Project 4: Antioxidant Protection by Bilirubin in Arsenic Induced Toxicity

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.