Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption

Abstract

In 1991, a group of 21 scientists gathered at the Wingspread Conference Center to discuss evidence of developmental alterations observed in wildlife populations after chemical exposures. There, the term "endocrine disruptor" was agreed upon to describe a class of chemicals including those that act as agonists and antagonists of the estrogen receptors (ERs), androgen receptor, thyroid hormone receptor, and others. This definition has since evolved, and the field has grown to encompass hundreds of chemicals. Despite significant advances in the study of endocrine disruptors, several controversies have sprung up and continue, including the debate over the existence of nonmonotonic dose response curves, the mechanisms of low-dose effects, and the importance of considering critical periods of exposure in experimental design. One chemical found ubiquitously in our environment, bisphenol-A (BPA), has received a tremendous amount of attention from research scientists, government panels, and the popular press. In this review, we have covered the above-mentioned controversies plus six additional issues that have divided scientists in the field of BPA research, namely: 1) mechanisms of BPA action; 2) levels of human exposure; 3) routes of human exposure; 4) pharmacokinetic models of BPA metabolism; 5) effects of BPA on exposed animals; and 6) links between BPA and cancer. Understanding these topics is essential for educating the public and medical professionals about potential risks associated with developmental exposure to BPA and other endocrine disruptors, the design of rigorously researched programs using both epidemiological and animal studies, and ultimately the development of a sound public health policy.

Figure 1

Chemical structures of BPA, DES, and estradiol. The structures of BPA and DES are more similar to one another than they are to the endogenous estradiol, indicating that chemicals with variable structures are capable of binding to the ER.

Figure 2

Hypothetical curves to illustrate the threshold (A), linear nonthreshold (B), and nonmonotonic (C) model dose response curves. In the threshold model, treatment with increasing doses of a drug has no effect until the “threshold” dose is reached, at which point an increase in response is observed. In the linear nonthreshold model, a response occurs even at the lowest treatment dose, and therefore effects at high doses can be used to predict responses at low doses. With a NMDR curve, an increase in dose does not necessarily correspond to an increase in response, such that, in this example, doses from 10⁻¹²-10⁻³ m result in an increase in response, and doses from 10⁻³-10⁷ m result in a decrease in response. These curves are common for endocrine endpoints. D, Examples of NMDR curves observed in mammary gland morphological parameters after administration of estradiol to ovariectomized females. The left y-axis is the number of terminal end buds (TEBs), and the right y-axis is total area of all TEBs; the TEB is an estrogen-dependent structure. [Panel D is reproduced from L. N. Vandenberg, et al.: J. Steroid Biochem Mol Biol 101:263–274 (49). Copyright 2006, with permission from Elsevier.]

Figure 3

Schematic diagram of the mouse reproductive tract showing the three possible intrauterine positions of female fetuses. Females located between two males are considered 2M, between a male and a female are considered 1M, and between only females are considered 0M. [Modified from F. S. vom Saal, et al.: J Reprod Fertil 62:33–37 (69). Copyright 1981, Society for Reproduction. Reproduced by permission.] Multiple studies have detected statistically significant differences in physiological, morphological, and behavioral parameters in mice dependent on position in the uterus during gestation.

Figure 4

Proposed mechanisms for the endpoints affected in perinatally BPA-exposed females. BPA binds ERs, including the classical ERs (ERα and ERβ) and mERs. This causes alterations at several levels of organization including tissues, cells, and gene expression. These alterations lead to diverse changes in estrogen-target organs including the brain, mammary gland, ovary, and uterus, among others. Additionally, changes in one target organ can lead to secondary alterations in other organs. In addition to these classical targets, other nonclassical targets of BPA action include bone, cardiovascular tissue, the pancreas, adipose tissue, and the immune system (not pictured).