Toxicokinetics of bisphenol A, bisphenol S, and bisphenol F in a pregnancy sheep model
Introduction
Worldwide annual production of plastics has reached 8300 million metric tons with ∼80% accumulating in the environment (Geyer et al., 2017) and many of which are considered to contain endocrine disrupting chemicals (EDCs) (Gore et al., 2014). Bisphenols are EDCs used in the manufacturing of plastics, epoxy resins, and a variety of plastic and paper consumer products and food (Liao et al., 2012a; Liao and Kannan, 2013). Among the leading bisphenols present in humans are bisphenol A (BPA), bisphenol S (BPS), and bisphenol F (BPF) (Liao et al., 2012a; Philips et al., 2018). Depending on the cohort, BPA, BPS, and BPF can be detected in up to 95.7, 89.4 and 66.5% of U.S. adults, respectively, of human urine samples (Liao et al., 2012b; Xue et al., 2015; Ye et al., 2015; Asimakopoulos et al., 2016; Lehmler et al., 2018; Philips et al., 2018; Rocha et al., 2018). BPS and BPF concentrations in humans are found in the same order of magnitude, but lower to that of BPA (Liao et al., 2012a; Ye et al., 2015). Despite the vast information available for BPA, much remains to be known regarding emerging BPA analogues (Chen et al., 2016; Wu et al., 2018). The detection of BPS, and to a lesser extent BPF, in human fetal cord blood (Kolatorova et al., 2018), the potential association between BPS exposure and gestational length (Wan et al., 2018a), and the fact that in mammals, fetal exposure to BPS can alter mammary gland development (Kolla et al., 2018), and that BPS and BPF can alter behavior (Catanese and Vandenberg, 2017; Ohtani et al., 2017), calls for the investigation of the materno-placental transfer of these bisphenols into the fetal compartment.
Recent studies have demonstrated that BPS can be acutely toxic in D. magna (Chen et al., 2002), induce neuronal dysfunction in zebrafish (Kinch et al., 2015) and C. elegans (Mersha et al., 2015) and impair fertility in aquatic species (Naderi et al., 2014; Qiu et al., 2015). In mammalian species, gestational or perinatal exposure to BPS induces obesity in mice offspring in a sex specific manner (Ivry Del Moral et al., 2016) and alters mammary gland development (Kolla et al., 2018). We have also recently demonstrated that gestational exposure to BPS reduces the endocrine secretory capacity of the placenta (Gingrich et al., 2018). Given the critical role of the placenta in pregnancy maintenance, oxygen and nutrient exchange with the developing fetus, and the detrimental effects that perturbations in placental homeostasis have on progeny outcomes (Gabory et al., 2013; Rosenfeld, 2015), understanding the toxicokinetics of BPS during pregnancy is much warranted. Although to a lesser extent, the effects of exposure to BPF have also been studied in vivo demonstrating that gestational BPF exposure alters neuronal behavior in mice (Ohtani et al., 2017).
Thus far, only one toxicokinetic study is available for BPS after oral administration in humans (Oh et al., 2018). However, this study was conducted in non-pregnant female and male individuals. Physiologically based toxicokinetic (PBTK) mathematical models integrate chemical absorption, distribution, metabolism, and excretion, and help generate health risk assessment for chemical and pharmaceutical exposures due to their predictive capabilities (Zhuang and Lu, 2016; Ke et al., 2018). Recent work focusing on the development of a PBTK model for emerging bisphenols, such as BPS and BPF, have explicitly called for in vivo toxicokinetic data for BPS, BPF, and BPAF using biomonitoring or animal studies (Karrer et al., 2018). However, this novel PBTK model has only been developed in a non-pregnancy model. Given that toxicokinetics of BPA can be modulated by pregnancy (Corbel et al., 2013), we aimed to study the toxicokinetics of BPS and BPF during pregnancy. Our work will enable future development of precise pregnancy PBTK models for emerging bisphenols. Toxicokinetics during pregnancy are far more complex with the inclusion of the maternal, placental and fetal compartments (Ke et al., 2018). However, ethical constraints do not allow for these toxicokinetics studies to be conducted in pregnant women. The use of refined fetal surgery techniques in a sheep animal model represents a unique opportunity to monitor the maternal, amniotic, and fetal compartments, key elements of pregnancy PBTK models (Ke et al., 2018). Sheep are excellent models to study placental function (Fowden et al., 2015; Mourier et al., 2017) and have been used for the study of feto-maternal transfer of drugs (Krishna et al., 2002; Ngamprasertwong et al., 2016) and EDCs (Corbel et al., 2013, 2015), as they allow for the simultaneous and longitudinal characterization of the pregnancy multi-compartment model in real time. The objective of this study was to comparatively determine the toxicokinetic profile of BPS, BPF and BPA in a pregnancy model by evaluating the maternal and the fetal compartments.
Section snippets
Chemicals
Bisphenols used included BPA (purity ≥ 99%, Cat#: 239658; Lot#: MKBQ5209V; Aldrich Chemical Co., Milwaukee, WI, USA), BPS (4,4′-sulfonyldiphenol, purity 99.7%, Cat#: 146915000, Lot#: A0337011, Acros Organics, Geel, Belgium), and BPF (purity 98%, Cat#: B47006; Lot#: 05712 ME; Sigma-Aldrich, St. Louis, MO, USA) dissolved in corn oil. The internal standards 13C12-BPA (99%), 13C12-BPS (98%) and 13C12-BPF (99%) were purchased from Cambridge Isotope Laboratories (Andover, MA, USA). β-glucuronidase
Maternal non-compartmental toxicokinetic analysis
Maternal bisphenol concentrations after a single s.c. dose of BPA, BPS, or BPF are shown on Fig. 2 and corresponding estimated toxicokinetic parameters using the above-referenced non-compartmental analysis are displayed on Table 2 (left panel). As described in the statistics' section, no significant differences were observed in maternal BPS toxicokinetics when comparing females exposed to only BPS (n = 3) vs. the mixture (BPA, BPS, and BPF) (n = 3) and thus all 6 females exposed to BPS were
Discussion
Fifteen different bisphenols exist, at least 8 are detectable in human urine, and concomitantly, BPA, BPS and BPF are detected in 95.7, 89.4 and 66.5% of U.S. adults, respectively (Lehmler et al., 2018). We have recently demonstrated that gestational exposure to BPS can result in placental dysfunction (Gingrich et al., 2018), and can also result in reproductive and metabolic disorders in the progeny (Ivry Del Moral et al., 2016; Kolla et al., 2018). Pregnancy toxicokinetics of less prevalent
Conclusion
To our knowledge, this is the first report on the toxicokinetics of either BPS or BPF in a pregnancy model. This study has not only demonstrated differences in toxicokinetic parameters among three of the most prevalent bisphenols, but also between differences in maternal and fetal toxicokinetics. Toxicokinetic differences among bisphenols call for a more careful approach when extrapolating kinetic information from one bisphenol chemical to another.
Disclosure statement
Authors have nothing to disclose.
Funding source
Research reported in this publication was supported the National Institute of Environmental Health Sciences (NIEHS) of the National Institute of Health (NIH) (1K22ES026208 and R01ES027863 to A.V-L.), Michigan State University (MSU), MSU AgBioResearch, and the United States Department of Agriculture (USDA) National Institute of Food and Agriculture (Hatch MICL02383). J.G. was supported by the BioMolecular Sciences graduate program at MSU, a doctoral fellowship award through the Environmental and
Acknowledgments
We thank Michigan State University (MSU) Sheep Teaching and Research Farm for help with animal procurement and husbandry, Dr. Jennifer Roberts for assistance with anesthetic induction, Ms. Ramona Ehrhardt for help with fetal catheterization, Dr. Robert Roth for experimental consultation, and Dr. Cesar Rosales-Nieto, Ms. Barbara Makela, Mr. Alex Mantey, and Ms. Jiongjie Jing for help during surgery and sample collection.
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