The Role of the mTOR Pathway in Developmental Reprogramming of Hepatic Lipid Metabolism and the Hepatic Transcriptome After Exposure to 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47)

By Joseph Paul McGaunn
iCons Year 4
Joseph McGaunn Senior Thesis
Executive Summary 

An emerging hypothesis links the epidemic of metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD) and diabetes with chemical exposures during development. Evidence from our lab and others suggests that developmental exposure to environmentally prevalent flame-retardant BDE47 may permanently reprogram hepatic lipid metabolism, resulting in an NAFLD-like phenotype. Additionally, we have demonstrated that BDE-47 alters the activity of both mTOR complexes (mTORC1 and 2) in hepatocytes. The mTOR pathway integrates environmental information from different signaling pathways, and regulates key cellular functions such as lipid metabolism, innate immunity, and ribosome biogenesis. Thus, we hypothesized that the developmental effects of BDE-47 on liver lipid metabolism are mTOR-dependent. To assess this, we generated mice with liver-specific deletions of mTORC1 or mTORC2 and exposed these mice and their respective controls perinatally to BDE-47. We found that developmental exposure to BDE-47 permanently reprograms gene expression related to hepatic lipid metabolism, innate immunity, and other key cellular functions in an mTORC1- and 2-dependent manner. Our results also provide a hypothetical model of gene-environment interaction in which early-life BDE-47 exposure triggers life-long reprogramming of liver lipid metabolism and other key cellular functions in an mTOR-dependent manner, and indicate that modulation of the mTOR pathway by environmental chemicals such as BDE-47 may lead to long-lasting changes in liver disease susceptibility.

Problem Keywords 
flame retardant
fatty liver disease
molecular biology
Scientific Keywords 

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