Bioactivation of PBDEs by Human Cytochrome P-450

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DESCRIPTION (provided by applicant): During the past decade both animal and human studies have supported an association between polybrominated diphenyl ether (PBDE) flame retardants and neurobehavioral / neurodevelopmental disorders, particularly following in utero and postnatal exposure. Recently, hydroxylated metabolites of PBDEs (OH- PBDEs) have been found to accumulate in human serum at levels similar to and in some cases greater than that of the parent PBDEs. The significance of this finding is heightened by mechanistic studies showing that OH-PBDEs are often more potent than parent compounds and contribute substantially to neurodevelopmental disorders via direct neurotoxicity involving dysregulation of Ca2+ signaling and/or indirectly through altered thyroid disruption. Together, these and other studies suggest that bioactivation by oxidative metabolism adds considerably to the neurotoxic potential of PBDEs. Thus, there is a critical need to further our understanding of PBDE metabolism in humans. The overall objectives of this application are to characterize the enzyme- and congener-specific metabolism of PBDEs in humans and investigate qualitative and quantitative differences in metabolism which are related to genetic variability in key biotransforming enzymes. We have recently found that 2,2',4,4'-tetra-(BDE-47) is metabolized specifically by human cytochrome P-450 2B6 (CYP2B6), which is known to exhibit up to 100-fold variability in hepatic protein expression, due to regulatory phenomena and common genetic polymorphisms. Thus, it is hypothesized that in addition to variable exposures, genetic variability in the CYP-specific metabolism of PBDEs contributes to interindividual variability in the body burden of PBDEs and the formation of toxic metabolites. The following aims will address this hypothesis and generate critical human data on the congener-specific metabolism of PBDEs. Aim 1 will conduct a qualitative and quantitative characterization of the human CYP-specific in vitro metabolism of 2,2',4,4'-tetra-(BDE-47), 2,2',4,5'-tetra-(BDE-49), 2,2',4,4',5-penta-(BDE-99), and 2,2',4,4',6- penta-(BDE-100), which are the most abundant congeners in humans, and are susceptible to metabolism that forms potentially toxicologically active metabolites. Interindividua variability in the in vitro metabolism of PBDEs will be assessed utilizing both human liver microsomes, with up to a 100-fold range in the level of CYP2B6 activity, and recombinant polymorphic variants of human CYP2B6. Aim 2 will identify and quantify OH-PBDEs in human milk and serum, and assess the potential impact of CYP2B6 genotype on the body burden of PBDEs which was previously found to vary by over a 100-fold in these subjects. The proposed studies will ultimately better inform future mechanistic and epidemiological studies investigating the potential of PBDEs and their metabolites to produce neurodevelopmental disorders. In addition, these studies will lead to the identification of potential genetic biomarkers that contribute to interindividual variability in the bioactivation of PBDEs and ultimately the relative susceptibility of individuals to potential adverse effects of these agents.