Lehmler, H.-J. | bioRxiv Science

bioRxiv2018

Atropselective Oxidation of 2,2′,3,3′,4,6′-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes: Involvement of Arene Oxide Intermediates

PCBs and their hydroxylated metabolites have been associated with neurodevelopmental disorders. Several neurotoxic congeners display axial chirality and atropselectively affect cellular targets implicated in PCB developmental neurotoxicity; however, only limited information is available regarding the metabolism of these congeners in humans. We hypothesize that the oxidation of 2,2',3,3',4,6'-hexachlorobiphenyl (PCB 132) by human liver microsomes (HLMs) is atropselective and displays inter-individual variability. To test this hypothesis, PCB 132 (50 M) was incubated with pooled or single donor HLMs for 10, 30 or 120 min at 37 {degrees}C, and levels and enantiomeric fractions of PCB 132 and its metabolites were determined gas chromatographically. The major metabolite formed by different HLM preparations was either 2,2',3,4,4',6'-hexachlorobiphenyl-3'-ol (3'-140) or 2,2',3,3',4,6'-hexachlorobiphenyl-5'-ol (5'-132). 2,2',3,3',4,6'-Hexachlorobiphenyl-4'-ol (4'-132) and 2,2',3,3',4,6'-hexachlorobiphenyl-4',5'-diol (4',5'-132) were minor metabolites. The second eluting atropisomer of PCB 132 was slightly enriched in some HLM incubations. The formation of the first eluting atropisomer of 3'-140 was nearly enantiospecific (EF > 0.8). The second eluting atropisomer of 5'-132 was enriched in all microsomal preparations investigated. EF values differed slightly between single donor HLM preparations (EF = 0.84 to 0.96 for 3'-140; EF = 0.12 to 0.19 for 5'-132). These findings suggest that there are inter-individual differences in the atropselective biotransformation of PCB 132 to OH-PCBs in humans that may affect neurotoxic outcomes.

pharmacology and toxicology↗

bioRxiv2017

Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect susceptibility to developmental polychlorinated biphenyl exposure in mice: Relevance to studies of human neurological disorders

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with the discovery of new sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but there is some evidence that high PCB exposure in adults increases the risk of Parkinsons disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect susceptibility to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity AhrbCyp1a2(-/-) mice were most susceptible compared with poor-affinity AhrdCyp1a2(-/-) and wild type AhrbCyp1a2(+/+) mice. Our follow-up studies assessed biochemical, histological and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in multiple tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated immune suppression with reduced thymus and spleen weights and significantly reduced thyroxine at P14. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented in Cyp1a2(-/-) mice. In contrast, we found no difference in tyrosine hydroxylase immuno-staining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinity AhrdCyp1a2(-/-) while AhrbCyp1a2(+/+) mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinsons disease.

pharmacology and toxicology↗