Epigenetic Regulation of Drug Metabolism by Developmental Exposure to PBDEs

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 DESCRIPTION (provided by applicant): Developmental exposure to the flame-retardant polybrominated diphenyl ethers (PBDEs) has attracted growing concerns recently, because these highly persistent environmental toxicants are accumulated much more in infants through breast milk, and produce multiple detrimental effects. Although a growing body of research has been done regarding the toxicities of PBDEs themselves, little is known about the potential involvement of PBDEs in modulating the pharmacokinetics of drugs in newborns and children, who are at a much higher risk of adverse drug reactions. More importantly, there is no information regarding whether developmental exposure to PBDEs produces long lasting modifications of drug metabolism beyond childhood. We and others have identified that PBDEs are novel activators of the major xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive and rostane receptor (CAR). Neonatal activation of CAR results in epigenetic memory on histone methylation signatures and permanent change of drug metabolism in mouse liver, whereas PXR also regulates distinct epigenetic modifiers. Thus the objective of this research is to utilize multidisciplinary approaches to strategically investigate he epigenetic mechanisms of PBDEs in modulating the transcriptional activities of PXR and CAR and drug-processing capacities during and beyond the neonatal period on a genome-wide scale. Our central hypothesis is: neonatal exposure to PBDEs activates CAR and/or PXR, which in turn reprograms the ontogeny of critical chromatin epigenetic modifiers (such as DNA and histone methylation as well as histone acetylation), leading to epigenetic memory and altered ontogeny of drug-processing genes (DPGs), and long-term alterations in the pharmacokinetics and toxicokinetics beyond childhood. We will test this hypothesis in 3 specific aims: Aim 1 will use xeno-sensor null mice and second- generation sequencing to determine the roles of PXR and CAR in modulating the chromatin epigenetic signatures and expression of DPGs following neonatal exposure to PBDEs; Aim 2 will determine the effect of silencing key chromatin epigenetic modifiers on the expression of PXR- and CAR-target genes in PBDE- treated primary hepatocytes; Aim 3 will determine the role of neonatal PBDE exposure in modulating xeno- sensor activities, chromatin epigenetic signatures, expression of DPGs, and pharmacokinetics of drugs in xeno-sensor humanized mice and human hepatocytes. We will also examine the species-differences in PXR and CAR in response to PBDE exposure. Overall, the proposed work will unveil for the first time critical epigenetic and PXR/CAR-mediated mechanisms underlying PBDE-mediated regulation of drug metabolizing enzymes and transporters in newborns, and more importantly, determine the potential long-term effects caused by neonatal PBDE exposure on epigenetic memory and drug-processing capacities in adults. Our study is a paradigm shift in pediatric pharmacology, and will provide the first mechanistic investigations of PBDE-mediated modulation of drug metabolism and transport in newborns on a genome-wide scale.