Arsenic is one of the world's most ubiquitous environmental toxicants, with humans being exposed from air, food and water. However, elevated arsenic levels in drinking water are the major cause of toxicity, and are a health issue in many of the communities in this country that are in proximity to Superfund sites. Chronic arsenic toxicity and the health issues linked to exposure have been termed arsenicosis by the World Health Organization, with toxicity being seen from skin manifestations to liver fibrosis and cancer. A prevailing theory in arsenic toxicity is its ability to induce oxidative stress, which then initiates cellular and molecular changes leading to tissue damage. Using new animal models that show sustained elevations in serum bilirubin, a potent and natural antioxidant, experiments will be conducted in collaboration with our SRP research colleagues to examine the impact of bilirubin induced antioxidant protection on the development of arsenic induced liver fibrosis and hepatocellular carcinoma (HCC). Steady-state levels of serum bilirubin are maintained by UDP-glucuronosyltransferase IAI (UGT1A1) metabolism. By modifying the expression levels of UGT1A1 in humanized UGT1 mice or through conditional deletion ofthe liver Ugt1 locus, the steady-state levels of serum bilirubin can be reset in both neonatal and adult mice, allowing us to investigate the actions of arsenic in inducing cellular programs responsible for gene expression, fibrosis and HCC. We will characterize the cellular and molecular actions of arsenic in humanized UGT1 (hUGTI) mice where it is shown that oral arsenic intake to neonatal mice dramatically induces intestinal UGT1A1 leading to a reversal in neonatal hyperbilirubinemia. These studies will provide new molecular mechanisms on the potential oxidative actions of acute oral arsenic exposure on induction of the human UGT1A1 gene. We will utilize a new conditional knockout model of the murine Ugtl locus showing elevated bilirubin levels when the Ugt1 locus is deleted in liver, generating UgtlAIHEP mice. In collaborations with Drs. Karin and Seki, antioxidant protection initiated by hUGTI mice expressing the promoter defective UGT1A1*28 allele and UgtIAHEP mice will be used in combination to examine the contribution of elevated serum bilirubin towards preventing genetically induced oxidative damage and arsenic initiated liver fibrosis and cancer. These studies will culminate in a more complete understanding of molecular and epigenetic effects of antioxidant protection on arsenic induced liver toxicity and disease.

Public Health Relevance

Oxidative induced tissue damage by environmental toxicants is a leading indicator of environmentally induced diseases. The development of these novel animal models showing heightened and naturally producing antioxidant protection will allow studies to conclude if oxidative damage is a leading indicator of toxicant tissue damage and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES010337-12
Application #
8463185
Study Section
Special Emphasis Panel (ZES1-JAB-J)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
12
Fiscal Year
2013
Total Cost
$277,369
Indirect Cost
$109,249
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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-κB 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

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