrO4 alone; as exposures continued, these burdens became greater in the rats inhaling BaCrO4 alone. Although inhalation of either Cr/O-3 mixture yielded significant differences in fluid Cr levels, the presence of 4 did lead to reductions in levels compared to those in rats inhaling either Cr agent alone. In postlavage lung tissue, there were time-dependent increases in Cr levels in rats from all exposure groups; however, the most dramatic increase occurred with rats exposed to BaCrO4 + O-3. Lastly, while significant solubility-dependent differences in the relative distribution of Cr among the three pulmonary compartments were discerned, a specific effect attributable to O-3 itself was not evident. The results of this study indicate that Cr retention and distribution within the lungs, as well as any effect from coexposure to O-3, are modulated by the solubility of the inhaled Cr particles
— id: 53149, year: 1997, vol: 9, page: 843, stat: Journal Article,

Immunotoxicity of medical devices
Rodgers, K; Klykken, P; Jacobs, J; Frondoza, C; Tomazic, V; Zelikoff, J
1997 MAR ;36(1):1-14, Fundamental & applied toxicology
Determination of the ability of a medical device to interact with the immune system currently involves assessment of the immunogenic potential and biocompatibility of the device or an extract of the device. However, implants are often in the body for extended periods of time and/or are placed by a surgical procedure that in and of itself will generate an acute inflammatory response, This symposium discussed studies that have been performed to evaluate the immunogenicity of various devices consisting of several different compositions (i.e., silicone, metals, and latex) in contact with different anatomical sites, the ability of a device to modulate an inflammatory response generated by a surgical procedure or trauma, and the response of the body to a material left in place for extended periods of time, This symposium brought together scientists from many different disciplines to begin to identify and fill in the gaps in this area. (C) 1997 Society of Toxicology
— id: 53210, year: 1997, vol: 36, page: 1, stat: Journal Article,

Eco Toxicology : responses, biomarkers and risk asssessment
Zelikoff, Judith T; Lynch JM; Shepers, James
Paris, France : Organisation of Economic Co-Operation and Development, 1997,
— id: 1224, year: 1997, vol: , page: , stat: ,

Modulators of immune responses: the evolutionary trail
Bayne CJ; Zelikoff JT
1996 Feb;17(2):55-57, Immunology today
The evolutionary aspects of immunoregulation and the immunotoxic effects of xenobiotics in species ranging from humans to marine invertebrates were discussed at a recent meeting. This report describes progress in our understanding of this fascinating field
— id: 66156, year: 1996, vol: 17, page: 55, stat: Journal Article,

Vanadium affects macrophage interferon-gamma-binding and -inducible responses
Cohen MD; McManus TP; Yang Z; Qu Q; Schlesinger RB; Zelikoff JT
1996 May;138(1):110-120, Toxicology & applied pharmacology
Mouse WEHI-3 cells were exposed overnight to vanadium [V; ammonium metavanadate (NH4VO3) or vanadium pentoxide (V2O5)] to determine whether documented V-induced immunomodulation might arise from altered macrophage (M phi) interactions with interferon-gamma (IFN gamma) or altered IFN gamma-inducible responses. Binding studies performed at 22 degrees C indicated that although NH4VO3-pretreated cells had approximately 48% fewer actively-binding Class I IFN gamma receptors, binding affinities were 1.5-fold greater than that of control cell receptors; Class II expression was unaffected but affinities were reduced 2-fold. Postbinding IFN gamma-receptor complex internalization was unaffected by V pretreatment. Spontaneous production of both hydrogen peroxide and superoxide anion was significantly increased by treatment with both V compounds. Total hydrogen peroxide and superoxide production was increased by stimulation of IFN gamma-primed cells with zymosan, but relative increases in primed V-treated cells were lower than that in controls. Vanadium-treated cells also displayed decreased rates of IFN gamma-induced changes in [Ca2+]i levels secondary to increased resting [Ca2+]i levels. Although V-treated cells did not display significant increases in I-A expression after IFN gamma treatment, increased numbers of I-A+ cells (irrespective of priming) and lower maximal antigen densities than observed on I-A+ control cells were evident. Results from this study show that V exposure may produce alterations in M phi-mediated functions, in part, by modifying cell interactions with IFN gamma and subsequent IFN gamma-dependent functional parameters
— id: 6988, year: 1996, vol: 138, page: 110, stat: Journal Article,

Pulmonary immunotoxicity of inhaled ammonium metavanadate in Fisher 344 rats
Cohen MD; Yang Z; Zelikoff JT; Schlesinger RB
1996 Oct;33(2):254-263, Fundamental & applied toxicology
Male Fisher 344 rats were exposed to 2 mg vanadium(V)/m3 (as ammonium metavanadate NH4VO3, 0.32 micron MMD) atmospheres for 8 hr/day for 4 days in a nose-only exposure system. In exposed rats, lung V burdens increased in a time-dependent fashion. Analysis of lung cells and lavage fluid 24 hr after the final exposure suggested that tissue damage and a strong inflammatory response was elicited; numbers of neutrophil and small macrophages (Mo), as well as levels of lavageable protein and lactate dehydrogenase, were significantly elevated as compared with levels observed with air-exposed rats. Vanadium also affected pulmonary alveolar Mo (PAM) capacities to produce and respond to immunoregulating cytokines. Inducible PAM production of tumor necrosis factor-alpha was significantly inhibited, as was the ability to increase cell surface Class II/I-A molecule expression in response to interferon-gamma (IFN gamma). PAM from V-exposed hosts were also inhibited in their ability to be primed by IFN gamma to produce superoxide anion and hydrogen peroxide in response to stimulation with opsonized zymosan. These studies indicate that short-term repeated exposure of rats to atmospheric V, at levels encountered in an occupational setting, can alter host pulmonary immunomocompetence, with one major effect occurring at the level of cytokine-related functions. These alterations may be underlying mechanisms for the well-documented increases in bronchopulmonary infections and cancers in workers chronically exposed to V-containing atmospheres
— id: 12523, year: 1996, vol: 33, page: 254, stat: Journal Article,

Effects of ozone upon macrophage-interferon interactions
Cohen MD; Zelikoff JT; Qu Q; Schlesinger RB
1996 Dec 18;114(3):243-252, Toxicology
Lung cell populations may be directly exposed to environmental airbone toxicants such as ozone (O3). Since pulmonary macrophages (M phi) play a pivotal role in host pulmonary immunocompetence, their function in this regard may be compromised by pollutant exposure thereby giving rise to an increased incidence of pulmonary disease. The current in vitro study was designed to provide some insight into possible mechanisms by which O3 induces decreased host pulmonary resistance against microbial pathogens. Specifically, this study investigated the impact of an acute O3 exposure upon the ability of a cultured mouse M phi cell line (WEHI-3) to interact with, and respond to, the major M phi-activating cytokine, interferon-gamma (IFN gamma). The results of this study indicate that WEHI-3 exposure to 1 ppm O3 for 4 h reduced both the binding of, and responsivity to, IFN gamma. Among the functional parameters affected by this inability to properly bind/respond to IFN gamma were: reactive oxygen intermediate production, phagocytic activity, and cellular calcium ion elevation; IFN gamma-enhanced expression of surface histocompatibility antigens was unaffected by O3 exposure. The reduced activity of any one of these critical M phi functions could provide a basis for previously-documented increases in microbial pathogen survival in the lungs, and overall compromise of host health following O3 exposure
— id: 10366, year: 1996, vol: 114, page: 243, stat: Journal Article,

Health risks associated with prenatal metal exposure
Zelikoff JT; Bertin JE; Burbacher TM; Hunter ES; Miller RK; Silbergeld EK; Tabacova S; Rogers JM
1995 May;25(2):161-170, Fundamental & applied toxicology
A symposium entitled Health Risks Associated with Prenatal Metal Exposure was held at the 33rd Annual Meeting of the Society of Toxicology (SOT) in Dallas, Texas. The symposium was cosponsored by the Metals and Reproductive and Developmental Specialty Sections of SOT and was designed to elaborate the health risks associated with in utero exposure to metals commonly found in the workplace and/or ambient environment on the mother and developing offspring. Epidemiological and toxicological evidence that demonstrates the health effects and underlying mechanisms associated with exposure to arsenic (As), lead (Pb), and methyl mercury (MeHg) were discussed, as well as the legal ramifications and personal implications associated with prenatal metal exposure. The following is a summary of each of the individual presentations
— id: 6879, year: 1995, vol: 25, page: 161, stat: Journal Article,

Immunotoxicity of low level cadmium exposure in fish: an alternative animal model for immunotoxicological studies
Zelikoff JT; Bowser D; Squibb KS; Frenkel K
1995 Jul;45(3):235-248, Journal of toxicology & environmental health
Cadmium represents a major aquatic pollutant in many parts of the world. Yet, despite the fact that cadmium accumulates in high concentrations in fish tissues, is found in polluted aquatic environments, and is carcinogenic and immunotoxic in a variety of mammalian species, the effects of cadmium on the immune responses of directly exposed aquatic species have not been clearly defined. This study was designed to assess the effects of in vivo cadmium exposure, at a concentration found in contaminated aquatic environments, on the immune defense mechanisms of fish. In this study, no effects were observed upon body weight, lysozyme activity, of cell viability, despite the high concentration of accumulated cadmium in the gills and liver. Furthermore, in the absence of any clinical manifestations or overt toxicity, exposure of rainbow trout to waterborne cadmium at 2 ppb altered macrophage-mediated immune functions, including phagocytosis and free radical production, in a time-dependent manner. Similar immunotoxic effects of cadmium have also been observed in mammals. Although interspecies comparisons between mammalian and fish immune responses are extremely complicated and need to be approached with caution, results from this study suggest the applicability of fish as an additional/alternative animal model for immunotoxicological studies
— id: 6880, year: 1995, vol: 45, page: 235, stat: Journal Article,

Effects of in vitro nickel exposure on the macrophage-mediated immune functions of rainbow trout (Oncorhynchus mykiss)
Bowser DH; Frenkel K; Zelikoff JT
1994 Mar;52(3):367-373, Bulletin of environmental contamination & toxicology
— id: 7877, year: 1994, vol: 52, page: 367, stat: Journal Article,

Immunotoxicity of particulate lead: in vitro exposure alters pulmonary macrophage tumor necrosis factor production and activity
Cohen MD; Yang Z; Zelikoff JT
1994 Aug;42(4):377-392, Journal of toxicology & environmental health
Rabbit pulmonary macrophages were exposed in vitro to particulate lead oxide (PbO) for periods of up to 72 h and then assayed for the activity of tumor necrosis factor-alpha (TNF alpha) released after stimulation with lipopolysaccharide (LPS). The levels of TNF alpha obtained from PbO-treated cells were decreased in a dose-dependent manner as compared with metal-free control cells for each time point examined. Cells treated simultaneously with both LPS and PbO yielded less monokine than did cells receiving LPS alone. In addition, incubation of cell-free TNF alpha with PbO resulted in a diminution of cytotoxicity directed against TNF alpha-sensitive tumor target cells. Macrophage burdens of PbO particles increased with both the length of incubation and concentration of PbO used; increases in cellular lead burdens were paralleled by reductions in cell viability. Thus, under in vitro conditions, PbO affects the levels of the immunoregulatory monokine TNF alpha and also disrupts its cytotoxic properties after release from activated macrophages
— id: 8386, year: 1994, vol: 42, page: 377, stat: Journal Article,

PULMONARY EFFECTS OF REPEATED EPISODIC EXPOSURES TO NITRIC-ACID VAPOR ALONE AND IN COMBINATION WITH OZONE
SCHLESINGER, RB; ELFAWAL, HAN; ZELIKOFF, JT; GORCZYNSKI, JE; MCGOVERN, T; NADZIEJKO, CE; CHEN, LC
1994 JAN-FEB ;6(1):21-41, Inhalation toxicology
Inhaled acids are associated with adverse health effects, a conclusion based largely on studies with particulate-associated acid sulfates. The acidic component of ambient air in some regions, such as California, contains nitric acid (HNO3) vapor, but there is a limited database concerning its biological effects. Furthermore, effects of HNO3 may be modulated by coexposure to other pollutants, such as ozone (O-3). Rabbits were exposed for 4 h/day, 3 days/wk for 4 wk to HNO3 vapor at 0, 50, 150, and 450 mu g/m(3) alone; 0.15 ppm 0(3) alone; or to a mixture of 50 mu g/m(3) HNO3 + 0.15 ppm 0(3). Exposure was followed by assays of biochemical markers in lavage fluid pulmonary macrophage function, and in vitro bronchial responsivity to smooth muscle constrictor challenge. Nitric acid had no effect on viability or numbers of cells recovered, nor on lactate dehydrogenase or total protein in lavage. All acid concentrations reduced both basal levels and stimulated production of superoxide anion by macrophages, while the release/activity of tumor necrosis factor by stimulated macrophages was reduced following exposure to greater than or equal to 150 mu g/m(3) HNO3. Bronchi from rabbits exposed to greater than or equal to 150 mu g/m(3) HNO3 exhibited reduced smooth muscle responsivity in vitro compared to control. Although exposure to the HNO3/O-3 mixture resulted in no interaction for most end points, antagonism was noted for stimulated superoxide production, while synergism was noted for spontaneous superoxide production and bronchial responsivity. Exposure to the mixture resulted in a total abrogation of response to spasmogens in most bronchi examined and a marked attenuation in others. These results indicate that HNO3, when inhaled in vapor phase, may adversely impact upon pulmonary health by affecting target sites throughout the lungs, and that inhalation of an HNO3/O-3 mixture can produce synergistic interaction in affecting some biological parameters
— id: 52566, year: 1994, vol: 6, page: 21, stat: Journal Article,

Immunotoxicity of sulfuric acid aerosol: effects on pulmonary macrophage effector and functional activities critical for maintaining host resistance against infectious diseases
Zelikoff JT; Sisco MP; Yang Z; Cohen MD; Schlesinger RB
1994 Sep 6;92(1-3):269-286, Toxicology
Despite the widespread occurrence of acidic sulfur oxides in the ambient environment and their potential risks to human health, effects associated with pulmonary immune defenses have been poorly studied. The current in vivo study was designed to provide some insight into this relatively unexplored area by investigating the impact of inhaled sulfuric acid on immune defense mechanisms critical for maintaining pulmonary resistance against infectious diseases. Results of this study demonstrate that repeated inhalation of sulfuric acid reduces the uptake and intracellular killing of pathogenic bacteria by exposed pulmonary macrophages, and depresses the activity/production of important biological modifiers critical for maintaining pulmonary immunocompetence. These findings have important implications for human health, and may contribute to a better understanding of the possible mechanism(s) underlying the epidemiological evidence which suggests an association between total sulfates in the ambient air and increased incidence of acute bronchitis and lower respiratory illness in school-age children
— id: 6788, year: 1994, vol: 92, page: 269, stat: Journal Article,

Immunomodulation by metals
Zelikoff JT; Smialowicz R; Bigazzi PE; Goyer RA; Lawrence DA; Maibach HI; Gardner D
1994 Jan;22(1):1-7, Fundamental & applied toxicology
A symposium entitled Immunomodulation by Metals was held at the 32nd Annual Meeting of the Society of Toxicology (SOT) in New Orleans, Louisiana. The symposium was co-sponsored by the Immunotoxicology and Metals Specialty Sections of SOT and was designed to describe the types of adverse immunological reactions which occur in response to environmental and/or occupational exposure to metals. Epidemiological evidence and underlying mechanisms responsible for the observed alterations were also discussed. The following is a summary of each of the individual presentations
— id: 6562, year: 1994, vol: 22, page: 1, stat: Journal Article,

Immunotoxicity of in vitro vanadium exposures: effects on interleukin-1, tumor necrosis factor-alpha, and prostaglandin E2 production by WEHI-3 macrophages
Cohen MD; Parsons E; Schlesinger RB; Zelikoff JT
1993 Apr;15(3):437-446, International journal of immunopharmacology
Treatment of cultured mouse macrophages with either of two different vanadium compounds was shown to affect the production/release of two major immunoregulatory cytokines. The pentavalent vanadium compound ammonium metavanadate was shown previously to disrupt cell-mediated immunity at the earliest stages of an in vivo anti-Listerial response, in that mice treated with vanadium displayed decreased accessory cell recruitment and numbers of activated macrophages at infection sites. To determine whether these effects were due to vanadium-induced alterations in the production of biologically-active mediators, mouse macrophage-like WEHI-3 cells were treated in vitro with ammonium metavanadate or vanadium pentoxide prior to stimulation with lipopolysaccharide endotoxin (LPS). After stimulation, monokine (tumor necrosis factor-alpha and interleukin-1) and prostaglandin E2 (PGE2) activities were assessed. Both vanadium compounds decreased recovered monokine activities; measured TNF alpha concentrations were also reduced. Spontaneous release of the IL-1/TNF-regulating prostanoid PGE2 was significantly increased by the highest concentration of vanadate tested, although LPS-stimulated PGE2 production was unaffected by either compound. These results indicate that, in vitro, pentavalent vanadium can interfere with immunoregulatory mediators critical for maintaining host immunocompetence
— id: 8422, year: 1993, vol: 15, page: 437, stat: Journal Article,

Biological markers of macrophage activation: applications for fish phagocytes
Enane NA; Frenkel K; O'Connor JM; Squibb KS; Zelikoff JT
1993 Sep;80(1):68-72, Immunology
The immune defence mechanisms of fish seem to be related and similarly competent to those of mammals. Because of this, there is an increased interest in the immune responses of fish as models for higher vertebrates in immunological/immunotoxicological studies. Macrophages (M phi), phagocytic cells of the mammalian and teleost immune system which reside in tissues, represent a quiescent population of cells. However, upon stimulation, alterations in the physiology of these resident M phi occur which can be defined in terms of activation. This study was undertaken to determine whether biological markers used to assess mammalian M phi activation are applicable for use with fish M phi. Cells were recovered from the peritoneal cavity of non-injected and Aeromonas salmonicida-injected fish, and differences between resident and elicited M phi were evaluated with respect to protein content, phagocytic competence, enzyme activities and hydrogen peroxide production. Results demonstrate that biological markers used to assess mammalian M phi activation, with the exception of acid phosphatase activity, can be used to characterize the activation state of trout M phi, and that the activation process in both fish and mammals may occur by similar mechanism(s)
— id: 6365, year: 1993, vol: 80, page: 68, stat: Journal Article,

EFFECTS OF INHALED NITRIC-ACID VAPOR ON PULMONARY IMMUNOCOMPETENCE - ALTERATIONS IN MACROPHAGE-MEDIATED IMMUNITY
SCHLESINGER, RB; ZELIKOFF, JT
1993 APR ;147(4):A384-A384, American review of respiratory disease
— id: 54157, year: 1993, vol: 147, page: A384, stat: Journal Article,

Inhalation of particulate lead oxide disrupts pulmonary macrophage-mediated functions important for host defense and tumor surveillance in the lung
Zelikoff JT; Parsons E; Schlesinger RB
1993 Aug;62(2):207-222, Environmental research
Lead, an immunomodulator and potential human carcinogen, is a major airborne pollutant in industrial environments which poses a serious threat to human health. Despite the wide-spread occurrence of respirable lead particles in the air, and the potential human health risks, effects associated with inhalation of particulate lead on the the lung have been poorly studied. This study was performed to determine whether inhalation of particulate lead oxide (PbO), at a concentration below the currently acceptable air lead standard for occupational exposure, disrupts macrophage (M phi) functions important for maintaining pulmonary immunocompetence. These functions include phagocytosis, production of reactive oxygen intermediates, and the biological activity of tumor necrosis factor-alpha (TNF-alpha). Rabbits exposed to PbO at 30 micrograms/m3 for 4 days (3 hr/day) were sacrificed and their lungs lavaged immediately, 24 hr, and 72 hr after the final exposure. Lactate dehydrogenase (a marker of lung cell damage) and lysozyme activity (a marker of lysosome permeability), measured in the lavage fluid, were significantly increased 24 and 72 hr after exposure. PbO produced neutrophil infiltration nor effects on M phi viability or total numbers. Effects on M phi functions were as follows. Phagocytic uptake of latex particles was reduced with increasing post-exposure time reaching a maximum inhibition at 72 hr. Inhalation of PbO enhanced hydrogen peroxide (H2O2) and superoxide anion radical (O2-) production in a time-dependent manner; effects on H2O2 began at 24 hr and were persistent up to 72 hr. Effects on TNF-alpha release/activity appeared earliest and were persistent up to 72 hr. Immediately and 24 hr after exposure, lipopolysaccharide-stimulated activity of TNF-alpha was depressed by 62 and 50%, respectively; after 72 hr, TNF-alpha release was significantly enhanced compared to control levels. Results demonstrate that the lung is a sensitive target for the toxic effects of inhaled lead. This study provides the first evidence that inhalation of particulate lead, at an occupationally relevant concentration, and in the absence of elevated blood lead levels, alters pulmonary M phi functions critical for lung defense against inhaled antigens. Our findings may have important implications for human health and should be considered when evaluating the health risks associated with inhaled lead
— id: 13094, year: 1993, vol: 62, page: 207, stat: Journal Article,

CONTRIBUTION OF SULFURIC-ACID TO RESPIRATORY-INFECTIONS
ZELIKOFF, JT; COHEN, MD; SISCO, MP; SCHLESINGER, RB
1993 APR ;147(4):A384-A384, American review of respiratory disease
— id: 54156, year: 1993, vol: 147, page: A384, stat: Journal Article,

Assessment of toxicologic interactions resulting from acute inhalation exposure to sulfuric acid and ozone mixtures
Schlesinger RB; Zelikoff JT; Chen LC; Kinney PL
1992 Aug;115(2):183-190, Toxicology & applied pharmacology
Studies examining effects of air pollutants often use single compounds, while 'real world' exposures are to more than one chemical. Thus, it is necessary to assess responses following inhalation of chemical mixtures. Rabbits were exposed for 3 hr to sulfuric acid aerosol at 0, 50, 75, or 125 micrograms/m3 in conjunction with ozone at 0, 0.1, 0.3, or 0.6 ppm, following which broncho-pulmonary lavage was performed. Various pulmonary response endpoints related to general cytotoxicity and macrophage function were examined. In addition, a goal of the study was to define an improved approach to the analysis of data sets involving binary pollutant mixtures. Results were evaluated using analysis of variance with multiple linear contrasts to determine the significance of any effect in the pollutant-exposed groups compared to sham control animals and to assess the type, and extent, of any toxicological interaction between acid and ozone. Interaction was considered to occur when the effects of combined exposure were either significantly greater or less than additive. Pollutant exposures had no effect on lavage fluid levels of lactate dehydrogenase, prostaglandins E2 and F2 alpha, nor on the numbers, viability, or types of immune cells recovered by lavage. Phagocytic activity of macrophages was depressed at the two highest acid levels and at all levels of ozone. Exposure to all mixtures showed significant antagonism. Superoxide production by stimulated macrophages was depressed by acid exposure at the two highest concentrations, while ozone alone had no effect. Significant antagonistic interaction was observed following exposure to mixtures of 75 or 125 micrograms/m3 acid with 0.1 or 0.3 ppm ozone. The activity of tumor necrosis factor elicited from stimulated macrophages was depressed by acid at 75 and 125 micrograms/m3 while ozone had no effect. Exposure to mixtures of 125 micrograms/m3 acid with 0.3 or 0.6 ppm ozone resulted in synergistic interaction. This study provided additional evidence for antagonism between two common air pollutants and demonstrated that the type of interaction between sulfuric acid and ozone depended upon the endpoint but that the magnitude of any interaction was not always related to the exposure concentrations of the constituent pollutants
— id: 13514, year: 1992, vol: 115, page: 183, stat: Journal Article,

Modulation of pulmonary immune defense mechanisms by sulfuric acid: effects on macrophage-derived tumor necrosis factor and superoxide
Zelikoff JT; Schlesinger RB
1992 Dec 4;76(3):271-281, Toxicology
There is considerable interest in the potential health effects resulting from inhalation of acidic aerosols. However, except for well documented irritant effects and acid-induced changes in lung clearance function, other potential health effects have not been well defined. This study was designed to provide further insight regarding the relationship of sulfuric acid aerosol to the pathogenesis of respiratory disease by describing the effects of inhaled acid on the release and/or activity of biologically active mediators critical for maintaining pulmonary immunocompetence and resistance against infectious diseases. Results of this study demonstrated that a single inhalation exposure of rabbits to environmentally relevant and higher concentrations of sulfuric acid depresses the release/activity of lipopolysaccharide-stimulated tumor necrosis factor-alpha and also reduces the ability of pulmonary macrophages to produce superoxide anion radical in response to opsonised zymosan. These findings should be considered when evaluating the health risks associated with sulfuric acid exposure
— id: 13341, year: 1992, vol: 76, page: 271, stat: Journal Article,

DNA damage by mercury compounds : an overview
Costa M; Christie NT; Cantoni O; Zelikoff JT; Wang XW; Rossman TG
Advances in mercury toxicology New York : Plenum Press, 1991,
— id: 4397, year: 1991, vol: , page: ?, stat: Chapter,

Development of fish peritoneal macrophages as a model for higher vertebrates in immunotoxicological studies. I. Characterization of trout macrophage morphological, functional, and biochemical properties
Zelikoff JT; Enane NA; Bowser D; Squibb KS; Frenkel K
1991 Apr;16(3):576-589, Fundamental & applied toxicology
The immune defense mechanisms of fish are not as well characterized as those of mammals but seem to be related and similarly competent. Because of this, there is an increased interest in the immune responses of fish as models for higher vertebrates in immunotoxicological studies. Prior to such studies, baseline criteria for specific components of the immune response needed to be established. For this study, we have examined trout macrophage morphology using light and scanning electron microscopy, phagocytic activity, random and stimulus-directed migration, and superoxide anion radical (O2-) production for resident and lipopolysacharide (LPS) or Aeromonas salmonicidae-elicited rainbow trout (Oncorhynchus mykiss) peritoneal macrophages (M phi). Following peritoneal lavage, greater than 89% of the cells were M phi as determined by differential counts and nonspecific esterase staining. Immunization with LPS and A. salmonicidae increased M phi number approximately 5 and 13-fold, respectively, and overall size. Trout M phi were phagocytically active engulfing serum opsonized latex particles and were mobile, migrating both randomly and in a directed fashion towards formyl-methionine-L-leucine-L-phenylalanine (FMLP) and trout serum-derived complement fragment C5a. Concentrations of FMLP (100 nM) and C5a (0.01-1%) effective for attracting trout M phi are the same as those used to attract rabbit M phi. Resident trout M phi produced negligable quantities of .O2- following stimulation with 1 micrograms/ml phorbol myristate acetate; Aeromonas-elicited M phi produced .O2- in a time-dependent manner which peaked after 60 min at 2.9 nmol per 2 x 10(5) cells and then declined. The results of this study provide a data base for future toxicological studies with trout peritoneal M phi and indicate the usefulness of this system for immunotoxicological studies
— id: 14093, year: 1991, vol: 16, page: 576, stat: Journal Article,

Immunomodulating effects of ozone on macrophage functions important for tumor surveillance and host defense
Zelikoff JT; Kraemer GL; Vogel MC; Schlesinger RB
1991 Dec;34(4):449-467, Journal of toxicology & environmental health
Ozone (O3) is a toxic gaseous pollutant that has been implicated in laboratory studies as a potential lung carcinogen or cocarcinogen in mice. To begin to assess the role of altered macrophage (M phi) responses as a possible mechanism by which O3 may influence carcinogenesis, we examined the effects of repeated in vivo O3 exposure on pulmonary M phi functional and biochemical activities deemed important in tumor surveillance, and host defense in general. Rabbits were exposed by inhalation to 1 ppm O3 for 3 d (2 h/d) and the lungs were lavaged immediately (t0) and 24 h (t24) after exposure. Results demonstrate that O3 reduced M phi viability and increased the number of neutrophils collected immediately after exposure. Effects of O3 on M phi movement were as follows: random migration was depressed immediately after the final exposure and chemotactic migration increased after 24 h. M phi-mediated cytotoxicity toward xenogeneic tumor cells in vitro was significantly depressed, compared to control, immediately and 24 h after O3 exposure. Release of cytotoxic factors deemed important for mediating tumor cell destruction was also assessed. Spontaneous and stimulated production of tumor necrosis factor, as measured by cytotoxicity toward LM cells (a clone of L-929 mouse fibroblasts), was unaffected by exposure to O3. Zymosan-stimulated production of superoxide anion radical (.O2-) was depressed at t0 and increased at t24; however, no significant effects on H2O2 production by resting or zymosan-stimulated M phi were observed at either time interval. Inhaled toxicants such as O3, which can compromise M phi functions important in tumor surveillance, could potentially alter host susceptibility to pulmonary cancer. Results of this study have important implications for human health, and demonstrate the need for further studies examining the carcinogenic/cocarcinogenic potential of O3
— id: 13836, year: 1991, vol: 34, page: 449, stat: Journal Article,

Comparative potency of inhaled acidic sulfates: speciation and the role of hydrogen ion
Schlesinger RB; Chen LC; Finkelstein I; Zelikoff JT
1990 Aug;52(2):210-224, Environmental research
Inhaled acidic sulfate aerosols affect various aspects of lung function, presumably by delivery of hydrogen ion (H+) to target sites. Recent evidence suggests that the relationship between response and H+ content of the exposure atmosphere may depend upon the specific sulfate species with which the H+ is associated. This study examined comparatively the effects of exposure to the two main ambient acidic sulfates, sulfuric acid (H2SO4) and ammonium bisulfate (NH4HSO4), using the phagocytic activity of alveolar macrophages as the endpoint. Rabbits were exposed to 250-2000 micrograms/m3 H2SO4 (as SO4(-2)) and 500-4000 micrograms/m3 NH4HSO4 (as SO4(-2)) for 1 hr/day for 5 days; bronchopulmonary lavage was then performed for recovery of free lung cells. Phagocytosis, measured by uptake of opsonized latex spheres in vitro, was altered by exposure to H2SO4 at concentrations greater than or equal to 500 micrograms/m3 and to NH4HSO4 at greater than or equal to 2000 micrograms/m3. Assessment of results in terms of the calculated hydrogen ion concentration in the exposure atmosphere showed that identical levels of H+ produced different degrees of response depending upon whether exposure was to H2SO4 or NH4HSO4. On the other hand, macrophages incubated in acidic environments in vitro responded similarly regardless of whether H2SO4 or NH4HSO4 was used to adjust the pH. Possible reasons for the difference in response observed in vivo and in vitro are discussed. Speciation of ambient acidic sulfate aerosols may be needed in atmospheric monitoring so as to assess the presence of H+ posing the greatest biologic hazard following inhalation exposure
— id: 39559, year: 1990, vol: 52, page: 210, stat: Journal Article,

Pulmonary arachidonic acid metabolism following acute exposures to ozone and nitrogen dioxide
Schlesinger RB; Driscoll KE; Gunnison AF; Zelikoff JT
1990 Dec;31(4):275-290, Journal of toxicology & environmental health
Ozone (O3) and nitrogen dioxide (NO2) are common air pollutants, and exposure to these gases has been shown to affect pulmonary physiology, biochemistry, and structure. This study examined their ability to modulate arachidonic acid metabolites (eicosanoids) in the lungs. Rabbits were exposed for 2 h to O3 at 0.1, 0.3, or 1 ppm; NO2 at 1, 3, or 10 ppm; or to a mixture of 0.3 ppm O3 and 3 ppm NO2. Groups of animals sacrificed either immediately or 24 h after each exposure underwent broncho-pulmonary lavage. Selected eicosanoids were assessed in lavage fluid by radioimmunoassay. Increases in prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha) were found immediately after exposure to 1 ppm O3. Exposure to 10 ppm NO2 resulted in a depression of 6-keto-PGF1 alpha, while thromboxane B2 (TxB2) was elevated after exposure to 1 ppm NO2 and depressed following 3 and 10 ppm. The O3/NO2 mixture resulted in synergistic increases in PGE2 and PGF2 alpha, with the response appearing to be driven by O3. This study has demonstrated that acute exposure to either O3 or NO2 can alter pulmonary arachidonic acid metabolism and that the responses to these oxidants differ, both quantitatively and qualitatively
— id: 14263, year: 1990, vol: 31, page: 275, stat: Journal Article,

Modulation of pulmonary eicosanoid metabolism following exposure to sulfuric acid
Schlesinger RB; Gunnison AF; Zelikoff JT
1990 Jul;15(1):151-162, Fundamental & applied toxicology
Eicosanoids (arachidonic acid metabolites) are potent biological mediators. Modulation of their metabolism by air pollutants may be a possible factor in the pathogenesis of environmentally related lung disease. Sulfuric acid (H2SO4) aerosols are components of ambient air in many areas. Rabbits were exposed to H2SO4 (0.3 microns) at 250, 500, or 1000 micrograms/m3 for 1 hr/day for 5 days. They were then euthanized, the lungs lavaged, and eicosanoid analyses performed by radioimmunoassay of acellular lavage fluid. An exposure-concentration-dependent decrease in levels of prostaglandins E2 and F2 alpha and thromboxane B2 was found; no change in leukotriene B4 was observed. Tracheal explants exposed to acidic environments in vitro also showed reduced production of PGE2, PGF2 alpha, and TxB2. Incubation with sodium sulfate (Na2SO4) showed no effect of the sulfate ion (SO4(2-)). This study, the first to examine eicosanoid production after in vivo exposure to pure H2SO4 droplets, indicates that such exposure can modulate arachidonic acid metabolism, and that this is likely due to the deposition of hydrogen ion (H+) on target tissue
— id: 17587, year: 1990, vol: 15, page: 151, stat: Journal Article,

Sulfadimethoxine pharmacokinetics and metabolism in the channel catfish (Ictalurus punctatus)
Squibb KS; Michel CM; Zelikoff JT; O'Connor JM
1988 ;30 Suppl 1:31-35, Veternary & human toxicology
The pharmacokinetics of sulfadimethoxine (SDM) blood clearance, gastrointestinal absorption and tissue distribution and elimination were determined in channel catfish (Ictalurus punctatus) after intravenous and oral dosing using radiolabelled SDM. Blood clearance of SDM in catfish was rapid compared to mammals when the drug was given iv. Results from in vitro equilibrium dialysis studies suggest that this is due to a lower binding of SDM to plasma proteins in fish (18.4%) compared to mammalian species (60-88%). Results from oral dose studies indicated that SDM is readily absorbed from the gastrointestinal tract in channel catfish and distributes rapidly to body tissues, primarily the muscle. With time, concentrations of SDM in muscle decrease and the drug accumulates in the bile, primarily as the N-acetyl-metabolite
— id: 11247, year: 1988, vol: 30 Suppl 1, page: 31, stat: Journal Article,

Genetic toxicology of lead compounds
Zelikoff JT; Li JH; Hartwig A; Wang XW; Costa M; Rossman TG
1988 Oct;9(10):1727-1732, Carcinogenesis
We have investigated the activity of insoluble and soluble lead compounds in inducing mutagenesis, cell transformation and sister chromatid exchange in mammalian cells. Insoluble lead sulfide, readily phagocytized, was more than four times as toxic to V79 cells on a microM basis, than two moderately soluble lead compounds although the exposure time for the soluble salts was five times longer. These findings demonstrate the importance of different cellular mechanism(s) of metal uptake and bioavailability. Both insoluble lead sulfide and more soluble lead nitrate were mutagenic at the HPRT locus in V79 cells. Although less mutagenic at the higher concentrations, lead nitrate at a concentration of 500 microM enhanced the mutation frequency greater than 6-fold above background following a 5-day exposure. Although the mechanism(s) by which lead induces mutations is unknown, failure of both compounds to induce SCE and DNA single-strand breaks, detectable by alkaline elution, suggests that lead-induced mutations may not be a result of direct damage to DNA but may occur via indirect mechanisms including disturbances in enzyme functions important in DNA synthesis and/or repair, or in DNA-helical structure. Lead acetate also transformed SHE cells in a dose-response fashion following a 48-h exposure. Our results indicate that lead compounds may be genotoxic by an indirect mechanism, and lend support to the view that lead is a carcinogen
— id: 10946, year: 1988, vol: 9, page: 1727, stat: Journal Article,

GENETIC TOXICOLOGY OF METAL-COMPOUNDS - AN EXAMINATION OF APPROPRIATE CELLULAR-MODELS
ROSSMAN, TG; ZELIKOFF, JT; AGARWAL, S; KNEIP, TJ
1987 MAY ;14(4):251-262, Toxicological & environmental chemistry
— id: 41713, year: 1987, vol: 14, page: 251, stat: Journal Article,

Differential phosphorylation events associated with phorbol ester effects on acceleration versus inhibition of cell growth
Zelikoff JT; Garte SJ; Belman S
1987 Jan 1;47(1):329-330, Cancer research
— id: 66157, year: 1987, vol: 47, page: 329, stat: Journal Article,

CYTOTOXICITY AND MUTAGENICITY OF INSOLUBLE METAL-SALTS IN V79 CELLS
Zelikoff, JT; Hartwig, A; Li, JH; Rossman, TG
1987 Mar;3(1):93-93, Cell biology & toxicology
— id: 31171, year: 1987, vol: 3, page: 93, stat: Journal Article,

TOXIC EFFECTS OF ENVIRONMENTALLY SIGNIFICANT PARTICLES USING CHINESE-HAMSTER LUNG-CELLS
ATKINS, NM; ZELIKOFF, JT; DAISEY, JM
1986 MAR ;22(3):A44-A44, In vitro
— id: 41347, year: 1986, vol: 22, page: A44, stat: Journal Article,

Sarcoid and cytotoxic lung antibodies
Ende N; Grizzanti JN; Orsi EV; Lubansky KP; Amoruso RC; Reichman LB; Zelikoff JT
1986 Dec 22;39(25):2435-2440, Life sciences
Fifteen cases of Sarcoidosis were investigated for the presence of complement dependent cytotoxicity against human lung cells grown in tissue culture. Significant levels were found in eleven cases. Absorption studies revealed that these antibodies associated with sarcoidosis could be absorbed by human lung fibroblasts but not by fibroblasts derived from human foreskin or kidney. Although we found a similar antibody frequently associated with extrinsic asthma we have only rarely found these antibodies in cases of tuberculosis, carcinoma of the lung, emphysema and intrinsic asthma
— id: 66158, year: 1986, vol: 39, page: 2435, stat: Journal Article,

Stimulation of cell growth and proliferation in NIH-3T3 cells by onion and garlic oils
Zelikoff JT; Atkins NM Jr; Belman S
1986 Sep;2(3):369-378, Cell biology & toxicology
Onion and garlic oil were seen to shorten the cell-doubling time and stimulate the growth and proliferation of NIH-3T3 cells. Following treatment with either onion or garlic oil, an increase in the growth rate and almost a 2-fold increase in cell number over the control was observed within a 24-hour period. Phorbol myristate acetate when given simultaneously with either oil appeared to nullify both effects. Following exposure to low doses (less than 10 micrograms/ml) of either oil, an increase in cell survival, not seen with the oil control tricaprylin, was observed following a 5-day exposure period. At higher concentrations cell survival decreased proportionately in all cases. The appearance of multinucleated cells, which increased with dose and time, was also observed following treatment with both garlic and onion oil
— id: 11436, year: 1986, vol: 2, page: 369, stat: Journal Article,

MUTAGENICITY OF SOLUBLE METAL-SALTS USING THE V79/HGPRT MUTATION ASSAY
ZELIKOFF, JT; ATKINS, N; ROSSMAN, TG
1986 FEB ;8(2):95-95, Environmental mutagenesis
— id: 41512, year: 1986, vol: 8, page: 95, stat: Journal Article,

COMPARISON OF THE CYTOTOXICITY OF SOLUBLE AND INSOLUBLE METAL-SALTS ON V79 CELLS
ZELIKOFF, JT; LI, JH; ROSSMAN, TG
1986 MAR ;22(3):A47-A47, In vitro
— id: 41348, year: 1986, vol: 22, page: A47, stat: Journal Article,

Antibodies to synovial-derived cells in patients undergoing artificial prosthesis implants
Ende N; Orsi EV; Buechel FF; Baturay NZ; Zelikoff JT
1985 ;3(1):78-83, Journal of orthopaedic research
In this preliminary study, the authors have found cytotoxic complement-dependent synovial antibodies in the serum of patients undergoing prosthesis implantation; these were particularly evident in those patients undergoing revision surgery. In order to demonstrate the synovial antibodies, it was necessary that the authors modify the method they had previously used in their studies of cytotoxic lung and kidney antibodies. While conventional trypsinization dispersion produced synovial target cells that would not react in the test system, mechanical dispersion successfully produced target cells sensitive to complement-dependent cytotoxic antibodies. In this study, synovial antibodies reacted similarly to cells derived from the synovium of different individuals, but they did not react to cells derived from tissues other than synovium. This tissue specificity was confirmed by absorption studies that indicated the synovial antibodies to be organ specific. Whether these cytotoxic synovial antibodies can be predictive of the impending loss of an artificial prosthesis, or somehow be directly involved in the failure mechanism of that prosthesis, will require additional studies
— id: 66160, year: 1985, vol: 3, page: 78, stat: Journal Article,

Balbc/3T3 cell transformation response to extracts of organic air samples as seen by their survival in aggregate form
Zelikoff JT; Daisey JM; Traul KA; Kneip TJ
1985 Oct;144(2):107-116, Mutation research
Extracts of organic matter from samples of airborne particulate matter have been shown to possess components capable of transforming mammalian cells. This study was done to determine if Balbc/3T3 cells exposed to extracts of air samples could, unlike their normal counterparts, in the absence of a surface for attachment, divide on agar to form aggregates, and if these cells would demonstrate a dose-response phenomenon. Untreated and solvent treated control cells failed to form large aggregates and showed a decline in viable cell number over a 6-day period. Cells treated with either cyclohexane or acetone extracts of airborne particulate matter showed a dose-response increase in cell number along with the formation of progressively larger aggregates, findings similar to those seen with the positive, benzo[a]pyrene (BaP), control. Furthermore, these findings are in direct agreement with those in the simultaneously performed standard cell transformation assay which required 21 days to perform. Results show that survival in aggregate form is a rapid in vitro test system capable of detecting potentially carcinogenic activity in complex environmental mixtures
— id: 66159, year: 1985, vol: 144, page: 107, stat: Journal Article,

A COMPARISON OF METAL TOXICITY IN A MICROTITRE ASSAY SYSTEM, USING ESCHERICHIA-COLI AND V79 CELLS
Zelikoff, JT; Agarwal, S; Rossman, TG
1985 ;7(1):7-8, Environmental mutagenesis
— id: 30881, year: 1985, vol: 7, page: 7, stat: Journal Article,

CYTO-TOXICITY OF FINE PARTICLES WITH AND WITHOUT ADSORBED POLYCYCLIC AROMATIC-HYDROCARBONS USING CHINESE-HAMSTER LUNG-CELLS (V79)
ZELIKOFF, JT; ATKINS, NM; ROSSMAN, TG; DAISEY, JM
1985 ;11(2-4):331-339, Environment international
— id: 41200, year: 1985, vol: 11, page: 331, stat: Journal Article,

EFFECT OF ONION AND GARLIC OIL ON 3T3 CELL-TRANSFORMATION
Zelikoff, JT; Belman, S
1985 ;21(3):A41-A41, In vitro cellular & developmental biology
— id: 30825, year: 1985, vol: 21, page: A41, stat: Journal Article,

STIMULATION OF CELL-GROWTH AND PROLIFERATION IN NIH-3T3 CELLS USING ONION AND GARLIC OIL
ZELIKOFF, JT; ATKINS, N; BELMAN, S
1984 ;20(3):276-276, In vitro
— id: 40965, year: 1984, vol: 20, page: 276, stat: Journal Article,

CELLULAR UPTAKE AND CYTO-TOXICITY OF FINE PARTICLES WITH ADSORBED BENZO(A)PYRENE USING CHINESEHAMSTER LUNG CELLS(V79)
ZELIKOFF, JT; ATKINS, N; ROSSMAN, T; DAISEY, JM
1984 ;6(3):435-435, Environmental mutagenesis
— id: 40939, year: 1984, vol: 6, page: 435, stat: Journal Article,

PHAGOCYTOSIS OF COAL FLY ASH (CFA) PARTICLES BY CHINESE-HAMSTER LUNG-CELLS (V79) USING LIGHT AND SCANNING ELECTRON-MICROSCOPY (SEM)
Zelikoff, JT; Orsi, EV; Daisey, JM
1984 ;52(1):A42-A42, Biology of the cell
— id: 31004, year: 1984, vol: 52, page: A42, stat: Journal Article,

BALB-3T3 CELL RESPONSE TO EXTRACTS OF ORGANIC AIR SAMPLES AS SEEN BY THEIR SURVIVAL IN AGGREGATE FORM
ZELIKOFF, JT; ATKINS, N; ORSI, EV; KNEIP, TJ
1983 ;19(3):266-267, In vitro
— id: 50961, year: 1983, vol: 19, page: 266, stat: Journal Article,