Bisphenol A environmental exposure and the detrimental effects on human metabolic health: is it necessary to revise the risk assessment in vulnerable population?

In the last decades, many reports have focused the attention on deleterious effects of novel environmental chemical compounds, including bisphenol A (BPA), on human health. BPA, a common and widely chemical contaminant acting as endocrine disruptor, accumulates in adipose tissue and may affect adipocyte metabolic and inflammatory functions. BPA, at low chronic doses, is now considered as an obesogen compound, and might contribute to the rise of metabolic syndrome, visceral adiposity and diabetes epidemics. The BPA worldwide presence in the environment is responsible for chronic exposure during vulnerable periods, such as foetal and neonatal life. The BPA source of contamination can occur via food, beverage, wastewater, air, dust and soil. BPA, as lipophilic compound, may accumulate into the adipose tissue already during foetal life and may affect adulthood health, through adverse effects on the growth and development of organs and tissues. Thus, based on several studies, it would be crucial to consider further actions aimed to refine risk assessment at least in vulnerable population, such as foetuses, infants and young children, to prevent metabolic diseases and obesity.


Introduction
range of concentrations in general environment, including water (river and sea), air and dust [5]. Of interest, BPA human daily intake occurs mostly via foods and beverages, but also via skin exposure after continuously handling thermal paper receipts in occupationally exposed populations such as cashiers, who handle receipts 40 or more hours per week [7].
In humans, BPA chronic exposure, even at nanomolar concentrations, has been reported to be deleterious, mainly involving human reproduction, development, metabolic and inflammatory pathways [1,2,[4][5][6]. The number of papers published on PubMed between 1975 and 2015 has been shown in Tables 2 and 3, reporting the main negative effects of BPA, that involve human and animal in vitro and in vivo studies, respectively. Several analyses, including human epidemiological studies, have supported the BPA "obesogen" effects [1,[3][4][5][6]8]. For instance, we have recently reported a significant activation of inflammatory pathways (JNK, STAT3 and NF-kB), with an increased  secretion of pro-inflammatory cytokines (IL-6 and INF-γ) in human adipocytes, incubated in vitro with 1 nM BPA for 24 h. This pro-inflammatory effect is associated with downregulation of the insulin signalling network and inhibition of insulin-stimulated glucose utilization [9]. Moreover, these results were confirmed in a cross-sectional study on a male population, where a significant correlation was found between BPA plasma levels, inflammation and visceral obesity [8]. In this context, it has been also reported a link between BPA plasma levels, markers of low-grade inflammation and insulin resistance in polycistic ovary syndrome [10], an enigmatic syndrome in which experimental exposure to industrial EDC further deteriorate the hormonal and fertility imbalances [11]. Thus, a putative mechanism by which BPA affects adipocyte metabolic functions and leads to insulin resistance, probably via inflammatory pathways has been hypothesized ( Fig. 1). Besides these well-documented molecular mechanisms on adipose tissue, inflammation and glucose metabolisms, several biological effects have been attributed to low-dose environmental BPA exposure [1,[3][4][5][6] (Tables 2,  3). Due to its ability to mimic oestrogen activity, BPA can enhance or inhibit the activity of endogenous oestrogens, mainly acting via nuclear oestrogen receptors ERα and ERβ, but also binding G-protein coupled oestrogen receptor (GPR30). Moreover, BPA could compete with 5α-dihydrotestosterone (DHT) for binding at the androgen receptor (AR) causing an anti-androgen effects, leading to male infertility, but also at thyroid hormone receptor (TR), with an interference on TR, affecting the brain morphology and expression of genes related to brain development. Another interesting BPA effect is on pancreatic beta-cells, where BPA can activate receptor-mediated pathways, influencing the rapid influx of calcium and increasing insulin release and glucose metabolism. On the immune system, BPA can affect the immune system functions in humans, involving autoimmunity, adaptative immune response, such as Th1 and Th2 responses, but also elicits differential responses on cytokine production, cell-type and stimulus specific [1,[3][4][5][6].

BPA and foetal exposure
The detrimental effects of BPA on tissue and organ development during foetal life are now well documented in literature, mainly in animal models ( Table 2). In humans, detectable BPA plasma and urine levels have been reported in several epidemiological studies, with higher values in children and consistent associations with metabolic alterations [1,[3][4][5][6]. As consequence of the BPA worldwide presence and to its ability to cross placenta, humans, during the whole life, including foetal and neonatal life, are chronically under BPA low doses exposure. Interestingly, when ingested, BPA is rapidly absorbed mainly at gastrointestinal level and partially inactivated in the liver and intestine via conjugation by uridine 5′-diphospho-glucuronosyltransferase (UDP-UGT) activity [1,[3][4][5][6]. Foetal liver has an immature system of detoxifying chemicals, in particular UDP-UGT activity is reduced, and the embryonic/foetal BPA exposure, with subsequently accumulation, may impair the tissue embryonic development and function, particularly affecting adipose tissue functions, insulin sensitivity and fat increase [6,12]. Moreover, these findings raise the possibility that BPA may alter regulatory genes of the adipogenesis process, at least in part by epigenetic mechanisms. It should be noticed that BPA doses, considered "safe" by the European Food Safety Authority (EFSA) [13], may reach "internal" exposure levels higher than those usually required to stimulate molecular endpoints in cultured cells [1,2,[4][5][6][7]. Indeed, BPA at environmental doses may be responsible for reprogramming of the endocrinemetabolic status, with development of systemic low-grade inflammation, insulin resistance and metabolic syndrome during the whole lifespan, particularly when other environmental challenges occur, such as high-fat diet [1-6, 8, 9, 12].
Considering the significant difference in BPA pharmacokinetic between animals and humans and in low-dose vs high-dose effects, additional in vivo and in vitro studies involving humans are needed to better define BPA metabolic effects. In particular, BPA deleterious effects should be better defined in vulnerable population, such as foetuses, infants and young children, where also cumulative with mixture of different environmental chemical pollutants may affect the correct tissue development and organogenesis. The embryonic critical window of exposure, can involve systemic metabolic homeostasis and adulthood health programming, in agreement with the new concept of "developmental origins of health and disease", which underlies foetal basis for adult diseases [12].
In other words, BPA foetal/neonatal exposure levels, which may be responsible for increased human health risk, should not be underestimated. Current researches are in progress to sort the effect of foetal programming as a contributing factor in adult metabolic diseases, particularly in obesity, insulin resistance, metabolic syndrome and diabetic epidemics [6,12].
Thus, although all of these hypotheses need thorough examination, caution should be given by National and International Regulatory Agencies, on the potential deleterious role of BPA [14] but also of BPA-like compounds (such as bisphenol F and bisphenol S), which are gradually replacing BPA in industrial applications [15].

Conclusions
In humans, the continuous BPA chronic exposure from canned goods, drinking plastic packaging and thermal paper must be reduced. To avoid the contact between plastic containers and food and beverage, particularly during foetal/neonatal life, must be the future goal, for example by privileging fresh foods. Interestingly, France has recently abolished BPA from all packaging food, to reduce drastically the BPA intake. Safety guidelines should give more attention to the potential consequence in vulnerable people worldwide, also considering that the BPA environmental exposure is modifiable through behavioural changes. A reduction of BPA exposure can represent an attractive target for prevention of diseases which represent a serious problem of global proportion and economic and social emergencies, such as obesity, metabolic syndrome and diabetes. Fig. 1 Putative scheme on bisphenol A (BPA) action in adipocyte. BPA can bind oestrogen receptors and/or TLR/ cytokine receptors. BPA may modulate cytokine synthesis by activation of JNK/STAT3/NFkB inflammatory pathway, and by influencing insulin network via IR/AKT down-regulation