Epigenetic mechanisms linking in utero cadmium exposure to hepatic steatosis

点击翻译按钮获取中文摘要

PROJECT SUMMARY The goal of this application is to facilitate the transition of the candidate to an independent environmental health science (EHS) researcher. His long-term career goal is to apply his skills in developmental biology and epigenetics to EHS, building a research program focused on the epigenetic mechanisms through which developmental exposures affect life-long health. His short-term goal is to train in mechanisms of toxicant- induced pathology and modeling human exposures in the mouse. He will capitalize on the EHS environment at NCSU, including the Center for Human Health and the Environment (CHHE; funded by an NIEHS P30) and the NIEHS T32 Training Grant. Key elements of the career development plan include support from a diverse committee, with expertise relating to all aspects of the proposal, spanning toxicology, genomics, environmental epigenetics and population health science. The candidate will participate in the course `Molecular & Biochemical Toxicology', present at meetings, and organize an environmental epigenetics workshop. The candidate's research project integrates with his career goals and training program. He will use epigenetics tools that have not been widely adopted by the EHS community, to demonstrate their value to the field. The project will determine if in utero exposure to environmentally-relevant doses of cadmium (Cd) can program hepatic steatosis, and will determine how epigenetic changes affect the transcription of genes regulating hepatic lipid metabolism. The project will focus on imprinted genes, expressed from only one allele, which are epigenetically modified by Cd and are critical regulators of liver lipid storage. The hypothesis is that in utero Cd exposure in mice disrupts DNA methylation at imprinting control regions, causing dysregulation of a network of imprinted genes, which contributes to the programming of hepatic steatosis in adulthood. To address this, a genetic model will be used that enables studies of imprinted genes not possible with standard mouse models. The specific aims are: Aim 1: Determine if in utero Cd exposure is sufficient to program hepatic steatosis in the fetus and in adulthood. Aim 2: Determine whether Cd-induced DNA methylation changes at imprinting control regions disrupt allele-specific transcription of the imprinted gene network during in utero development, contributing to the pathophysiological effects of Cd exposure. The long-term objective is to establish a mouse model of human in utero exposure to understand how low doses of Cd program adult disease. The mechanisms of action of Cd are poorly defined, and the study is therefore relevant to the mission of the NIEHS. While the focus of this proposal will be on epigenetic changes in hepatoblasts and hepatocytes, which are most relevant to the study of steatosis, we will determine whether these changes are reflected in peripheral blood, which will be important for the identification of biomarkers in accessible tissues. The application includes an integrated career development and research plan, enabling the candidate to apply his existing skills to EHS to develop a niche that is competitive for NIEHS R01 funding.