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

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-1-ene (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 Met-759 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 molecules for disrupting AR- and PR-mediated pathways, thus, helping in design of less potent alternatives for commercial use.

The effects of different bisphenol derivatives on oxidative stress, DNA damage and DNA repair in RWPE‐1 cells: A comparative study

“…BPA has the ability to bind and activate estrogen receptor (ER) subtypes (i.e., ERα, ERβ and particularly ERγ) (Teng et al, ). It has also been suggested to disturb the normal functioning of ER receptors, although it has lower affinity for nuclear ERs than estradiol (Rehan et al, ). Due to abundant exposure, the general population has higher circulating concentrations of BPA when compared to estradiol.…”

“…Due to abundant exposure, the general population has higher circulating concentrations of BPA when compared to estradiol. BPA can also disrupt androgenic signaling pathways, which play important roles in male sex organ development and reproductive functions (Rehan et al, ; Sidorkiewicz, Zaręba, Wołczyński, & Czerniecki, ; Teng et al, ).…”

Expression of Steroid Receptors in Ameloblasts during Amelogenesis in Rat Incisors

“…Among them, BPA has been shown to bind the estrogen receptors (ERα and ERβ) (Delfosse et al, 2012), GPR30 (or GPER) (Pupo et al, 2012) and ERRγ with a high affinity (Liu et al, 2012). It also directly or indirectly interferes with the activity of the androgen receptor (AR), the progesterone receptor (PGR), the glucocorticoid receptor (GR), and the PPARγ (Acconcia et al, 2015; Rehan et al, 2015). The mechanism of action of BPA in dental cells is even less evident as its putative receptors are poorly defined in dental tissues, except for ERα (Jedeon et al, 2014a).…”

Endocrine Disruption by Mixtures in Topical Consumer Products

“…The correlation between BPA, diabetes and obesity [82,130,131], hormone dependent cancers and reproductive impairment is well documented in animals but still limited to case studies [132] and to controversial data in human. Several metabolites of BPA are also being investigated as suspected endocrine disruptors [133]. The molecule was originally considered to show weak affinity for the estrogen receptors, however recent studies have shown it to be rather more effective than previously thought.…”