Isaac I. Wirgin

The Atlantic tomcod, Microgadus tomcod, from the Hudson River provides a unique opportunity to study the molecular aspects of genetic susceptibility to neoplasia in an outbred model organism that 1) exhibits an unusually high prevalence of hepatocellular carcinomas (more than 90% in 2-yr-old fish), 2) is exposed to high levels of environmentally borne chemical carcinogens, and 3) can be used to investigate the effects of controlled laboratory model-chemical exposures on sensitive early-life stages.

We examined the effects of the interactions of genetic variation and exposure to high levels of Hudson River-borne xenobiotics on the structure and expression of carcinogenically relevant genes, such as K-ras, aromatic hydrocarbonreceptor (Ahr) and cytochrome P4501A (CYP1A1). We found activated K-ras in a high percentage of tomcod liver-tumor DNAs, a transcribed genetic polymorphism in the 3' untranslated region of CYP1A1 in Hudson River tomcod that is not observed in cancer-free populations of tomcod.

Currently, we study the functional significance of genetic variation in this model relevant to: 1) the role of K-ras oncogene activation in early neoplastic events and hepatocarcinogenesis progression in tomcod livers, 2) the effects of environmentally relevant polychlorobiphenyl (PCB) promotion on clonal expansion of initiated cells, and 3) the molecular mechanisms of CYP1A1 gene regulation in environmentally exposed tomcod from the Hudson River. We also explore the effects of inter-specific and inter-individual differences in Ahr gene expression levels on CYP1A1 gene expression and transcription inhibition in halogenated aromatic hydrocarbon-exposed fish.