Abstract
The model xeno-estrogen bisphenol A (BPA) has been extensively studied over the past two decades, contributing to major advances in the field of endocrine disrupting chemicals research. Besides its well documented adverse effects on reproduction and development observed in rodents, latest studies strongly suggest that BPA disrupts several endogenous metabolic pathways, with suspected steatogenic and obesogenic effects. BPA's adverse effects on reproduction are attributed to its ability to activate estrogen receptors (ERs), but its effects on metabolism and its mechanism(s) of action at low doses are so far only marginally understood. Metabolomics based approaches are increasingly used in toxicology to investigate the biological changes induced by model toxicants and chemical mixtures, to identify markers of toxicity and biological effects. In this study, we used proton nuclear magnetic resonance (1H-NMR) based untargeted metabolite profiling, followed by multivariate statistics and computational analysis of metabolic networks to examine the metabolic modulation induced in human hepatic cells (HepG2) by an exposure to low and very low doses of BPA (10−6M, 10−9M, and 10−12M), vs. the female reference hormone 17β-estradiol (E2, 10−9M, 10−12M, and 10−15M). Metabolomic analysis combined to metabolic network reconstruction highlighted different mechanisms at lower doses of exposure. At the highest dose, our results evidence that BPA shares with E2 the capability to modulate several major metabolic routes that ensure cellular functions and detoxification processes, although the effects of the model xeno-estrogen and of the natural hormone can still be distinguished.
Highlights
In the field of endocrine disrupting chemicals (EDCs), bisphenol A (BPA) is among the xeno-estrogens that have been the subject of the most extensive studies over the past two decades
Studies carried out in rodents pre- and postnatally exposed to BPA have demonstrated significant changes in metabolic functions, evidenced by effects on lipogenesis, glucose, or insulin regulation, and body weight gain [2]. These endpoints were not taken so far into account in the final risk characterization of BPA exposure, they have been clearly mentioned in the EFSA opinion on the risks to public health related to the presence of BPA in foodstuffs
We previously demonstrated in CD1 mice and Sprague Dawley rats, that the metabolome is modulated in these animals following perinatal exposure to low doses of BPA [10–12]
Summary
In the field of endocrine disrupting chemicals (EDCs), bisphenol A (BPA) is among the xeno-estrogens that have been the subject of the most extensive studies over the past two decades. Studies carried out in rodents pre- and postnatally exposed to BPA have demonstrated significant changes in metabolic functions, evidenced by effects on lipogenesis, glucose, or insulin regulation, and body weight gain [2]. These endpoints were not taken so far into account in the final risk characterization of BPA exposure, they have been clearly mentioned in the EFSA opinion on the risks to public health related to the presence of BPA in foodstuffs. This proposal has been adopted by ECHA’s member state committee
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