Effects of 3,3’-Dichlorobiphenyl (PCB-11) on the expression of CYP2A, 2B, and 2F enzymes in the liver and brain of CYP2A6-humanized, CYP2B6-humanized, or wild-type mice

Abstract

<b>Abstract ID 28389</b> <b>Poster Board 221</b> Polychlorinated biphenyls (PCBs) are ubiquitous environmental pollutants that have been linked to adverse human health effects. Human exposure to PCBs occurs via dermal absorption, inhalation, and oral ingestion. Legacy PCBs are widely accepted developmental neurotoxicants that cause cognitive deficits. Cytochrome P450 enzymes metabolize PCBs to hydroxylated metabolites (OH-PCBs), some of which are more toxic than their parent compounds. PCB 11, a lower chlorinated (LC)-PCB, is one of the major PCB congeners detected in in contemporary human serum samples. The aim of this study is to test whether PCB 11 exposure induces the expression of P450 enzymes in the liver and the brain that may be involved in its PCB metabolism. The effects of PCB 11 on human CYP2A6 and CYP2B6 expression were studied using CYP2A6-humanized and CYP2B6-humanized mice, respectively, which are on a <i>Cyp2abfgs</i>-null background. The effects of PCB 11 on mouse CYP2A5, CYP2B10, and CYP2F2 expression were also examined in wild-type C57BL/6 mice. Mice were exposed to PCB 11 (500 μmol/kg b.w.) or peanut oil (vehicle control) via oral gavage. CYP expression at the mRNA and protein levels was examined 24 h after exposure, using qRT-PCR and western blot analysis, respectively. The results indicated that CYP2A6 expression was not induced by PCB 11 in the CYP2A6-humanized mouse model; in contrast, in the CYP2B6-humanized mouse model, PCB 11 increased CYP2B6 mRNA and protein levels in the liver by ∼11 and ∼2 times, respectively, but had no effect on CYP2B6 (mRNA) expression in the brain. In wild-type mice, PCB 11 induced hepatic CYP2A5 and CYP2B10, but not CYP2F2, and brain CYP2B10, but not CYP2A5, mRNA levels in female mice only. These results provide the basis for identifying potential PCB 11 exposure-induced changes in hepatic and brain PCB11 metabolism and OH-PCB metabolite levels and the relationship of these changes to neurotoxic outcomes following developmental exposures to PCB 11. supported in part by NIH grant ES014901