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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.

Rehan M, Ahmad E, Sheikh IA, Abuzenadah AM, Damanhouri GA, Bajouh OS, AlBasri SF, Assiri MM, Beg MA - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.

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.

No MeSH data available.


Related in: MedlinePlus

Two dimensional structures of bisphenol A (BPA), 4-Methyl-2,4-bis-(p-hydroxyphenyl)pent-1-ene (MBP), and 4-tert-octylphenol (OP).The hydroxyl groups (-OH) are shown in red color.
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pone.0138438.g001: Two dimensional structures of bisphenol A (BPA), 4-Methyl-2,4-bis-(p-hydroxyphenyl)pent-1-ene (MBP), and 4-tert-octylphenol (OP).The hydroxyl groups (-OH) are shown in red color.

Mentions: 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 been published on BPA human exposure assessment and epidemiology (reviewed in [13]). The general population is exposed to the BPA through ingestion of contaminated food and drink stored in BPA containing plastic containers, inhalation of contaminated air and dust, and skin contact. A recent report [14] has shown that most human neonates are also exposed to BPA through colostrum and dairy product intake.


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.

Rehan M, Ahmad E, Sheikh IA, Abuzenadah AM, Damanhouri GA, Bajouh OS, AlBasri SF, Assiri MM, Beg MA - PLoS ONE (2015)

Two dimensional structures of bisphenol A (BPA), 4-Methyl-2,4-bis-(p-hydroxyphenyl)pent-1-ene (MBP), and 4-tert-octylphenol (OP).The hydroxyl groups (-OH) are shown in red color.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4574962&req=5

pone.0138438.g001: Two dimensional structures of bisphenol A (BPA), 4-Methyl-2,4-bis-(p-hydroxyphenyl)pent-1-ene (MBP), and 4-tert-octylphenol (OP).The hydroxyl groups (-OH) are shown in red color.
Mentions: 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 been published on BPA human exposure assessment and epidemiology (reviewed in [13]). The general population is exposed to the BPA through ingestion of contaminated food and drink stored in BPA containing plastic containers, inhalation of contaminated air and dust, and skin contact. A recent report [14] has shown that most human neonates are also exposed to BPA through colostrum and dairy product intake.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.

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.

No MeSH data available.


Related in: MedlinePlus