Androgen and Progesterone Receptors Are Targets for Bisphenol A (BPA), 4-Methyl-2,4-bis-(P-Hydroxyphenyl)Pent-1-Ene—A Potent Metabolite of BPA, and 4-Tert-Octylphenol: A Computational Insight

RESEARCH ARTICLE Androgen and Progesterone Receptors Are Targets for Bisphenol A (BPA), 4-Methyl-2,4bis-(P-Hydroxyphenyl)Pent-1-Ene—A Potent Metabolite of BPA, and 4-Tert-Octylphenol: A Computational Insight Mohd Rehan1, Ejaz Ahmad1, Ishfaq A. Sheikh1, Adel M. Abuzenadah2, Ghazi A. Damanhouri1, Osama S. Bajouh3, Samera F. AlBasri3, Mansour M. Assiri3, Mohd A. Beg1* 1 King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia, 2 KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia, 3 Department of Obstetrics and Gynecology, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia OPEN ACCESS Citation: Rehan M, Ahmad E, Sheikh IA, Abuzenadah AM, Damanhouri GA, Bajouh OS, et al. (2015) Androgen and Progesterone Receptors Are Targets for Bisphenol A (BPA), 4-Methyl-2,4-bis-(PHydroxyphenyl)Pent-1-Ene—A Potent Metabolite of BPA, and 4-Tert-Octylphenol: A Computational Insight. PLoS ONE 10(9): e0138438. doi:10.1371/ journal.pone.0138438 Editor: Mohammad Saleem, Hormel Institute, University of Minnesota, UNITED STATES Received: June 30, 2015 Accepted: August 31, 2015 Published: September 17, 2015 Copyright: © 2015 Rehan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper. Funding: This project was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, under grant no. 434/019-T. The authors, therefore, acknowledge with thanks DSR technical and financial support. Competing Interests: The authors have declared that no competing interests exist. * Abstract Exposure to toxic industrial chemicals that have capacity to disrupt the endocrine system, also known as endocrine disrupting chemicals (EDCs), has been increasingly associated with reproductive problems in human population. Bisphenol A (BPA; 4,4'-(propane-2,2-diyl) diphenol) and 4-tert-octylphenol (OP; 4-(1,1,3,3-tetramethylbutyl)phenol) are among the most common environmental contaminants possessing endocrine disruption properties and are present in plastics, epoxy resins, detergents and other commercial products of common personal and industrial use. A metabolite of BPA, 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1ene (MBP) is about 1000 times more biologically active compared to BPA. Epidemiological, clinical, and experimental studies have shown association of BPA and OP with adverse effects on male and female reproductive system in human and animals. The endocrine disruption activity can occur through multiple pathways including binding to steroid receptors. Androgen receptor (AR) and progesterone receptor (PR) are critical for reproductive tract growth and function. Structural binding characterization of BPA, MBP, and OP with AR and PR using molecular docking simulation approaches revealed novel interactions of BPA with PR, and MBP and OP with AR and PR. For BPA, MBP, and OP, five AR interacting residues Leu-701, Leu-704, Asn-705, Met-742, and Phe-764 overlapped with those of native AR ligand testosterone, and four PR interacting residues Leu-715, Leu-718, Met-756, and Met759 overlapped with those of PR co-complex ligand, norethindrone. For both the receptors the binding strength of MBP was maximum among the three compounds. Thus, these compounds have the potential to block or interfere in the binding of the endogenous native AR and PR ligands and, hence, resulting in dysfunction. The knowledge of the key interactions and the important amino-acid residues also allows better prediction of potential of xenobiotic PLOS ONE | DOI:10.1371/journal.pone.0138438 September 17, 2015 1 / 18 Androgen and Progesterone Receptors and Endocrine Disruptors molecules for disrupting AR- and PR-mediated pathways, thus, helping in design of less potent alternatives for commercial use. Introduction Infertility, defined as a condition when couples are unable to have children, is one of the major problems affecting human health and socio-cultural life. Nearly 72 million couples constituting about 15% of the reproductive-age couples across the world are affected by infertility [1]. Infertility is a public problem and it not only affects the couple’s life but it also affects the health care services and social environment. Depression, grief, guilt, shame, and inadequacy with social isolation are commonly experienced by the infertile couples [2,3]. In general, about 80– 85% of cases of infertility are either due to individual male or female factors or due to combination of problems in both partners [4]. The remaining 15–20% cases are due to unexplained infertility and no diagnosis can be made after a complete investigation. Exposure to toxic industrial chemicals that have capacity to disrupt the functions of the endocrine system, also known as endocrine disrupting chemicals (EDCs), in the environment has been increasingly associated with reproductive problems leading to infertility in human population [5,6]. Detection of EDCs in human serum and other fluids has led to the suggestions that these compounds may have adverse effects on the hormonal milieu of the human body leading to various endocrinological and reproductive impairments [7,8]. Bisphenol A (BPA; 4,4'-(propane-2,2-diyl)diphenol) and 4-tert-octylphenol (OP; 4-(1,1,3,3-tetramethylbutyl)phenol) are among the most common environmental contaminants possessing endocrine disruption properties and are known to have weak estrogenic activity. A potent metabolite of BPA, 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) has 1000 times stronger binding activity compared to BPA for estrogen receptors [9,10]. Two-dimensional chemical structures of BPA, MBP, and OP are presented in Fig 1. A study [11] conducted by the Centers for Disease Control and Prevention, USA revealed that 93% of the 2517 human urine samples contained detectable levels of BPA indicating ubiquitous exposure of the human population. BPA is a high production volume chemical used worldwide in the plastic industry and OP is widely used in surfactants, detergents, and cleaners in domestic and industrial products. The annual production of BPA in the world currently is about 8 billion pounds with about 100 tons getting released into the atmosphere each year [12]. The plastics and epoxy resins containing BPA are used in products such as water bottles, baby bottles, eyeglass lenses, medical equipment, toys, CDs/DVDs, cell phones, consumer electronics, household appliances, sports safety equipment, airplanes, and automobiles that impact our daily lives. Epoxy resins containing BPA are used as liners for most food and beverage cans, adhesives, industrial protective coatings, and automotive primers. Many extensive studies have b (...truncated)