Phthalate Mixture induced Epigenetic Regulations in Adipose Tissues

PROJECT SUMMARY: Exposure to environmental chemicals has adverse effects on the health and survival of humans. Emerging evidence supports the idea that exposure to endocrine disrupting chemicals can perturb an individual’s metabolic set point and as a result, increase the individual’s propensity towards metabolic diseases. Recent evidence also suggests that environmental factors can regulate epigenetic modifications resulting in type 2 diabetes and obesity (together called “diabesity”) or other metabolic diseases. Even though over-nutrition is an important factor in the development of metabolic syndrome, there is an emerging hypothesis that several chemicals including a group of plasticizers called 'phthalates' may play a role in enhancing this epidemic of disordered intermediary metabolism. More than 18 billion pounds of phthalates are used worldwide each year, with humans being exposed daily. However, evidence for their mechanisms of action have not been elucidated. The Choudhury lab recently demonstrated that benzyl butyl phthalate exposure causes metabolic aberrations in vivo. However, phthalates regulation of an epigenetic modifier histone deacetylase Sirt3, which has been shown to play a significant role in the development of metabolic syndrome due to over-nutrition, is not known. Furthermore, no studies have been reported investigating the phthalates-induced interactive epigenetic events regulating metabolic abnormalities. Therefore, there is a critical need to investigate the effect of phthalates in the development of metabolic dysfunction and their effects on epigenetic regulation of Sirt3 in vivo using more than a single dose. This is important due to high human exposure to phthalates particularly because it currently is not possible to eliminate phthalate exposure. The long-term goal is to understand how environmental contaminants program epigenetic fetal metabolic pathways, how these changes may persist after birth and increase susceptibility to adult metabolic disease, and identify clinical targets. The central hypothesis of the proposed research is that an environmentally relevant phthalate mixture causes insulin resistance and mitochondrial dysfunction through miRNA-lncRNA-Sirt3 mechanisms that involve sex-specific effects on various adipose tissues and a rationally designed mitigation strategy can prevent or treat phthalate induced metabolic dysfunction. To test this hypothesis, following three Specific Aims will be carried out: 1) Determine the effects of adult and in utero exposure to an environmentally relevant phthalate mixture (MIX) on Sirt3 regulation in adipose tissues. 2) Identify the effects of an environmentally relevant phthalate mixture (MIX) on miRNA-lncRNA regulation in the adult and offspring’s adipose tissues. 3) Determine the adverse metabolic effect of exposure to an environmentally relevant phthalate mixture (MIX) on insulin signaling and potential reversal of the phthalate-induced effects. This hypothesis-driven proposal addresses the novel idea that a mixture of phthalates regulates epigenetic mechanisms of diabesity using innovative approaches at the molecular, organ/tissue, and whole animal levels.