Possible Obesogenic Effects of Bisphenols Accumulation in the Human Brain

www.nature.com/scientificreports OPEN Received: 20 June 2017 Accepted: 8 May 2018 Published: xx xx xxxx Possible Obesogenic Effects of Bisphenols Accumulation in the Human Brain Pantelis Charisiadis 1, Xanthi D. Andrianou1, Thomas P. van der Meer2, Wilfred F. A. den Dunnen3, Dick F. Swaab4, Bruce H. R. Wolffenbuttel2, Konstantinos C. Makris1 & Jana V. van Vliet-Ostaptchouk 2 Evidence of bisphenols’ obesogenic effects on humans is mixed and inconsistent. We aimed to explore the presence of bisphenol A (BPA), bisphenol F (BPF) and chlorinated BPA (ClBPA), collectively called the bisphenols, in different brain regions and their association with obesity using post-mortem hypothalamic and white matter brain material from twelve pairs of obese (body mass index (BMI) >30 kg/m2) and normal-weight individuals (BMI <25 kg/m2). Mean ratios of hypothalamus:white matter for BPA, BPF and ClBPA were 1.5, 0.92, 0.95, respectively, suggesting no preferential accumulation of the bisphenols in the grey matter (hypothalamic) or white matter-enriched brain areas. We observed differences in hypothalamic concentrations among the bisphenols, with highest median level detected for ClBPA (median: 2.4 ng/g), followed by BPF (2.2 ng/g) and BPA (1.2 ng/g); similar ranking was observed for the white matter samples (median for: ClBPA-2.5 ng/g, BPF-2.3 ng/g, and BPA1.0 ng/g). Furthermore, all bisphenol concentrations, except for white-matter BPF were associated with obesity (p < 0.05). This is the first study reporting the presence of bisphenols in two distinct regions of the human brain. Bisphenols accumulation in the white matter-enriched brain tissue could signify that they are able to cross the blood-brain barrier. During the past four decades, a dramatic increase in the global prevalence of obesity has been documented, with estimates of 641 million obese individuals in 2014, worldwide, versus 105 million in 19751. It is widely accepted that the main driver of this obesity epidemic is modern lifestyle that combines excessive caloric intake with sedentary behaviour. The response to the ‘obesogenic’ environment is further modulated by individual genetic predisposition to gain weight2. However, the rapid pace at which the obesity epidemic occurs cannot be solely explained by these established risk factors3. A growing body of evidence suggests that exposure to certain environmental pollutants called endocrine-disrupting chemicals (EDC) may be another important contributor to the development of obesity4. Obesity is a complex endocrine disorder characterized by disruption of multiple hormonal systems involved in the control of body metabolism3,4. The recent scientific declaration called Parma consensus defined the metabolic disruptors such as EDC that may interfere with hormone actions play a key role in altering susceptibility to obesity and related chronic diseases including metabolic syndrome and diabetes3. The most prominent example of such metabolic disruptors includes various bisphenols that are extensively used in epoxy resins and other plastic products5. The major bisphenols are: (i) bisphenol A (BPA), one of the highest volume production chemicals in the world, (ii) BPA structural analogs, usually substituting BPA in polymeric matrices of commercial formulations such as bisphenol F (BPF) or bisphenol S (BPS), and (iii) chlorinated BPA derivatives (ClBPA) formed when BPA in the environment reacts with disinfectant chlorine or chlorinated oxidants6. The widespread detection of these chemicals in human biospecimen suggests ubiquitous exposures to bisphenols5,7. Animal and in-vitro studies have highlighted the metabolic effects of bisphenols, with BPA analogs or derivatives showing equal, if not greater endocrine disruptive activity than that of BPA6,8,9. 1 Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology, Limassol, 3041, Cyprus. 2Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 3Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 4Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. Correspondence and requests for materials should be addressed to K.C.M. (email: ) or J.V.v.V.-O. (email: ) SCIENTIfIC REPOrtS | (2018) 8:8186 | DOI:10.1038/s41598-018-26498-y 1 www.nature.com/scientificreports/ Evidence of bisphenols’ obesogenic effects on humans is mixed and inconsistent. While epidemiological studies reported positive associations between BPA exposures and obesity in adults, children and adolescents10–12, major controversy continues about how to link the concentrations of short half-lived BPA detected in human samples with adverse health effects. To date, a few biological modes of action have been proposed by which bisphenols may exert changes in body weight, including binding to thyroid receptor13 and alteration of thyroid hormone levels (reviewed by Andra and Makris14); activation of PPARy15 and glucocorticoid receptors16; regulation of adipocyte differentiation17 and absorption of lipids by adipocytes18. BPA is also shown to have insulinotropic action and adverse effects on glucose metabolism through estrogen receptors19,20. Altogether, the data indicate the high potency of bisphenols to interfere with a wide range of endocrine physiological networks. One of the potential endpoints for bisphenols action on metabolism may be the hypothalamus, a brain structure that plays a crucial role in energy balance control21,22. The hypothalamic infundibular nucleus is the central area of metabolic regulation, consisting mainly of grey matter23,24. However, before reaching the inner brain areas (e.g. white matter and lipid-enriched areas), bisphenols have to cross the blood-brain barrier that generally protects the brain from exposures to harmful substances, including toxins and bacteria25. Scarce data of passage across the blood-brain barrier exist for compounds, such as methylated mercury or lead ions25. These charged ions have been shown to cross through the endothelial cells of the blood-brain barrier under certain circumstances26. So far, such evidence is lacking for bisphenols in human studies. To assess the potential accumulation of bisphenols in different regions of the human brain and their possible interference with central regulation of body weight, we examined the presence of BPA, BPS and ClBPA in hypothalamic and white matter-enriched areas and their association with obesity. Materials and Methods Study Design and Tissue Sample Collection. Brain samples were obtained from the Netherlands Brain Bank (NBB) Netherlands Institute for Neuroscience (open access: www.brainbank.nl). All material has been collected from donors for or from whom a written informed consent for a brain autopsy and the use of the materia (...truncated)