Metabolic changes associated with polybrominated biphenyls and polychlorinated biphenyls in the Michigan PBB registry

Background: Polybrominated Biphenyls (PBBs) and Polychlorinated Biphenyls (PCBs) are endocrine-disrupting chemicals (EDCs). In Michigan, people were exposed to PBBs during a time-limited contamination event in the 1970s and are continuously exposed to PCBs. Using high-resolution metabolomics (HRM), this study aimed to identify biological mechanisms underlying human health effects of PBB and PCB exposure. Methods: HRM profiling was conducted on serum samples from the Michigan PBB Registry collected from a subset of 500 individuals representing both F0 (directly exposed to PBB) and F1 (exposed through parents) generations from 2011 to 2014. This study measured PBB-153 stratified by generation and ƩPCB (PCB-118, PCB-138, PCB-153, and PCB-180) in the total combined subset (as all experienced direct PCB exposure). Metabolite and metabolic pathway perturbation were evaluated using an untargeted HRM workflow. Results: Both exposure measures had high detection levels. Mean levels were 1.75-ng/mL (SD: 13.9) for PBB-153 and 1.04-ng/mL (SD: 0.788) for ΣPCBs. 124 and 86 metabolomic features were significantly associated with PBB-153 in F0 and F1 (p<0.005), respectively. There were 2,861 features associated with ΣPCB (FDR corrected p<0.2). Pathway enrichment analysis revealed perturbations associated with ΣPCB in numerous oxidative stress and inflammation pathways (e.g., carnitine shuttle, glycosphingolipid, and vitamin B9 metabolism). Perturbations associated with PBB-153 in F0 were related to oxidative stress pathways (e.g., pentose phosphate and vitamin C metabolism) and in F1 were related to energy production (e.g., pyrimidine, aminosugars, and lysine metabolism). Authentic chemical standards were used to confirm the chemical identity of 29 metabolites associated with ΣPCB levels and 10 metabolites associated with PBB-153 levels. Conclusions: Our results demonstrated that serum PBB-153 and ΣPCB levels were associated with perturbations in inflammation and oxidative stress-related pathways, which differed when stratified by generation. These findings support future investigations of molecular mechanisms underlying PBB and PCB exposure on health, emphasizing exposure timing.