Czech J. Anim. Sci., 61, 2016 (10): 433–449 Review doi: 10.17221/81/2015-CJAS Bisphenol S instead of bisphenol A: a story of reproductive disruption by regretable substitution – a review T. Žalmanová1, K. Hošková1, J. Nevoral2,3, Š. Prokešová1, K. Zámostná1, T. Kott4, J. Petr2 1Department of Veterinary Sciences, Faculty of Agrobiology, Food and Natural Resources, Czech University of Life Sciences Prague, Prague, Czech Republic 2Laboratory of Reproductive Medicine, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic 3Department of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic 4Institute of Animal Science, Prague-Uhříněves, Czech Republic ABSTRACT: A range of substances that are released into the environment, foodstuffs and drinking water as a result of human activity were originally considered relatively harmless, and it was only later that their adverse effects were discovered. In general the use of such substances is currently restricted, and they are often replaced by other substances. This applies also in the case of a range of endocrine disruptors. These substances have the capacity to disturb the balance of physiological functions of the organism on the level of hormonal regulation, and their pleio- tropic spectrum of effects is very difficult to predict. Endocrine disruptors include the currently intensively studied bisphenol A (BPA), a prevalent environmental pollutant and contaminant of both water and foodstuffs. BPA has a significantly negative impact on human health, particularly on the regulation mechanisms of reproduction, and influences fertility. The ever increasingly stringent restriction of the industrial production of BPA is leading to its replacement with analogues, primarily with bisphenol S (BPS), which is not subject to these restrictions and whose impacts on the regulation of reproduction have not yet been exhaustively studied. However, the limited number of studies at disposal indicates that BPS may be at least as harmful as BPA. There is therefore a potential danger that the replacement of BPA with BPS will become one of the cases of regrettable substitution, in which the newly used substances manifest similar or even worse negative effects than the substances which they have replaced. The objec- tive of this review is to draw attention to ill-advised replacements of endocrine disruptors with substances whose effects are not yet tested, and which may represent the same risks for the environment, for the reproduction of males and females, and for human health as have been demonstrated in the case of the originally used substances. Keywords: human health; environment; endocrine disruptor; reproduction; oocyte; sperm INTRODUCTION earlier or later that they are harmful to the environ- ment and/or human health. Notorious cases include Many substances have been introduced into use the mass use of DDT as an insecticide (http://apps. with great hopes, only for it to be demonstrated who.int/iris/handle/10665/40018), thalidomide Supported by the Ministry of Agriculture of the Czech Republic (Project No. QJ1510138 and Project No. MZeRO0714), by the Ministry of Education, Youth and Sports of the Czech Republic (Project No. LO1503 under the NPU I program), by the Internal Grant Agency of the Czech University of Life Sciences Prague (CIGA) (Project No. 20132035), and by the Grant Agency of the Charles University in Prague (PRVOUK P36 program). 433 Review Czech J. Anim. Sci., 61, 2016 (10): 433–449 doi: 10.17221/81/2015-CJAS as a drug for pregnant women (McBride 1961), or may be linked to significant reproductive risks. The more recently neonicotinoid insecticides used for aim of this review is to point to the replacement of the protection of fields against seed-destroying BPA by BPS as a “regrettable substitution”. insects (Blacquiere et al. 2012). Substances whose negative effects on the environment or human health Endocrine disruptors were detected only after a long period of use also include endocrine disruptors (Damstra et al. 2002). A less harmful substitute is currently searched The detection of the negative effects of abun- for a number of substances that had previously dantly used substances leads to a dramatic restric- been considered safe from a toxicological perspec- tion of their use and their substitution with other tive and finally appeared to exert various negative substances. In a range of cases this brings about effects on health. This category of compounds a genuine improvement. For example, chromated includes substances referred to summarily as en- copper arsenate (CCA) used for wood preserva- docrine disruptors (Clayton 2011). According to tion was demonstrated to be a substance with the US Environmental Protection Agency, endo- carcinogenic effects, and as a result was replaced crine disrupting chemicals (EDCs) are defined as with alkaline copper quaternary (ACQ). ACQ does “exogenous agent(s) that interfere(s) in synthesis, not contain arsenic or chrome, and although it is secretion, transport, metabolism, binding action, just as effective as CCA against wood destroy- or elimination of natural blood-borne hormones ing arthropods, its impacts on the environment that are present in the body and are responsible and human health are fundamentally less serious for homeostasis, reproduction, and developmental (Landrigan et al. 2004). processes” (Diamanti-Kandarakis et al. 2009). On the other hand, we have been witnesses to EDCs manifest a range of particular properties. substitutions of harmful substances which have later Their hormone-like effects may be suppressed or been shown to be highly problematic. For example, may fade away entirely in the case that the concen- 2,3-butanedione, which occurs naturally in butter, tration of EDCs is higher than the physiological has been produced synthetically and added to foods level of their hormonal counterpart. This ability in order to impart a buttery flavour. When it was of agents to attain paradoxically stronger effects demonstrated that 2,3-butanedione damaged lung in low doses than in high ones (vom Saal and tissue, it was replaced by 2,3-pentanedione, which Welshons 2005) is termed the “low dose effect” however was subsequently proven to have similar (Grasselli et al. 2010; Vandenberg et al. 2012). The negative effects on lung tissue as 2,3-butanedione low dose hypothesis posits that exogenous che- (Hubbs et al. 2012). There are far more similar ex- micals that interact with hormone action can do amples of “regrettable substitutions” (Fahrenkamp- so in a quite specific manner. In accordance with Uppenbrink 2015; Zimmerman and Anastas 2015). that, mentioned traditional toxicological endpoints In these cases, negative impacts on reproduction are are not capable to preclude adverse outcome, as often subsequently detected. For example, in the EDCs act with dose responses, that are nonlinear case of pyrethroids, which replaced older insecticide and potentially non-monotonic (Vandenberg et al. agents such as organocholorines, organophosphates 2012). In the case the relationship between dose or carbamates, and which were considered harmless and response is nonlinear, any prediction is even to mammals, negative impacts were demonstrated on more complex. Therefore, the low dose definition the maturation of mammal oocytes (Petr et al. 2013). was extended by the effects of non monotonic From the perspective of reproductive risks, the response curves. The mechanisms responsible substitution of bisphenol A (BPA), a widely used for the non-linear effects are described in detail component of plastics and many other materials, (Vandenberg et al. 2012), usually in connection with its analogue bisphenol S (BPS) appears to be with an interaction between a ligand (hormone or potentially problematic. BPA has been proven to be EDC) and a hormone receptor (Vandenberg 2014). a strong endocrine disruptor, and its use has been Non-linear dose-response patterns are com- restricted. Many products are sold with a “BPA-free” monly observed with endogenous and synthetic guarantee. Because BPA is substituted in a range agonists (e.g. numerous drugs, hormones, peptides) of cases by BPS, these products are not however that activate and inhibit receptor-mediated signal “bisphenol-free” (Glausiusz 2014), and their use pathways that affect various biological functions 434 Czech J. Anim. Sci., 61, 2016 (10): 433–449 Review doi: 10.17221/81/2015-CJAS (A) the hormone estradiol (Dodds and Lawson 1936). Despite a very strong estrogen activity, BPA has been commercially used since 1957, and despite (B) the fact that its endocrine-disrupting activity was discovered (Krishnan et al. 1993), BPA has become a high production volume chemical (Wang et al. 2012). Worldwide annual production, which in the case of BPA reached 4.6 million t in 2012, is constantly (C) increasing. Its production was estimated at 5.4 mil- lion t in 2015 (Merchant Research & Consulting, http://mcgroup.co.uk/researches/bisphenol-a-bpa). BPA is present especially in polycarbonate plas- Figure 1. Chemical structure of bisphenol A (A), bisphe- tics, epoxide resins, and several paper products nol S (B), bisphenol F (C) (Ehrlich et al. 2014), and as a result it is used in a variety of commonly used consumer products such (Calabrese and Baldwin 2001; Calabrese 2005). Ho- as thermal recipes, cosmetics, dental materials, wever, EDCs can also produce non monotonic dose medicinal tubes, utensils, toys, baby feeding bot-