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 #
5P42ES010337-13
Application #
8659423
Study Section
Special Emphasis Panel ()
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
13
Fiscal Year
2014
Total Cost
$281,723
Indirect Cost
$99,967
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Fan, Weiwei; Evans, Ronald M (2017) Exercise Mimetics: Impact on Health and Performance. Cell Metab 25:242-247
Chen, Shujuan; Lu, Wenqi; Yueh, Mei-Fei et al. (2017) Intestinal NCoR1, a regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia. Proc Natl Acad Sci U S A 114:E1432-E1440
Lu, Wenqi; Rettenmeier, Eva; Paszek, Miles et al. (2017) Crypt Organoid Culture as an in Vitro Model in Drug Metabolism and Cytotoxicity Studies. Drug Metab Dispos 45:748-754
Reinders, Megan E; Wardi, Gabriel; Bettencourt, Ricki et al. (2017) Increased Risk of Death, in the Hospital and Outside the Intensive Care Unit, for Patients With Cirrhosis After Cardiac Arrest. Clin Gastroenterol Hepatol 15:1808-1810
Liu, Yuanli; Yu, Chuanbai; Cao, Zhixin et al. (2017) A Highly Sensitive Enzymatic Catalysis System for Trace Detection of Arsenic in Water. Chemistry 23:10289-10292
Vollmann, Elisabeth H; Cao, Lizhi; Amatucci, Aldo et al. (2017) Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing. Mol Ther Nucleic Acids 7:314-323
He, Nanhai; Fan, Weiwei; Henriquez, Brian et al. (2017) Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc Natl Acad Sci U S A 114:12542-12547
Shalapour, Shabnam; Lin, Xue-Jia; Bastian, Ingmar N et al. (2017) Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551:340-345
Yoda, Emiko; Paszek, Miles; Konopnicki, Camille et al. (2017) Isothiocyanates induce UGT1A1 in humanized UGT1 mice in a CAR dependent fashion that is highly dependent upon oxidative stress. Sci Rep 7:46489
Koyama, Yukinori; Wang, Ping; Liang, Shuang et al. (2017) Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis. J Clin Invest 127:1254-1270

Showing the most recent 10 out of 370 publications