Chemical Carcinogenesis in Feral Fish: Uptake, Activation, and Detoxication of Organic Xenobiotics

The high prevalence of liver neoplasms in English sole (Parophrys vetulus) and substantially lower prevalence of neoplasms in a closely related species, starry flounder (Platichthys stellatus) captured from industrialized waterways, provide a unique opportunity to compare biochemical processes involved in chemical carcinogenesis in feral fish species. Because levels of aromatic hydrocarbons (AHs) in urban sediments are correlated with prevalences of liver neoplasms in English sole, we have initiated detailed studies to evaluate the effects of endogenous and exogenous factors on uptake, activation and detoxication of carcinogenic AHs, such as benzo[a]pyrene (BaP), using spectroscopic, chromatographic, and radiometric techniques. The results obtained thus far show that sole readily takes up AHs associated with sediment from urban areas and that the presence of other xenobiotics, such as PCBs, in sediment increases tissue concentrations of BaP metabolites. Extensive metabolism of BaP occurred whether sole was exposed to this AH via sediment, per os, or intraperitoneally. Substantial modification of hepatic DNA occurred and persisted for a period of 2-4 weeks after a single exposure to BaP. The level of covalent binding of BaP intermediates to hepatic DNA was 10-fold higher in juvenile than adult sole and 90-fold higher in juvenile sole than in Sprague-Dawley rat, a species which is resistant to BaP-induced hepatocarcinogenesis. The level of chemical modification of hepatic DNA in juvenile flounder was 2-4 fold lower than that for juvenile sole and concentration of BaP 7,8-diol glucuronide in bile of sole was significantly higher than that in flounder bile, although the rate of formation of BaP 7,8-diol by hepatic microsomes was comparable for both species. Moreover, liver microsomes from both species, in the presence of exogenous DNA, metabolized BaP into essentially a single adduct, identified as (+)anti-7,8-diol-9,10-epoxy-7,8,9,10-tetrahydroBaP-dG. These results, along with our findings that hepatic GST activity in flounder was two times higher than in sole, demonstrate that microsomal metabolism of BaP does not accurately reflect the differences in the ability of these fish to form BaP-DNA adducts in vivo and also suggest that detoxication of reactive intermediates is an important factor in determining the levels of DNA modification by AHs and resulting toxic effects in feral fish.