Superfund site xenobiotics and other environmental toxicants are human health hazards whose toxicity is, in part, associated with altered patterns of gene expression. The goal of this project is to provide molecular mechanisms and models for exposure, focusing on the """"""""classic"""""""" xenobiotic receptors (XenRs) PXR and CAR, and their induction of gene networks encoding the Phase I, II and III clearance pathways. Accordingly, to define the chemical space of XenRs in response to environmental toxins, in Aim II we will initiate a comparative chemical library screen using high throughput (HT) cell based luciferase reporter assays. Recently, we have determined that the nuclear receptor ERalpha is capable of responding to anticoagulants, antibacterial and anti-inflammatory drugs thus identifying it as a candidate xenobiotic sensor. Therefore as part of this Aim we will include ERalpha in the above XenRs screen. Some of our HT screens will include extracts gathered from Superfund sites by the Research Translation Core. Comparative gene expression studies will be conducted in Aim II to establish the overlap of ERalpha dependent gene regulation with known PXR and CAR target genes. The in vivo relevance will be established using a humanized hPXR/hCAR reporter mouse.
In Aim III we will determine how XenRs control the xenobiotic response at the genome-wide level. Chromatin immunoprecipitation coupled with massively parallel deep sequencing (ChlPSeq) will be used to identify PXR, CAR and ERalpha cistromes, before and after treatment with high affinity agonists to reveal unique and common (core) xenobiotic networks. The aggregate binding sites will comprise a """"""""xenobiotic cistrome"""""""". Finally, in Aim I, we describe a new HT screening platform called NHR Transcriptional Promoter Ontology which allows us to explore xenobiotic regulation by all human NHRs (+/- ligands) by screening against a panel of ~300 drug metabolism reporter constructs comprised of P450 and conjugation enzyme and transporter sets. This is a unique opportunity to redefine the molecular basis of NHR-xenobiotic regulation and will provide a new roadmap for future study. We will collaborate with the Research Translation Core and Community Engagement Core to share this work with our SRP tribal science partners, industry, EPA, and ATSDR.
This proposal is directed at developing and implementing new scientific approaches to identify the transcriptional regulatory responses elicited by xenobiotics and pollutants found at Superfund sites. Our studies will provide advanced insight into the molecular mechanisms that lead to environmental illness and dramatically improve our understanding of the consequences of exposure to Superfund contaminants.
|Wall, Christopher E; Yu, Ruth T; Atkins, Anne R et al. (2016) Nuclear receptors and AMPK: can exercise mimetics cure diabetes? J Mol Endocrinol 57:R49-58|
|Liu, Weilin; Struik, Dicky; Nies, Vera J M et al. (2016) Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 113:2288-93|
|Hirashima, Rika; Michimae, Hirofumi; Takemoto, Hiroaki et al. (2016) Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity. Mol Pharmacol 90:265-74|
|Park, Charlie C; Nguyen, Phirum; Hernandez, Carolyn et al. (2016) Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients with Biopsy-proven Nonalcoholic Fatty Liver Disease. Gastroenterology :|
|Guo, Lan; Ganguly, Abantika; Sun, Lingling et al. (2016) Global Fitness Profiling Identifies Arsenic and Cadmium Tolerance Mechanisms in Fission Yeast. G3 (Bethesda) 6:3317-3333|
|Karin, Michael; Dhar, Debanjan (2016) Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2. Carcinogenesis 37:541-6|
|Booth, D R; Ding, N; Parnell, G P et al. (2016) Cistromic and genetic evidence that the vitamin D receptor mediates susceptibility to latitude-dependent autoimmune diseases. Genes Immun 17:213-9|
|Umemura, Atsushi; He, Feng; Taniguchi, Koji et al. (2016) p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells. Cancer Cell 29:935-48|
|Liu, Miao; Chen, Shujuan; Yueh, Mei-Fei et al. (2016) Cadmium and arsenic override NF-ÎºB developmental regulation of the intestinal UGT1A1 gene and control of hyperbilirubinemia. Biochem Pharmacol 110-111:37-46|
|Hsin, I-Fang; Montano, Erica; Seki, Ekihiro (2016) Finding a new role for NEMO: A key player in preventing hepatocyte apoptosis and liver tumorigenesis by inhibiting RIPK1. Hepatology 64:295-7|
Showing the most recent 10 out of 331 publications