Genomic comparisons between hepatocarcinogenic and non-hepatocarcinogenic organophosphate insecticides in the mouse liver.

Short-term biomarkers of toxicity have an increasingly important role in the screening and prioritization of new chemicals. In this study, we examined early indicators of liver toxicity for three reference organophosphate (OP) chemicals, which are among the most widely used insecticides in the world. The OP methidathion was previously shown to increase the incidence of liver toxicity, including hepatocellular tumors, in male mice. To provide insights into the adverse outcome pathway (AOP) that underlies these tumors, effects of methidathion in the male mouse liver were examined after 7 and 28 day exposures and compared to those of two other OPs that either do not increase (fenthion) or possibly suppress liver cancer (parathion) in mice. None of the chemicals caused increases in liver weight/body weight or histopathological changes in the liver. Parathion decreased liver cell proliferation after 7 and 28 days while the other chemicals had no effects. There was no evidence for hepatotoxicity in any of the treatment groups. Full-genome microarray analysis of the livers from the 7 and 28 day treatments demonstrated that methidathion and fenthion regulated a large number of overlapping genes, while parathion regulated a unique set of genes. Examination of cytochrome P450 enzyme activities and use of predictive gene expression biomarkers found no consistent evidence for activation of AhR, CAR, PXR, or PPARα. Parathion suppressed the male-specific gene expression pattern through STAT5b, similar to genetic and dietary conditions that decrease liver tumor incidence in mice. Overall, these findings indicate that methidathion causes liver cancer by a mechanism that does not involve common mechanisms of liver cancer induction.

Suppression of apoptotic signaling in rat hepatocytes by non-dioxin-like polychlorinated biphenyls depends on the receptors CAR and PXR.

Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) represent a sub-group of persistent organic pollutants found in food, environmental samples and human and animal tissues. Promotion of pre-neoplastic lesions in rodent liver has been suggested as an indicator for a possible increased risk of liver cancer in humans exposed to NDL-PCBs. In rodent hepatocytes, suppression of DNA damage-triggered apoptosis is a typical mode of action of liver tumor promoters. Here, we report that NDL-PCBs suppress apoptosis in rat hepatocytes treated in culture with an apoptogenic dose of UV light. Suppression became less pronounced when the constitutive androstane receptor (CAR) and/or the pregnane-X-receptor (PXR) where knocked-out using siRNAs, while knocking-out both receptors led to a full reconstitution of apoptosis. In contrast, suppression of apoptosis by the CAR or PXR activators phenobarbital or dexamethasone were CAR- or PXR-specific. Induction and suppression of apoptosis were paralleled by changes in caspase 3/7, 8 and 9 activities. Our findings indicate that NDL-PCBs can suppress UV-induced apoptosis in rat hepatocytes by activating CAR and PXR. It needs further investigation if these mechanisms of action are also of relevance for human liver.