Assessing Metabolic Differences Associated with Exposure to Polybrominated Biphenyl and Polychlorinated Biphenyls in the Michigan PBB Registry

Background: Polybrominated biphenyls (PBB) and polychlorinated biphenyls (PCB) are persistent organic pollutants with potential endocrine-disrupting effects linked to adverse health outcomes.Objectives: In this study, we utilize high-resolution metabolomics (HRM) to identify internal exposure and biological responses underlying PCB and multigenerational PBB exposure for participants enrolled in the Michigan PBB Registry.Methods: HRM profiling was conducted on plasma samples collected from 2013 to 2014 from a subset of participants enrolled in the Michigan PBB Registry, including 369 directly exposed individuals (F0) who were alive when PBB mixtures were accidentally introduced into the food chain and 129 participants exposed to PBB in utero or through breastfeeding, if applicable (F1). Metabolome-wide association studies were performed for PBB-153 separately for each generation and Sigma PCB (PCB-118, PCB-138, PCB-153, and PCB-180) in the two generations combined, as both had direct PCB exposure. Metabolite and metabolic pathway alterations were evaluated following a well-established untargeted HRM workflow.Results: Mean levels were 1.75 ng/mL [standard deviation (SD): 13.9] for PBB-153 and 1.04 ng/mL (SD: 0.788) for Sigma PCB. Sixty-two and 26 metabolic features were significantly associated with PBB-153 in F0 and F1 [false discovery rate (FDR) p<0.2], respectively. There were 2,861 features associated with Sigma PCB (FDR p<0.2). Metabolic pathway enrichment analysis using a bioinformatics tool revealed perturbations associated with Sigma PCB in numerous oxidative stress and inflammation pathways (e.g., carnitine shuttle, glycosphingolipid, and vitamin B9 metabolism). Metabolic perturbations associated with PBB-153 in F0 were related to oxidative stress (e.g., pentose phosphate and vitamin C metabolism) and in F1 were related to energy production (e.g., pyrimidine, amino sugars, and lysine metabolism). Using authentic chemical standards, we confirmed the chemical identity of 29 metabolites associated with Sigma PCB levels (level 1 evidence).Conclusions: Our results demonstrate that serum PBB-153 is associated with alterations in inflammation and oxidative stress-related pathways, which differed when stratified by generation. We also found that Sigma PCB was associated with the downregulation of important neurotransmitters, serotonin, and 4-aminobutanoate. These findings provide novel insights for future investigations of molecular mechanisms underlying PBB and PCB exposure on health