Developmental exposure to Bisphenol A and susceptibility to liver injury

University Of Rhode Island, Kingston RI

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Abstract

? DESCRIPTION (provided by applicant): Hepatic detoxification of chemicals and drugs from the body is accomplished by the hepatocytes via hepatic biotransformation and biliary excretion. ATP-binding cassette, sub-family C (CFTR/MRP), member 2 (ABCC2, aka MRP2), is a membrane-bound efflux transporter that transports organic anions out of the hepatocytes and into bile, playing critical role in this process. Numerous environmental chemicals, drugs, and endogenous metabolites are ABCC2 substrates. Disruption of ABCC2 function leads to disrupted bile flow, drug disposition, and drug-induced liver injury. We will be utilizing bispheno A (BPA), a plastics component, as a tool to understand how early life exposure to affects hepatic biliary excretion later in life. Our data illustrate that BPA exposure during gestation and lactation decreased liver ABCC2 expression and hepatic function of adult males that were >135 days old, which had no BPA exposure after weaning via increased histone deacetylase 2 (Hdac2) and decreased acetylated Histone H3 at the mouse ABCC2 promoter. In this proposal, we seek to ask whether our observation with BPA exposure has a toxicological consequence to liver and better understand whether modulation of ABCC2 and Hdac2 expression/function can restore the observed decrease in biliary excretion. We hypothesize that BPA exposure decreases biliary expression via down regulation of ABCC2 promoter activity via Hdac2 and Nrf2-dependent mechanisms. The observed decrease in biliary excretion increases susceptibility to hepatotoxicants that undergo biliary excretion. Specific Aim 1 will characterize the role of ABCC2 in adult liver excretion after perinatal BPA exposure. First, we will test whether restoration of ABCC2 protein expression in adult male progeny will restore the observed decrease in biliary excretion caused by developmental BPA exposure. We will next test whether perinatal BPA exposure alters susceptibility of adult male progeny to liver injury induced by hepatotoxicants. Specific Aim 2 will characterize whether of NRF2 and histone deacetylase 2 increase Abcc2 expression and can restore biliary excretion. Our BPA exposure model elucidated that BPA increases Hdac2 association at the mouse ABCC2 promoter. We will further determine whether Hdac2 is a modulator of ABCC2 expression in this model through genetic and pharmacological approaches and whether forced expression of NRF2 can restore ABCC2 expression and bile flow. Outcome: This work will significantly impact the field of liver health - demonstrating: 1) hepatic biliary function via ABCC2 is susceptible to reprogramming by chemical exposure, 2) early life exposure changes susceptibility to liver injury later in life, ) Identify Hdac2 as a potential target to restore bile flow. AREA impact: This project will provide an excellent intellectual and technical training environment for undergraduates and enhance the research capacity at the University of Rhode Island.