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 contaminants that can cause neurotoxicity. PCBs, such as PCB 95 (2,2′,3,5′,6-pentachlorobiphenyl), can be metabolized by cytochrome P450 enzymes into neurotoxic metabolites. To better understand how the metabolism of PCB 95 affects neurotoxic outcomes, we conducted a study on the disposition of PCB 95 in transgenic mouse models. The mice were given a single oral dose of PCB 95 (1.0 mg/kg) and were euthanized 24 h later for analysis. PCB 95 levels were highest in adipose tissue, followed by the liver, brain, and blood. 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 enrichment of aS-PCB 95 in female mice, with a less pronounced enrichment in KO than WT and KI mice. Ten hydroxylated PCB 95 metabolites were detected in blood and tissue across all exposure groups. The metabolite profiles differed across tissues, while sex and genotype-dependent differences were less pronounced. Total OH-PCB levels were highest in the blood, followed by the liver, adipose tissue, and brain. Total OH-PCB blood levels were lower in KO than in WT mice, while the opposite trend was observed in the liver. In male mice, total OH-PCB metabolite levels were 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 disposition of PCB 95 and its metabolites in different types of mice, demonstrating the usefulness of these transgenic mouse models for characterizing the role of PCB metabolism in PCB neurotoxicity.


Table of Contents
Chemicals S3 Table S1. Unique chemical identifiers of the analytical standards used in this study. S4 Table S2. Summary of animal body weights and tissue weights organized by sex and exposure.
S5 Table S3. Method detection limits (ng) and limits of detection (ng/g tissue) of the gas chromatographic quantification of PCB 95 and its metabolites.
S6 Table S4. Percent recoveries for surrogate recovery standards using liquid-liquid (LLE) or pressurized liquid extraction (PLE) for the analysis of PCB 95 and its hydroxylated metabolites in blood and tissue samples.
S7 Table S5. Table S5. Percent recovery of the Ongoing Precision and Recovery standards (i.e., PCB 95 and its available hydroxylated metabolites) in method blanks and tissue blanks using liquid-liquid (LLE) or pressurized liquid extraction (PLE) extraction procedures.
S8 Table S6. Levels of PCB 95 and its hydroxylated metabolites in adipose, blood, brain, and liver tissue (ng/g tissue).
S4 Table S1. Unique chemical identifiers of PCB and PCB metabolites discussed in this study.