In a review article published on November 14, 2017 in the peer-reviewed journal Hormones and Behavior, Harry McKay from the Baylor College of Medicine, Houston, U.S., and Alfonso Abizaid from Carleton University, Ottawa, Canada, discussed the “receptor ecosystem” for bisphenol A (BPA, CAS 80-05-7). The authors pointed out that BPA is “a well-known endocrine disrupting compound (EDC), capable of affecting the normal function and development of the reproductive system, brain, adipose tissue, and more.” However, “comparatively little” is known about the molecular mechanisms which bring about these “diverse and well characterized effects.” This, the authors argued, is because “BPA has traditionally been regarded as a primarily estrogenic EDC, and this perspective is often what guides research into the effects of BPA.” However, in silico and in vitro studies have demonstrated that “BPA binds with a significant number of hormone receptors, including a number of nuclear and membrane-bound estrogen receptors, androgen receptors, as well as the thyroid hormone receptor, glucocorticoid receptor, and PPARγ.” Taking into account the “increased diversity of receptor targets” may help explaining “some of the more puzzling aspects of BPA pharmacology, including its non-monotonic dose-response curve, as well as experimental results which disagree with estrogenic positive controls,” the authors concluded.
Several structurally related molecules, including bisphenol S (BPS, CAS 80-09-1), bisphenol F (BPF, CAS 620-92-8), bisphenol B (BPB, CAS 77-40-7), and bisphenol AF (BPAF, CAS 1478-61-1), have been suggested and may currently be used as BPA replacements in several applications (FPF reported). Ongoing human exposure to some of these molecules has already been confirmed by biomonitoring studies (FPF reported). Though undesired, the ability of most BPA analogues to exert estrogenic effects similar to those of BPA itself has been conclusively demonstrated (FPF reported). Furthermore, some BPA alternatives, even if deliberately chosen to lack interactions with estrogen receptor, such as tetramethyl bisphenol F (TMBPF, CAS 5384-21-4), could nonetheless interact with other molecular receptors, such as androgen receptor (FPF reported). These actions may be either specific for a certain molecule or similar to those already known for BPA, and potency to induce a certain effect may also vary in both directions (i.e., in a particular interaction, a particular analogue could perform weaker or stronger than BPA).
For example, Mingxin Shi and colleagues from the Department of Physiology, Southern Illinois University School of Medicine, U.S., found that BPA and two of its analogues, BPS and bisphenol E (BPE, CAS 2081-08-5), exerted similar effects on reproductive functions in mice, including reduction of sperm counts or motility and disruption of germ cell development in males, acceleration of puberty onset in females, and increase in steroid hormone levels in both genders. John Moreman and colleagues from Biosciences, College of Life and Environmental Sciences, University of Exeter, United Kingdom, used transgenic zebrafish larvae to study estrogen receptor activation by BPA and its analogues, and reported a rank order BPAF>BPA=BPS>BPF for estrogenicity in this model. They also observed that BPAF was the most toxic among the substances examined. Another study with zebrafish embryos and cell lines, performed by Vincent Le Fol and colleagues from INERIS, Verneuil-en-Halatte, France, confirmed the estrogenicity of BPA analogues in this model, and further reported that BPS and BPF were slightly more potent than BPA on the two subtypes of zebrafish estrogen receptor beta, with different estrogenic potency demonstrated in vitro and in vivo. Further, a study by Lin-Ying Cao and colleagues from the State Key Laboratory of Environmental Chemistry and Ecotoxicology, Chinese Academy of Sciences, China, found that BPA and six of its common analogues could directly bind to the G protein-coupled estrogen receptor (GPER); BPAF and BPB had an about 9-fold higher binding affinity to GPER compared to BPA. GPER is an important node in the pathway underlying the nongenomic (extranuclear) actions of EDCs which typically occur at low doses and have been implicated in diabetes- and cardiovascular disease-relevant actions of BPA (FPF reported).
With regard to the latter disease, Sanghamitra Pal and colleagues from the Molecular Neurotoxicology Laboratory, University of Kalyani, India, demonstrated that exposure to BPS in rats promoted haemolysis, increased total blood glucose levels, and altered cholesterol-, triglyceride- and lipoprotein-related blood parameters in a manner suggesting an augmentation of cardiovascular risks. Chao Zhao and colleagues from the State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, China, using metabolomics and lipidomics, showed that macrophages exposed to environmentally relevant concentrations of BPS had disrupted energy metabolism and exhibited altered expression and secretion of cytokines, indicative of immunotoxicity and potential pro-inflammatory consequences for the organism. In another in vitro study, carried out by Aneta Macczak and colleagues from the Department of Biophysics of Environmental Pollution, Faculty of Biology and Environmental Protection, University of Łódź, Poland, BPS had significantly lower effects on oxidative stress parameters in human red blood cells compared to BPA. In contrast, BPAF showed the strongest alterations in reactive oxygen species (ROS) formation, lipid peroxidation, and levels of antioxidant enzymes in this study. A similar rank order of potency was reported by the same group in their studies of BPA and its analogues’ effects on hemoglobin oxidation and hemolytic changes and on the membrane fluidity and protein activities in erythrocytes.
Davy Guignard and colleagues from the Research Centre in Food Toxicology (Toxalim), University of Toulouse, France, showed that exposure to BPA at low levels representative of human exposure significantly altered the thyroid hormone balance in pregnant ewes, with actions likely exerted at the level of deiodinases. BPA analogues may also be able to affect diverse aspects of thyroid signaling. For example, Sangwoo Lee and colleagues from the School of Public Health, Seoul National University, Republic of Korea, investigated thyroid disrupting effects of nine structural analogues of BPA using rat pituitary and thyroid follicular cells. They found effects on several genes regulating thyroid hormone synthesis, and reported that BPS and two other BPA analogues had a potency greater than that of BPA in this regard. Another study, by Zhang Yin-Feng and colleagues from the State Key Laboratory of Environmental Chemistry and Ecotoxicology, Chinese Academy of Sciences, China, found that BPF and BPS could bind to thyroid hormone receptors, albeit with a potency lower than that of BPA. They further showed that all three bisphenols were able to induce the transcription of thyroid hormone-responsive genes in Pelophylax nigromaculatus tadpoles, thus demonstrating the ability to interfere with thyroid hormone signaling pathways in vivo.
The growing body of evidence demonstrates that many BPA substitutes are indeed “regrettable” in a sense that they are by far not free from potential endocrine activities. Some analogues, most notably BPAF, may even show higher potency to induce certain effects compared to BPA. Of interest, BPAF was also found to have much higher half-lives in farm and forest soils in the environment compared to BPA and BPS, suggesting a higher potential for environmental effects. According to a recent market survey in the EU, a large variety of bisphenols may be currently in use (FPF reported), with many BPA analogues having insufficient data to judge on their potential EDC properties (FPF reported). In light of this, several organizations, for example the Green Science Policy Institute and the International Chemical Secretariat, have called for risk assessment of bisphenols as a class, not substance by substance.
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