Exposure To Arsenite During Fetal Development Increases Susceptibility To Fatty Liver Disease And Alters Hepatic Transport

Abstract

Arsenic is common metalloid that is found globally. Its ubiquitous nature means that large portions of the global population are exposed through a variety of pathways. Arsenic is a known human carcinogen and its role in the development of cardiovascular and metabolic disease has become more completely characterized in the past decades. However, the examination of arsenic exposure during embryonic development at relatively low level exposures is an emergent area where lots of questions remain unanswered. As arsenic is difficult and costly to remove from water, the investigation of exposures in vulnerable populations at relevant concentrations is necessary to justify remediation efforts. This dissertation work examines fetal arsenic metabolism contributing to the understanding of tissue specific arsenic effects during embryonic development. Following that, the focus shifts to fetal and early life exposure to arsenite at 100 parts per billion in drinking water (10 times higher than the EPA mandated limit in municipal water but common in well water globally) and how it contributes to the severity and incidence of diet-induced non-alcoholic fatty liver disease (NAFLD). NAFLD is the most prevalent chronic liver disease in the United States and it contributes to increased cardiovascular morbidity and mortality. NAFLD also results in alterations in hepatic drug metabolism and disposition which contributes to adverse drug reactions. We demonstrate similar effects in arsenic potentiated NAFLD in addition to changes in transporter expression with arsenic exposure alone independent of triglyceride accumulation associated with NAFLD. Taken together, this work highlights deleterious health effects of low level arsenic exposure during development and demonstrates the need for further investigation of developmental arsenic effects.