Relationships between Isomeric Metabolism and Regioselective Toxicity of Hydroxychrysenes in Embryos of Japanese Medaka latipes)

Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) are ubiquitous contaminants that can be formed through oxidation of parent PAHs. Our previous studies found 2-hydroxychrysene (2-OHCHR) to be significantly more toxic to Japanese medaka embryos than 6-hydroxychrysene (6-OHCHR), an example of regioselective toxicity. We have also previously identified a sensitive developmental window to 2-OHCHR toxicity that closely coincided with liver development, leading us to hypothesize that differences in metabolism may play a role in the regioselective toxicity. To test this hypothesis, Japanese medaka embryos were treated with each isomer for 24 h during liver development (52-76 hpf). Although 6-OHCHR was absorbed 97.2 +/- 0.18% faster than 2-OHCHR, it was eliminated 57.7 +/- 0.36% faster as a glucuronide conjugate. Pretreatment with cytochrome P450 inhibitor, ketoconazole, reduced anemia by 96.8 +/- 3.19% and mortality by 95.2 +/- 4.76% in 2-OHCHR treatments. Formation of chrysene-1,2-diol (1,2-CAT) was also reduced by 64.4 +/- 2.14% by ketoconazole pretreatment. While pretreatment with UDP-glucuronosyltransferase inhibitor, nilotinib, reduced glucuronidation of 2-OHCHR by 52.4 +/- 2.55% and of 6-OHCHR by 63.7 +/- 3.19%, it did not alter toxicity for either compound. These results indicate that CYP-mediated activation, potentially to 1,2-CAT, may explain the isomeric differences in developmental toxicity of 2-OHCHR.

Automated summary

Previous studies have shown that 2-hydroxychrysene (2-OHCHR) is more toxic than 6-hydroxychrysene (6-OHCHR), reflecting regioselective toxicity. Our hypothesis is that differences in metabolism may contribute to the regioselective toxicity. Our experiments on Japanese medaka embryos indicate that CYP-mediated activation, potentially to 1,2-CAT, may explain the developmental toxicity differences of 2-OHCHR.