Getting Big on BPA: Role for BPA in Obesity?

Abstract

Bisphenol-A (BPA) is one of the most widely used industrial chemicals with applications in the construction of food and drink containers from which it can leach and enter the body (1). It is no surprise then that the vast majority of humans have low but detectable levels of BPA in blood and urine (2). BPA has also been detected in breast milk and fetal fluids, indicating that even infants are widely exposed (3). Whether this exposure is harmful for humans has been vigorously debated for a number of years, and there is substantial evidence to support both sides of this issue (4–6). In the present issue of Endocrinology, Wei et al. (7) contribute important new observations that support a role for fetal/neonatal exposure to low doses of BPA in contributing to increased body weight and hyperinsulinemia and impaired glucose tolerance in adults. Importantly, these effects were exacerbated when exposed pups were weaned onto a high-fat diet, an experimental manipulation meant to emulate the typical energy-rich diet available in developed societies. In this study, Wistar rats were administered one of three BPA doses (50, 250, and 1250 μg/kg·d along with corn oil control) by oral gavage from inception to weaning. Unfortunately, BPA concentrations in fluids and tissues of treated animals were not analyzed in this study so it is not possible to directly compare exposures in this study to other studies or to humans in general. However, it was recently reported that after administering a single 400 μg/kg body weight dose of BPA to mice, the maximum serum concentration at 1 h was 3.28 ng/ml (8), suggesting that exposure to the 50 μg/kg dose in the study by Wei et al. (7) likely resulted in a serum concentration of less than 1 ng/ml, which would be on the low end of serum BPA concentrations reported for humans (2). Interestingly, the effects reported by Wei et al. (7) were all observed at the lowest dose, with no effects observed at higher doses, suggesting that low-dose exposures might be more important for metabolic actions of BPA (9). In the study by Wei et al. (7), BPA-treated animals were heavier and on the high-fat diet, this difference appeared earlier (9 wk on high fat diet vs. 19 wk on regular chow). Serum insulin was elevated in BPA-treated animals, and both hyperinsulinemia and elevated fasting glucose were evident in BPA-treated animals on the high-fat diet that also manifested at an earlier age compared with animals on regular chow. BPA exposure also produced glucose intolerance in an oral glucose tolerance test that was accompanied by elevated serum insulin. A mild reduction in whole-body insulin sensitivity in BPA-treated rats on normal chow was exacerbated on the high-fat diet and affected both males and females. Cellular and mitochondrial irregularities were observed in β-cells and overall islet size was increased in BPA-treated animals. When analyzed in vitro, islets from either sex produced more insulin in high-glucose medium, whereas after a high-fat diet treatment, insulin secretion was reduced in islets from males but increased in islets from females in high-glucose medium. BPA treatment also resulted in a higher body fat content with larger adipocytes and elevated triglyceride levels. Taken together, these observations clearly demonstrate that the 50 μg/kg·d dose of BPA substantially and significantly altered glucose and lipid homeostasis in these rats in a way that is consistent with the development of diabetes and metabolic syndrome. The results of this study are consistent with a number of previous reports in various rodent models using multiple routes of administration that together support a role for fetal/neonatal BPA exposure in adversely affecting metabolism in adults (4, 10, 11). Whereas the study by Wei et al. (7) is quite clear about the effects of BPA on metabolism, not all studies have found that BPA induces alterations in body weight or metabolism. In a study published last year in Endocrinology, Ryan et al. (12) found that perinatal exposure of CD-1 mice to a low BPA dose were heavier at the weanling stage, but their adult body weights were not different from untreated mice, even on a high-fat diet. In this study, a dose of 0.25 μg/kg·d BPA was administered to pregnant females in their chow to reflect the suspected adult dietary exposure in the United States. Again, BPA concentrations in serum or tissues were not reported so it is not possible to directly compare these results with other studies or with the study by Wei et al. (7). However, this very low dose may be too low to induce lasting effects on body weight and glucose homeostasis as observed by Wei et al. (7) and was almost certainly below levels reported in human serum (8). In another recent study, ethynyl estradiol was compared with BPA because BPA is considered a weak estrogen using classical bioassays, although BPA has also been reported to act on membrane estrogen receptors at nearly equimolar concentrations to estradiol (1, 13). Although estradiol altered anogenital distance and pup body weight and reduced overall fertility, no effects of BPA were noted (14). This study was carried out in Long-Evans rats with dosing of the pups achieved via the mother during gestation. Long-Evans rats are not particularly sensitive to estrogen's effects, and the highest dose of BPA was not sufficiently elevated to account for the more than 1000-fold difference in estrogen activity between estradiol and BPA, suggesting that again this dose may not have been sufficient to model the effects of human exposures to BPA (15). Once again, BPA concentrations were not reported for these animals making direct comparisons with other rodent studies or to human BPA exposures challenging. Why is it important to determine whether developmental exposure to BPA, as well as other endocrine-disrupting compounds and organic pollutants, has a deleterious effect on adult body weight and glucose and lipid homeostasis in humans? The prevalence of obesity in America has reached epidemic status with more than one third of Americans being obese and another third overweight (16). Obesity is a leading risk factor for insulin resistance and type 2 diabetes, contributing to a parallel increase in type 2 diabetes incidence in the United States (17, 18). Moreover, metabolic syndrome, a heterogeneous metabolic disorder that includes insulin resistance and type 2 diabetes along with central obesity, dyslipidemia, hypertension, and fatty liver, is also increasing in incidence over the same time period (19). Whereas the cause of the obesity epidemic is multifactoral and not entirely clear, the recent acceleration in incidence is too rapid to be accounted for by genetics and even by the wide availability of calorie-rich foods (20). Because the obesity epidemic also coincides with a rapid increase in industrial chemical exposure, the hypothesis that chemical exposures (particularly during development), combined with genetic predisposition and consumption of a high-calorie diet, are major contributors to the obesity epidemic has been proposed (21, 22). Furthermore, if this hypothesis is correct, preventing developmental exposures might be a viable strategy to reduce obesity incidence. Therefore, determination of whether BPA exposure really does increase the incidence of obesity and other metabolic disorders in humans is vital for improving the health of Americans and potentially to protect the next generation from the ravages of obesity and metabolic disease. Where do we go from here? Despite the weakness of not reporting BPA concentrations in serum or tissues, the study by Wei et al. (7) clearly points to the possibility that fetal/neonatal exposure to BPA exacerbates the effects of a high-fat diet in inducing metabolic disorders including obesity, insulin resistance, and glucose intolerance. In addition, the fact that some studies find direct evidence for BPA's role in altering metabolism, whereas others find little or none, emphasizes the need for developing a standard animal model that closely mimics the effects of BPA in humans as well as establishing optimal dosing, route of administration, and the most sensitive exposure window so that the effects of BPA can be accurately assessed and compared. Assessing the actual BPA concentrations in embryos, pups, and adults administered BPA by various routes in these studies should be a critical component of future studies until an optimal dose and route can be determined that will reliably model the human condition. Also of critical importance is defining mechanisms, molecular and epigenetic, that can account for the effects of BPA exposure on adult metabolism. The study by Wei et al. (7) clearly shows the potential for developmental BPA exposures to contribute to adult metabolic disease, but the applicability of these findings to human obesity, diabetes, and metabolic syndrome remains to be firmly established.