Association between CYP2A6 genetic variants and serum concentrations of highly persistent OH-PCBs and their parent...

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants, whose hydroxylated metabolites (OH-PCBs) accumulate in humans and may exhibit more potent effects than their parent compounds. This study investigated serum concentrations of several persistent OH-PCBs and their parent PCBs in 129 Japanese participants, with a focus on the influence of the CYP2A6*4 gene deletion variant on OH-PCB formation in PCB metabolism. Blood samples (n = 129) were genotyped for CYP2A6 (*1, *4, *7, and *9) and CYP2B6 variants. OH-PCBs and PCBs were quantified by gas chromatography-mass spectrometry. Concentrations and metabolite-to-parent ratios were compared among three CYP2A6 genotype groups (*1/*1 as wild-type, *1/*4, *4/*4; n = 49) and multiple linear regression evaluated associations between CYP2A6 genotype and OH-PCB/PCB ratios, adjusting for CYP2B6 genotype, age, and body mass index. Jonckheere-Terpstra trend test showed significant genotype-dependent decreasing trends in metabolite-to-parent ratios of four of the six OH-PCBs to their parent PCBs (3'-OH-PCB138, 4-OH-PCB146, 3-OH-PCB153, 4-OH-PCB187). In multiple linear regression, carriers of CYP2A6 *4 showed significantly lower ratios for 3-OH-PCB153 to PCB-153 (β = -0.304 per *4 allele, 95 % CI: [-0.496, -0.112], p = 0.003) and 4-OH-PCB187 to PCB-187 (β = -0.093, 95 % CI: [-0.175, -0.011], p = 0.028). No significant decreasing trends were observed for other OH-PCBs after adjustment. In conclusion, the CYP2A6*4 loss-of-function variant is associated with reduced metabolic conversion of certain PCBs to OH-PCBs, suggesting that CYP2A6 genetic variation may modulate individual susceptibility to the health risks of PCB exposure.