Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): Evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation

Angle, Brittany M.; Phuong, Rylee; Ponzi, Davidé; Stahlhut, Richard W.; Drury, Bertram E.; Nagel, Susan C.; Welshons, Wade V.; Besch‐Williford, Cynthia; Palanza, Paola; Parmigiani, Stefano; Saal, Frederick S. vom; Taylor, Julia A.

doi:10.1016/j.reprotox.2013.07.017

Cited by 257 publications

(207 citation statements)

References 92 publications

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“…Our data can be considered additional evidence that BPA at low doses may act not only via ERa but also by activating non-canonical ER pathways. The up-regulation of leptin mRNA levels is very intriguing and agrees with the results of a previous study (Angle et al 2013). Leptin production by adipocytes is proportional to their fat content; leptin serum levels are higher in obese subjects, and are directly correlated to adipose mass and adipocyte contents (Fried et al 2000, Yang & Barouch 2007.…”

Section: Discussionsupporting

confidence: 89%

Bisphenol A effects on gene expression in adipocytes from children: association with metabolic disorders

Menale¹,

Piccolo²,

Cirillo³

et al. 2015

Journal of Molecular Endocrinology

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Bisphenol A (BPA) is a xenobiotic endocrine-disrupting chemical. In vitro and in vivo studies have indicated that BPA alters endocrine-metabolic pathways in adipose tissue, which increases the risk of metabolic disorders and obesity. BPA can affect adipose tissue and increase fat cell numbers or sizes by regulating the expression of the genes that are directly involved in metabolic homeostasis and obesity. Several studies performed in animal models have accounted for an obesogen role of BPA, but its effects on human adipocytesespecially in children -have been poorly investigated. The aim of this study is to understand the molecular mechanisms by which environmentally relevant doses of BPA can interfere with the canonical endocrine function that regulates metabolism in mature human adipocytes from prepubertal, non-obese children. BPA can act as an estrogen agonist or antagonist depending on the physiological context. To identify the molecular signatures associated with metabolism, transcriptional modifications of mature adipocytes from prepubertal children exposed to estrogen were evaluated by means of microarray analysis. The analysis of deregulated genes associated with metabolic disorders allowed us to identify a small group of genes that are expressed in an opposite manner from that of adipocytes treated with BPA. In particular, we found that BPA increases the expression of pro-inflammatory cytokines and the expression of FABP4 and CD36, two genes involved in lipid metabolism. In addition, BPA decreases the expression of PCSK1, a gene involved in insulin production. These results indicate that exposure to BPA may be an important risk factor for developing metabolic disorders that are involved in childhood metabolism dysregulation.

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Section: Discussionsupporting

confidence: 89%

Bisphenol A effects on gene expression in adipocytes from children: association with metabolic disorders

Menale¹,

Piccolo²,

Cirillo³

et al. 2015

Journal of Molecular Endocrinology

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“…Further research using fetal liver tissue has also identified specific relationships between BPA and repetitive DNA elements, where nonmonotonic relationships between BPA exposure and DNA methylation were observed in several repeat families, including LINE1 [78]. Nonmonotonic relationships have previously been observed in prenatal mouse exposure models both with respect to both epigenomic and metabolic end points [79][80][81]. However, previous research, using both LUMA and pyrosequencing, did not identify a relationship between global methylation and BPA exposure in fetal liver or kidney, but did note a positive relationship between BPA exposure and LINE1 methylation in the placenta [82].…”

Section: Endocrine Disruptorsmentioning

confidence: 86%

Effects of Prenatal Exposure to Endocrine Disruptors and Toxic Metals on The Fetal Epigenome

2017

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Exposure to environmental contaminants during pregnancy has been linked to adverse outcomes at birth and later in life. The link between prenatal exposures and latent health outcomes suggests that these exposures may result in long-term epigenetic reprogramming. Toxic metals and endocrine disruptors are two major classes of contaminants that are ubiquitously present in the environment and represent threats to human health. In this review, we present evidence that prenatal exposures to these contaminants result in fetal epigenomic changes, including altered global DNA methylation, gene-specific CpG methylation and microRNA expression. Importantly, these changes may have functional cellular consequences, impacting health outcomes later in life. Therefore, these epigenetic changes represent a critical mechanism that warrants further study.

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“…Additional studies are needed to assess the occurrence, frequency, and implicated endpoints for NMDRCs in in vivo studies of BPA and for other EDCs. NMDRCs have been reported for BPA in a number of studies of laboratory animals (see for example (Angle et al, 2013;Ayyanan et al, 2011;Cabaton et al, 2011;Jenkins et al, 2011;Marmugi et al, 2012;Xu et al, 2010)), but the majority of studies examining rodents or aquatic animals have used fewer than six doses (Richter et al, 2007;vom Saal and Hughes, 2005;Welshons et al, 2006), and thus NMDRCs are likely to be more difficult to observe or detect.…”

Section: Non-monotonicity Is Common For In Vitro Studies Of Bpamentioning

confidence: 99%

Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol a as a Case Study

Vandenberg¹

2013

Dose-Response

303

156

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ᮀ Non-monotonic dose response curves (NMDRCs) have been demonstrated for natural hormones and endocrine disrupting chemicals (EDCs) in a variety of biological systems including cultured cells, whole organ cultures, laboratory animals and human populations. The mechanisms responsible for these NMDRCs are well known, typically related to the interactions between the ligand (hormone or EDC) and a hormone receptor. Although there are hundreds of examples of NMDRCs in the EDC literature, there are claims that they are not 'common enough' to influence the use of high-to-low dose extrapolations in risk assessments. Here, we chose bisphenol A (BPA), a well-studied EDC, to assess the frequency of non-monotonic responses. Our results indicate that NMDRCs are common in the BPA literature, occurring in greater than 20% of all experiments and in at least one endpoint in more than 30% of all studies we examined. We also analyzed the types of endpoints that produce NMDRCs in vitro and factors related to study design that influence the ability to detect these kinds of responses. Taken together, these results provide strong evidence for NMDRCs in the EDC literature, specifically for BPA, and question the current risk assessment practice where 'safe' low doses are predicted from high dose exposures.

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Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): Evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation

Cited by 257 publications

References 92 publications

Bisphenol A effects on gene expression in adipocytes from children: association with metabolic disorders

Bisphenol A effects on gene expression in adipocytes from children: association with metabolic disorders

Effects of Prenatal Exposure to Endocrine Disruptors and Toxic Metals on The Fetal Epigenome

Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol a as a Case Study

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