The Molecular Mechanism of Bisphenol A (BPA) as an Endocrine Disruptor by Interacting with Nuclear Receptors: Insights from Molecular Dynamics (MD) Simulations

Li, Lanlan; Wang, Qian Qian; Zhang, Yan; Niu, Yuzhen; Yao, Xiaojun; Liu, Huanxiang

doi:10.1371/journal.pone.0120330

Cited by 85 publications

(68 citation statements)

References 57 publications

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“…In fact, high doses of E 2 treatment are needed to induce complete male to female sex reversal in rainbow trout, tilapia and other teleosts (Krisfalusi & Nagler 2000, Bhandari et al 2005, Gennotte et al 2014. This might be explained by the following two possible reasons: i) though the ovarian differentiation occurs earlier than testicular differentiation, the male determining gene, such as amhy in tilapia, expresses even earlier than the female pathway genes (Eshel et al 2014, Li et al 2015a, and therefore high doses of E 2 are needed to antagonize the male pathway genes, which is further supported by the differential sensitivity of XY and YY genotypes to embryonic induced-feminization (Gennotte et al 2014); and ii) almost all steroidogenic enzyme genes are expressed in XX gonads but not in XY gonads at 5 dah (Tao et al 2013), and therefore high doses of E 2 are needed to induce those genes, especially cyp19a1a, expression for ovarian differentiation. Signals of Dmrt1 and Cyp19a1a could be simultaneously detected at 10 dah in the MT-XX gonad while Cyp19a1a disappeared latter on.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous exposure to estrogen and androgen resulted in feminization and endocrine disruption

Chen¹,

Jiang²,

Feng³

et al. 2016

Journal of Endocrinology

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Estrogen, which is synthesized earlier in females than androgen in males, is critical for sex determination in non-mammalian vertebrates. However, it remains unknown that what would happen to the gonadal phenotype if estrogen and androgen were administrated simultaneously. In this study, XY and XX tilapia fry were treated with the same dose of 17a-methyltestosterone (MT) and 17b-estradiol (E 2 ) alone and in combination from 0 to 30 days after hatching. Treatment of XY fish with E 2 resulted in male to female sex reversal, while treatment of XX fish with MT resulted in female to male sex reversal. In contrast, simultaneous treatment of XX and XY fish with MT and E 2 resulted in female, but with cyp11b2 and cyp19a1a co-expressed in the ovary. Serum 11-ketotestosteron level of the MT and E 2 simultaneously treated XX and XY female was similar to that of the XY control, while serum E 2 level of these two groups was similar to that of the XX control. Transcriptomic cluster analysis revealed that the MT and E 2 treated XX and XY gonads clustered into the same branch with the XX control. However a small fraction of genes, which showed disordered expression, may be associated with stress response. These results demonstrated that estrogen could maintain the female phenotype of XX fish and feminize XY fish even in the presence of androgen. Simultaneous treatment with estrogen and androgen up-regulated the endogenous estrogen and androgen synthesis, and resulted in disordered gene expression and endocrine disruption in tilapia.

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Section: Discussionmentioning

confidence: 99%

Simultaneous exposure to estrogen and androgen resulted in feminization and endocrine disruption

Chen¹,

Jiang²,

Feng³

et al. 2016

Journal of Endocrinology

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“…Bisphenol A is commonly present in food packaging and is known to affect the normal function of nuclear receptors at very low doses. The simulations provided structural support for the capability of this xenoestrogen to bind to these receptors, where it appears to mimic the action of the natural hormone and keeps the nuclear receptors in active conformations [234]. These results could form the basis for identification of safer alternatives for BPA and safer packaging.…”

Section: Molecular Dynamicsmentioning

confidence: 78%

Applying Computational Scoring Functions to Assess Biomolecular Interactions in Food Science: Applications to the Estrogen Receptors

Spyrakis

Cozzini

Kellogg

2016

Nuclear Receptor Research

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Abstract. During the last decade, computational methods, which were for the most part developed to study protein-ligand interactions and especially to discover, design and develop drugs by and for medicinal chemists, have been successfully applied in a variety of food science applications [1,2]. It is now clear, in fact, that drugs and nutritional molecules behave in the same way when binding to a macromolecular target or receptor, and that many of the approaches used so extensively in medicinal chemistry can be easily transferred to the fields of food science. For instance, nuclear receptors are common targets for a number of drug molecules and could be, in the same way, affected by the interaction with food or food-like molecules. Thus, key computational medicinal chemistry methods like molecular dynamics can be used to decipher protein flexibility and to obtain stable models for docking and scoring in food-related studies, and virtual screening is increasingly being applied to identify molecules with potential to act as endocrine disruptors, food mycotoxins, and new nutraceuticals [3][4][5]. All of these methods and simulations are based on protein-ligand interaction phenomena, and represent the basis for any subsequent modification of the targeted receptor's or enzyme's physiological activity. We describe here the energetics of binding of biological complexes, providing a survey of the most common and successful algorithms used in evaluating these energetics, and we report case studies in which computational techniques have been applied to food science issues. In particular, we explore a handful of studies involving the estrogen receptors for which we have a long-term interest.

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“…Bisphenol A (BPA) (chemical structure of HO-C6H4-C(CH3)2-C6H4-OH) is an alkylphenol endocrine disruptor chemical (6) which was first synthesized by a Russian chemist Aleksandr Dianin in 1891. The ability of BPA to act as an estrogen agonist was not found until 1936 (7).…”

Section: Sources Of Exposure To Bpa and Its Derivativesmentioning

confidence: 99%

Bisphenol A and Male Reproductive System

Amraje¹,

Köylü²,

Dizakar³

et al. 2018

GMJ

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Bisphenol A (BPA) is an alkylphenol endocrine disruptor chemical (EDC). It is a building block for polycarbonate (PC) plastics and epoxy resins and it is used in food packaging, canned foods, baby bottles, baby food jars and medical devices. Recently, researchers have shown an increased interest in BPA and its effect on reproduction, neurodevelopment and metabolism. The experimental data are rather controversial, and there is no general consensus about BPA's effects. In this review, potential impacts of the BPA on male reproductive system in prenatal and postnatal period are summarized.

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The Molecular Mechanism of Bisphenol A (BPA) as an Endocrine Disruptor by Interacting with Nuclear Receptors: Insights from Molecular Dynamics (MD) Simulations

Cited by 85 publications

References 57 publications

Simultaneous exposure to estrogen and androgen resulted in feminization and endocrine disruption

Simultaneous exposure to estrogen and androgen resulted in feminization and endocrine disruption

Applying Computational Scoring Functions to Assess Biomolecular Interactions in Food Science: Applications to the Estrogen Receptors

Bisphenol A and Male Reproductive System

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