A Bisphenol by Any Other Name…

Over the last 10 years, a large number of studies have examined the effects of exposure to endocrine-disrupting chemicals (EDCs). These range widely from epidemiological, toxicological, and ecological studies, to animal studies examining the effects of EDCs on development, reproduction, and metabolism (1–14). In 2009, The Endocrine Society published its first policy statement on EDCs, advocating for funding of EDC research, recommending research priorities, and working to increase public awareness about EDC exposure (15). This year, they released a second statement, in which the authors reviewed a carefully selected, up-to-date literature on developmental EDC exposure and made further recommendations for how the research community can continue to inform physicians and policymakers (16). So far, only 1 major change in policy has been made based on these and other recommendations, but there may be other changes to come (17). In 2012, the United States Food and Drug Administration concluded that there was enough scientific evidence to ban the use of 1 EDC, bisphenol A (BPA), in baby bottles and children's cups (18, 19). However, BPA is still found in thermal receipts, canned foods, and other products, and there are many other EDCs being used to produce consumer goods.

Recently, evidence has been mounting to support the ban of one of the substitutes for BPA used by manufacturers, bisphenol S (BPS) (20–22). Like BPA, BPS is also detectible in human urine (23), is capable of activating estrogen and androgen receptor signaling pathways (24, 25), and has been shown to alter development, reproduction, and behavior (25–27). In this edition of Endocrinology, Qiu et al (28) build on the existing BPS literature, performing a side-by-side comparison of the effects of BPA and BPS exposure during embryonic development on the zebrafish reproductive axis. They show that both BPA and BPS have dose-dependent effects on GnRH neuron number in the forebrains of zebrafish embryos, and increase kiss1, gnrh3, and esr1 gene expression. They then use pharmacological approaches to dissect the underlying mechanisms of BPA/BPS effects on gene expression. Interestingly, all 3 of the pathways examined: estrogen receptor signaling, thyroid hormone receptor activation, and aromatase activity, were necessary to observe the full effects of BPA/BPS on the changes in gene expression in the reproductive neuroendocrine axis.

A number of studies, using various model organisms, chemicals, and exposure paradigms, have previously shown that the kisspeptin system can be altered by EDC exposure (11, 29–32). Similarly, thyroid hormone signaling (33, 34), estrogen receptor expression (11, 12), and the aromatase pathway (35) have also been altered by other EDCs. However, Qiu et al are the first to report on direct effects of low dose developmental exposure across multiple signaling pathways (28). Although their results are not completely straightforward, they do establish some principles that could be useful for the future study of these and other EDCs. Already, several consortiums are hard at work establishing protocols for the thorough study of EDC effects (36–39). In addition, there are groups developing cell-based screens for chemicals (40–43), which, in the future, may be used before chemicals being introduced onto the market. Data are accumulating in support of the notion that EDCs produce transgenerational epigenetic modifications (10–12, 44–47). This evidence obligates the scientific community to extend beyond traditional endpoints and pathways to more whole-system, unbiased approaches. This will rely upon teams of researchers working together using standardized processes in order to understand the full complement of mechanisms through which these chemicals are capable of acting. Although Qiu et al (28) are certainly not the first to point out that the “safer” alternatives to known EDCs may not be safer, it is important that the scientific community continues to build evidence to support skepticism about the chemicals we are exposed to on a daily basis.