Enantiomeric Fractions Reveal Differences in the Atropselective Disposition of 2,2,3,5,6-Pentachlorobiphenyl (PCB 95) in Wildtype, Cyp2abfgs-Null, and CYP2A6-Humanized Mice

Polychlorinated biphenyls (PCBs) are environmental contaminantsthat can cause neurotoxicity. PCBs, such as PCB 95 (2,2 & PRIME;,3,5 & PRIME;,6-pentachlorobiphenyl),can be metabolized by cytochrome P450 enzymes into neurotoxic metabolites.To better understand how the metabolism of PCB 95 affects neurotoxicoutcomes, we conducted a study on the disposition of PCB 95 in transgenicmouse models. The mice were given a single oral dose of PCB 95 (1.0mg/kg) and were euthanized 24 h later for analysis. PCB 95 levelswere highest in adipose tissue, followed by the liver, brain, andblood. Adipose tissue levels were significantly higher in wild-type(WT) mice than in Cyp2abfgs-null (KO) or CYP2A6-transgenic (KI) mice.We also observed genotype-dependent differences in the enrichmentof aS-PCB 95 in female mice, with a less pronounced enrichment inKO than WT and KI mice. Ten hydroxylated PCB 95 metabolites were detectedin blood and tissue across all exposure groups. The metabolite profilesdiffered across tissues, while sex and genotype-dependent differenceswere less pronounced. Total OH-PCB levels were highest in the blood,followed by the liver, adipose tissue, and brain. Total OH-PCB bloodlevels were lower in KO than in WT mice, while the opposite trendwas observed in the liver. In male mice, total OH-PCB metabolite levelswere significantly lower in KI than in WT mice in blood and the liver,while the opposite trend was observed in female mice. In conclusion,the study highlights the differences in the atropselective dispositionof PCB 95 and its metabolites in different types of mice, demonstratingthe usefulness of these transgenic mouse models for characterizingthe role of PCB metabolism in PCB neurotoxicity.