Effect of Pregnancy on the Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers and Their Hydroxylated Metabolites in Female Mice

Abstract

Chiral PCBs, such as PCB 95, are developmental neurotoxicants that undergo atropisomeric enrichment in non-pregnant, adult mice. Because pregnancy is associated with changes in hepatic cytochrome P450 enzyme activity as well as lipid disposition and metabolism, this study investigates the effect of pregnancy on the maternal disposition of chiral PCBs. Female C57Bl/6 mice (8 weeks old) were dosed daily beginning 2 weeks prior to conception and continuing throughout gestation and lactation (56 days total) with racemic PCB 95 (0, 0.1, 1.0 or 6.0 mg/kg body wt/day) in peanut butter. Levels and chiral signatures of PCB 95 and its hydroxylated metabolites (OH-PCBs) were determined in adipose, blood, brain and liver. Tissue levels of PCB 95 increased 4 to 12 fold with increasing dose, with considerable enrichment of the second eluting atropisomer in all tissues (EF range 0.11 to 0.26). OH-PCBs displayed atropisomeric enrichment in blood and liver, but were not detected in adipose and brain. Levels of PCB 95 and its metabolites were 2 to 11 fold lower in pregnant dams relative to those previously reported in non-pregnant age-matched female mice; however, PCB 95 and OH-PCB profiles and chiral signatures were similar between both studies. In contrast, human brain samples contained racemic PCB 95 residues (EF=0.50). These results demonstrate that changes in cytochrome P450 enzyme activity and lipid disposition during pregnancy reduce the PCB body burden in dams, but do not affect metabolite profiles or chiral signatures. The differences in chiral signatures between mice and humans suggest species-specific differences in atropisomeric disposition, the toxicological significance of which remain to be determined.

Polychlorinated Biphenyls (PCBs): Risk Factors for Autism Spectrum Disorder?

“…Further complicating the interpretation of the impact of metabolism on PCB developmental neurotoxicity, studies in mice have shown that not only can the tissue distribution of parent PCBs and their metabolites differ, but for chiral PCBs, which includes many RyR-active PCBs, the enantiomeric enrichment of parent versus metabolites can differ in a tissue-specific manner [98]. Furthermore, PCB metabolism can be altered by pregnancy [99]. These studies highlight the need for a better understanding of how the biotransformation of PCBs contributes to overall NDD risk.…”

Sources and toxicities of phenolic polychlorinated biphenyls (OH-PCBs)

“…This observation is not surprising given the diversity of expression of cytochrome P-450 enzymes across species. In vivo studies also reveal the formation of chiral OH-PCB metabolites in rats (Kania-Korwel et al 2008c) and mice (Kania-Korwel et al 2015, Kania-Korwel et al 2012, Kania-Korwel et al 2017, Wu et al 2015) exposed orally or intraperitoneally to a racemic PCB congener. There is also evidence that plants, such as poplar plants, metabolize chiral PCBs to chiral OH-PCB metabolites (Ma et al 2016, Zhai et al 2011a).…”

2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Is Atropselectively Metabolized to para-Hydroxylated Metabolites by Human Liver Microsomes

“…18 Studies in pregnant mice exposed to PCB 95 during gestation and lactation showed no detectable levels of 4′-95 in the blood and liver of the dams. 8 …”