Carchia, Emanuele (2014) Toxicogenomics in the analysis of Endocrine Disrupting Chemicals effects on pancreatic islet Function: the bisphenol A case. [Tesi di dottorato]

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Abstract

Bisphenol A (BPA) is widely used in plastic products. It is classified as an Endocrine Disrupting Chemical and has been associated to several endocrine-related disorders. The widespread exposure and the health effects are of concern. Epidemiological studies and in vivo and in vitro experiments correlate the BPA exposure to alterations of pancreatic islets, liver and adipose tissue functions. Given these data, its prevalence in the environment and the presence in serum from humans worldwide, BPA may play a role in the rapid increase of incidence of metabolic disorders. In this work we studied the effects of low doses of BPA on ex vivo primary murine pancreatic islets through a toxicogenomical approach. We found, through trascriptome analysis,that BPA is able to alter the expression of specific genes involved in mitochondrial functions, ROS detoxification and insulin exocytosis signal generation. Moreover, we demonstrated that BPA exposure impairs islets viability and promotes apoptosis in dose-dependent manner. Finally, we assessed that this apoptosis triggering is due to a BPA-dependent increase of ROS that activate the NFkB pathway. Taken together, our results suggest that exposure to low doses of BPA interferes with mitochondrial functions, which, in turn, leads to intracellular ROS increase, NFkB pathway activation and, finally, to apoptosis. Therefore, this work confirms the detrimental effects of BPA on pancreatic islet functions, shedding a new light on its mechanism of action.

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