Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers.

The gut microbiome is a novel frontier in xenobiotic metabolism. Polybrominated diphenyl ethers (PBDEs), especially BDE-47 (2, 2', 4, 4'-tetrabromodiphenyl ether) and BDE-99 (2, 2', 4, 4',5-pentabromodiphenyl ether), are among the most abundant and persistent environmental contaminants that produce a variety of toxicities. Little is known about how the gut microbiome affects the hepatic metabolism of PBDEs and the PBDE-mediated regulation of drug-processing genes (DPGs) in vivo. The goal of this study was to determine the role of gut microbiome in modulating the hepatic biotransformation of PBDEs. Nine-week-old male C57BL/6J conventional (CV) or germ-free (GF) mice were treated with vehicle, BDE-47 or BDE-99 (100 µmol/kg) for 4 days. Following BDE-47 treatment, GF mice had higher levels of 5-OH-BDE-47 but lower levels of four other metabolites in liver than CV mice; whereas following BDE-99 treatment GF mice had lower levels of four minor metabolites in liver than CV mice. RNA sequencing demonstrated that the hepatic expression of DPGs was regulated by both PBDEs and enterotypes. Under basal conditions, the lack of gut microbiome upregulated the Cyp2c subfamily but downregulated the Cyp3a subfamily. Following PBDE exposure, certain DPGs were differentially regulated by PBDEs in a gut microbiome-dependent manner. Interestingly, the lack of gut microbiome augmented PBDE-mediated upregulation of many DPGs, such as Cyp1a2 and Cyp3a11 in mouse liver, which was further confirmed by targeted metabolomics. The lack of gut microbiome also augmented the Cyp3a enzyme activity in liver. In conclusion, our study has unveiled a novel interaction between gut microbiome and the hepatic biotransformation of PBDEs.

Occupational and dietary differences in hydroxylated and methoxylated PBDEs and metals in plasma from Puget Sound, Washington, USA region volunteers.

Electronic waste (E-waste) recycling is a rapidly growing occupation in the USA with the potential for elevated exposure to flame retardants and metals associated with electronic devices. We previously measured polybrominated diphenyl ethers (PBDEs) in plasma from E-waste workers and found them similar to non-E-waste workers. This study focused on structurally related PBDE derivatives, the hydroxylated (OH-PBDEs) and methoxylated (MeO-PBDEs) forms along with metals known to occur in E-waste. Humans can metabolize PBDEs and some MeO-PBDEs into OH-PBDEs, which is a concern due to greater health risks associated with OH-PBDEs. We measured 32 different OH-PBDEs and MeO-PBDEs in plasma samples provided by 113 volunteers living in the greater Puget Sound region of Washington State, USA. We measured 14 metals in a subset of 10 E-waste and 10 non-E-waste volunteers. Volunteers were selected based on occupational and dietary habits: work outdoors and consume above average amounts of seafood (outdoor), electronic waste recycling (E-waste) or non-specific indoor occupations (indoor). A two-week food consumption diary was obtained from each volunteer prior to blood sampling. OH-PBDEs were detected in all volunteers varying between 0.27 and 102 ng/g/g-lipid. The MeO-PBDEs were detected in most, but not all volunteers varying between n.d. - 60.4 ng/g/g-lipid. E-waste recyclers had OH-PBDE and MeO-PBDE plasma levels that were similar to the indoor group. The outdoor group had significantly higher levels of MeO-PBDEs, but not OH-PBDEs. Comparison of plasma concentrations of BDE-47 with its known hydroxylated metabolites suggested OH-PBDE levels were likely determined by biotransformation and at least two subpopulations identified differing in their apparent rates of OH-PBDE formation. The metals analysis indicated no significant differences between E-waste workers and non-E-waste workers. Our results indicate E-waste workers do not have elevated plasma levels of these contaminants relative to non-E-waste workers.

Polybrominated diphenyl ethers (PBDEs) in plasma from E-waste recyclers, outdoor and indoor workers in the Puget Sound, WA region.

Polybrominated diphenyl ethers (PBDEs) were widely used as flame retardants in consumer products including electronic devices. Important routes of human exposure are contaminated food and contact with dust. In this study, we measured twelve PBDEs in household/workplace dust and blood plasma samples provided by 113 volunteers living in the Puget Sound region, WA and working at electronic waste (E-waste) recycling sites (n = 29) or non-specific indoor (n = 57) or outdoor occupations (n = 27). The volunteers in the outdoor group were also selected because of a history of high seafood consumption habits. Results indicated the sum PBDE levels varied between <2.5 and up to 310 ng g-1 lipid. E-waste recyclers were predominantly men, generally consumed low amounts of seafood, and had PBDE blood levels (geometric mean, GM = 26.56 ng g-1 lipid) that were similar to indoor workers (GM = 27.17 ng g-1 lipid). The sum PBDE levels were highest in the outdoor group (GM = 50.63 ng g-1 lipid). Dust samples from E-waste sites were highly enriched with BDE-209 and BDE-153 relative to non-E-waste businesses and homes. The concentrations of these BDE congeners in dust at E-waste sites were ∼32-39 times higher than in dust from other sites. However, the detection rate of BDE-209 in plasma was low across all groups (13%) and no statistical comparisons were made. Our results suggest that E-waste recyclers in this study population did not have elevated PBDE levels in comparison to volunteers working in other types of occupations.

Polybrominated diphenyl ethers and their hydroxylated and methoxylated derivatives in seafood obtained from Puget Sound, WA.

Synthetic polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental contaminants and known to occur in most food items. Consumer fish products have been identified as having some of the highest PBDE levels found in USA food sources. Natural formation of hydroxylated (OH-) and methoxylated (MeO-) PBDEs are also known to occur in simple marine organisms, which may be bioaccumulated by seafood. In this study, we report findings of an initial survey of PBDE, OH-PBDE and MeO-PBDE content in common seafood items available to residents living in the Puget Sound region of Washington State. Seafood samples were either purchased from local grocery stores or caught off the coast of SE Alaska and in Puget Sound. The edible portions of the seafood were analyzed, which for finfish was white muscle (skinless fillets) and for shellfish, either the entire soft tissue (bivalves) or processed meat (calamari, shrimp and scallops). Results indicated that finfish typically had higher levels of PBDEs compared to shellfish with BDE-47 and BDE-99 as the most common congeners detected. Among shellfish, bivalves (clams and mussels) were notable for having much higher levels of OH- and MeO-PBDEs compared to other types of seafood with 6'-OH-BDE-47 and 2'-MeO-BDE-68 being the more common OH- and MeO- congeners, respectively. Based on our results and recent updates to daily fish consumption rates, estimated intake rates for Washington State residents will be between 34 and 644ngPBDEs/day, depending on species consumed. For the OH- and MeO- forms, daily exposure is much more variable but typically would range between 15 and 90ng/day for most seafood types. If shellfish are primarily consumed, OH-PBDE intake could be as high as 350ng/day. These daily intake rates for PBDEs are higher than most dietary intake rates calculated for populations in other world regions.