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Assessment of mechanisms associated with energy homeostasis disruption after bisphenol a or s exposures through untargeted metabolomics

Grant number: 18/19554-0
Support type:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): January 02, 2019
Effective date (End): July 30, 2019
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Fernando Barbosa Júnior
Grantee:Lara Ferreira Azevedo
Supervisor abroad: Nicola Zamboni
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : Swiss Federal Institute of Technology Zurich, Switzerland  
Associated to the scholarship:16/10456-0 - Evaluation of protein expression and biochemical parameters related to diabetes mellitus type II and dyslipidemias in animals exposed to the contaminants bisphenol A and S, BP.DD

Abstract

Bisphenols are endocrine disruptors commonly used in the manufacture of plastic products and extensively studied regarding their potential adverse effects on the endocrine system and organs that are subject to endocrine regulation. In the last decades, many scientific reports showed that bisphenol A (BPA), an endocrine disruptor, can adversely affect energy metabolism, leading to impairment of glucose homeostasis and alterations in lipid metabolism. On the other hand, BPA indiscriminate use in consumer products has raised concerns from scientific and public authorities and, since then, many countries have banned its use as a plasticizer and begun to use its analog bisphenol S (BPS) to replace it. However, recent experimental data show that exposure to BPS seems to lead to similar outcomes as BPA and that it can also disrupt energy metabolism. Many studies were designed to understand the mechanisms of toxicity by which bisphenols trigger the metabolic disruption and advances in the field suggest that BPA can direct affect pancreatic cells function, disrupting synthesis and release of hormones essential to energy homeostasis, such as insulin and glucagon. In fact, recent findings from our group (from proteomics analysis) corroborate the literature. In this sense, the aim of this study is to investigate the metabolic changes in pancreatic and hepatic tissues as well as in HepG2 cells after exposure to low doses of BPA or BPS in order to elucidate the metabolic pathways affect by these compounds as well as integrate the results with our previous findings to better understand the pathways of toxicity leading to its adverse outcomes to energy homeostasis. In this regard, baseline metabolic characterization of liver and pancreas extracts obtained from male Wistar rats chronically exposed to approximately 50 µg/kg/day of BPA or BPS - collected to perform proteomic analysis from the initial doctorate proposal - as well as of cellular extracts obtained from HepG2 cellular cultures (intracellular fluid and extracellular spent medium) treated for 24 and 48 hours with concentrations of BPA or BPS pre established by preliminary cytotoxicity assays will be subjected to non-targeted metabolomics analyses by flow injection for polar extracts and LC-MS for lipids on an Agilent 6550 QTOF and a Thermo QExactive HF-X UHPLC systems. Eventually, 13C-metabolic flux analysis will be performed in vitro if specific pathways are suggested to be of relevance from untargeted metabolomics data. Differential and statistical data analyses will be done in Matlab or R starting from the simplest procedures (univariate statistical testing, enrichment analyses) and progressing towards more complex techniques (network topology).

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