Bisphenol-A analogs induce lower urinary tract dysfunction in male mice.

Bisphenol-A (BPA), an estrogenic endocrine disrupting chemical, significantly impacts numerous diseases and abnormalities in mammals. Estrogens are known to play an important role in the biology of the prostate; however, little is known about the role of bisphenols in the etiology of prostate pathologies, including benign prostate hyperplasia (BPH) and associated lower urinary tract dysfunction (LUTD). Bisphenol-F (BPF) and bisphenol-S (BPS) are analogs often used as substitutes for BPA; they are both reported to have in vitro and in vivo estrogenic effects similar to or more potent than BPA. The objective of this study was to assess the role of these bisphenols in the development of LUTD in adult male mice. In adult mice exposed to BPA, BPS or BPF, we examined urinary tract histopathology and physiological events associated with urinary dysfunction. Mice treated with bisphenols displayed increased bladder (p < 0.005) and prostate (p < 0.0001) mass, and there was an increased number of prostatic ducts in the prostatic urethra (p < 0.05) and decreased size of the urethra lumen (p < 0.05) compared to negative controls. After two months of bisphenol exposure, mice displayed notable differences in cystometric tracings compared to controls, consistent with LUTD. Treatment of male mice with all bisphenols also induced voiding dysfunction manifested by detrusor instability and histologic changes in the prostatic urethra of male rodents, consistent with LUTD. Our results implicate BPA and its replacements in the development and progression LUTD in mice and provide insights into the development and progression of BPH/LUTS in men.

Identification of the Active Ingredient and Beneficial Effects of Vitex rotundifolia Fruits on Menopausal Symptoms in Ovariectomized Rats.

Estrogen replacement therapy is a treatment to relieve the symptoms of menopause. Many studies suggest that natural bioactive ingredients from plants resemble estrogen in structure and biological functions and can relieve symptoms of menopause. The fruit of V. rotundifolia, called "Man HyungJa" in Korean, is a traditional medicine used to treat headache, migraine, eye pain, neuralgia, and premenstrual syndrome in Korea and China. The aim of the present study was to confirm that V. rotundifolia fruit extract (VFE) exerts biological functions similar to those of estrogen in menopausal syndrome. We investigated its in vitro effects on MCF-7 cells and in vivo estrogen-like effects on weight gain and uterine contraction in ovariectomized rats. Using the polar extract, the active constituents of VFE (artemetin, vitexicarpin, hesperidin, luteolin, vitexin, and vanillic acid) with estrogen-like activity were identified in MCF-7 cells. In animal experiments, the efficacy of VFE in ameliorating body weight gain was similar to that of estrogen, as evidenced from improvements in uterine atrophy. Vitexin and vitexicarpin are suggested as the active constituents of V. rotundifolia fruits.

Impacts of brewing time, brewing temperature and brands on the leaching of phthalates and bisphenol A in dry tea.

Although tea is often considered a healthy drink, there is the possibility for it to contain bisphenol A and phthalates. This project was designed to quantitate the amount of these compounds when tea was prepared in a variety of conditions, and with a variety of different brands and flavours. BPA and phthalates were extracted using solid phase extraction and quantitated using gas chromatography - mass spectrometry. The leaching concentration of di-n-butyl phthalate, a major phthalate in dry tea samples, increased with respect to both brewing time and temperature at rates of 5.9 ng/g/min and 2.3 ng/g/°C, respectively. Loose leaf green teas showed lower concentrations of contaminants than bagged teas. The highest concentrations found of all compounds were for benzylbutyl phthalate in both Brand2 English breakfast and Brand2 green teas with concentrations of 244 ± 76 ng/g and 197 ± 9 ng/g, respectively. Di-n-butyl phthalate, benzylbutyl phthalate and bis-2-ethylhexyl phthalate were all present in concentrations of 50 ng/g or more in 3 or more samples.

The combined toxicity of ultra-small SiO2 nanoparticles and bisphenol A (BPA) in the development of zebrafish.

The complex combined effects of nanoparticles and environmental pollutants in the aqueous environment will inevitably affect aquatic ecosystem and human life. Bisphenol A (BPA) is listed as a typical kind of endocrine disruptors, there is little research about the joint toxicity of co-exposure of SiO2 nanoparticles (NPs) and BPA. In this study, fluorescent ultra-small SiO2 NPs (US-FMSNs) around 6.3 nm were synthesized and investigated for their combined effects with BPA on zebrafish during the early developmental stages within 4-168 h post fertilization (hpf). The results showed that US-FMSNs could accumulate in the chorion, abdomen and intestine in zebrafish. In addition, the different concentration (0.1, 1, 10 µg/mL) of BPA and US-FMSNs (200 µg/mL) demonstrated strong impact on multiple toxic endpoints at four periods (72, 96, 120, 168 hpf). We found US-FMSNs had no significant toxic effect on zebrafish, while BPA (10 µg/mL) showed a degree of developmental toxicity. Compared with single BPA (10 µg/mL) exposure, combined exposure enhanced the developmental toxicity of zebrafish, including increased mortality, decreased hatching rate and body length, and decreased activity of total superoxide dismutase (T-SOD) and increased malondialdehyde (MDA) levels. Our results indicated that US-FMSNs and BPA induced oxidative stress, and the effect of the co-exposure was less than that of single exposure (10 µg/mL). This study hereby provides a basis for the potential ecological and health risks of SiO2 NPs and BPA exposure.

Adsorptive removal of endocrine disrupting compounds from aqueous solutions using magnetic multi-wall carbon nanotubes modified with chitosan biopolymer based on response surface methodology: Functionalization, kinetics, and isotherms studies.

Recently, the presence of endocrine disrupting compounds in the environment has emerged as a global and ubiquitous problem. In this study, a novel synthesis of magnetically carbon nanotube modified with biological polymeric was successfully prepared. The effect of different parameters on the Bisphenol A (BPA) adsorption was studied. A prediction model for BPA adsorption was extended based on the Central Composite Design. Also, the prepared biopolymeric nanotubes were characterized by FT-IR, XRD, TEM, FE-SEM. The surface morphology of nanocomposite was observed, increased carbon nano tube size, and the levels after surface deposition were completely covered by chitosan proteins. The results of our experiments showed that optimum adsorption conditions was achieved at t = 76 min, BPA concentration 6.5 mg/L, adsorbent dosage 1 g/L and pH = 6.2.The data obtained in this study followed the Langmuir isotherm model and the pseudo-second order model. The maximum monolayer adsorption capacity of nanocomposite for BPA was 46.2 mg/g at 20 °C. This study showed that the adsorption of BPA onto nanocomposite was spontaneous and thermodynamically desirable.

Bisphenol A binding promiscuity: A virtual journey through the universe of proteins.

Significant efforts are currently being made to move toxicity testing from animal experimentation to human relevant, mechanism-based approaches. In this context, the identification of molecular target(s) responsible for mechanisms of action is an essential step. Inspired by the recent concept of polypharmacology (the ability of drugs to interact with multiple targets) we argue that whole proteome virtual screening might become a breakthrough tool in toxicology reflecting the real complexity of chemical-biological interactions. Therefore, we investigated the value of performing ligand-protein binding prediction screening across the full proteome to identify new mechanisms of action for food chemicals. We applied the new approach to make a broader comparison between bisphenol A (BPA) (food-packaging chemical) and the endogenous estrogen, 17ß-estradiol (EST). Applying a novel high-throughput ligand-protein binding prediction tool (BioGPS) by the Amazon Web Services (AWS) cloud (to speed-up the calculation), we investigated the value of performing in silico screening across the full proteome (all human and rodent x-ray protein structures available in the Protein Data Bank). The strong correlation between in silico predictions and available in vitro data demonstrates the high predictive power of the method used. The most striking results obtained was that BPA was predicted to bind to many more proteins than the ones already known, most of which were common to EST. Our findings provide a new and unprecedented insight on the complexity of chemical-protein interactions, highlighting the binding promiscuity of BPA and its broader similarity compared to the female sex hormone, EST.

A Novel Adsorbent Albite Modified with Cetylpyridinium Chloride for Efficient Removal of Zearalenone.

Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin and constitutes a potential health threat to humans and livestock. This study aimed to explore the potential of albite modified by the cationic surfactant cetylpyridinium chloride (CPC) as ZEN adsorbent. The organoalbite (OA) was characterized by SEM analysis, XRD analysis, FTIR spectroscopy, thermal analysis, and BET gas sorption measurement. In vitro adsorption of ZEN by OA was carried out by simulating the pH conditions of the gastrointestinal tract. The characterization results showed that the surface of OA changed from hydrophilic to hydrophobic after modification. Adsorption kinetic studies showed that ZEN adsorption behavior of OA occurred by chemisorption. The equilibrium adsorption data fitted well with the Langmuir isotherm, indicating that the adsorption process of ZEN by OA was monolayer. The maximum adsorption capacity (qm) values of OA for ZEN were 10.580 and 9.287 mg/g at pH 7 and pH 3, respectively. In addition, OA had a low desorption rate (about 2%), and co-existing amino acids (i.e., Lys and Met), vitamins (i.e., VB1 and VE), and minerals (i.e., Fe2+ and Ca2+) did not affect the removal of ZEN. These results demonstrate that OA could be a promising mycotoxin adsorbent for removing the hydrophobic, weakly polar ZEN.

Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors.

Bisphenol A (BPA) is used as an industrial raw material for polycarbonate plastics and epoxy resins; however, various concerns have been reported regarding its status as an endocrine-disrupting chemical. BPA interacts not only with oestrogen receptors (ERs) but constitutive androstane receptor, pregnane X receptor, and oestrogen-related receptor γ (ERRγ); therefore, the bisphenol structure represents a privileged structure for the nuclear-receptor superfamily. Here, we screen 127 BPA-related compounds by competitive-binding assay using [3H]oestradiol and find that 20 compounds bind to ERα with high affinity. We confirm most of these as ERα agonists; however, four compounds, including bisphenol M and bisphenol P act as novel antagonists. These structures harbour three benzene rings in tandem with terminal hydroxy groups at para-positions, with this tandem tri-ring bisphenol structure representing a novel privileged structure for an ERα antagonist. Additionally, we perform an ab initio calculation and develop a new clipping method for halogen bonding or non-covalent interaction using DV-Xα evaluation for biomolecules.

Simultaneous analysis of bisphenol A fractions in maternal and fetal compartments in early second trimester of pregnancy.

Background Bisphenol A (BPA) is an estrogenic, endocrine-disrupting compound widely used in the industry. It is also a ubiquitous environmental pollutant. Its presence was confirmed in human fetuses, which results from maternal exposure during pregnancy. The mechanisms behind maternal-fetal transfer, and relationships between pregnant women and fetal exposures remain unclear. The aim of this study was to assess the impact of maternal exposure to BPA on the exposure of the fetus. Methods Maternal plasma and amniotic fluid samples were collected from 52 pregnant women undergoing amniocentesis for prenatal diagnosis of chromosomal abnormalities. BPA was measured by gas chromatography-mass spectrometry (GC-MS). The permeability factor - a ratio of fetal-to-maternal BPA concentration - was used as a measure delineating the transplacental transfer of BPA. Results The median concentration of maternal plasma BPA was 8 times higher than the total BPA concentration in the amniotic fluid (8.69 ng/mL, range: 4.3 ng/mL-55.3 ng/mL vs. median 1.03 ng/mL, range: 0.3 ng/mL-10.1 ng/mL). There was no direct relationship between the levels of BPA in maternal plasma and amniotic fluid levels. The permeability factor, in turn, negatively correlated with fetal development (birth weight) (R = -0.54, P < 0.001). Conclusion Our results suggest that the risk of fetal BPA exposure depends on placental BPA permeability rather than the levels of maternal BPA plasma concentration and support general recommendations to become aware and avoid BPA-containing products.

Profiling of bisphenol A and eight its analogues on transcriptional activity via human nuclear receptors.

Several bisphenol A (BPA) analogues have been detected in environmental samples, foodstuffs, and/or human biological samples, and there is concern regarding their potential endocrine-disrupting effects. In this study, we characterized the agonistic and/or antagonistic activities of BPA and eight its analogues against human estrogen receptors (ERα/ß), androgen receptor (AR), glucocorticoid receptor (GR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR). All the test compounds, except for bisphenol P (BPP), showed both ERα and ERß agonistic activities, with bisphenol AF (BPAF) being the most potent. On the other hand, BPAF and BPP showed ERα and ERß antagonistic activities. Interestingly, their ER activities demonstrated a preference toward ERß. All the test compounds, except for bisphenol S, showed AR antagonistic activities, with bisphenol E being the most potent. Weak GR antagonistic activities were also found in BPA and five its analogues. PXR agonistic activity was observed in the six compounds, with bisphenol Z being the most potent. Results of the CAR assay revealed that BPA and five its analogues acted as CAR inverse agonists. Taken together, these results suggested that BPA analogues demonstrate multiple effects via human nuclear receptors in a similar manner to BPA, and several analogues might have more potent endocrine-disrupting activity than does BPA.

Nonsteroidal estrogen receptor isoform-selective biphenyls.

Estrogen receptor (ER) has been a therapeutic target to treat ER-positive breast cancer, most notably by agents known as selective estrogen receptor modulators (SERMs). However, resistance and severe adverse effects of known drugs gave impetus to the search for newer agents with better therapeutic profile. ERα and ERß are two isoforms sharing 56% identity and having different physiological functions and expressions in various tissues. Only two residues differ in the active sites of the two isoforms motivating us to design isoform-selective ligands. Guided by computational docking and molecular dynamics simulations, we have designed, synthesized, and tested, substituted biphenyl-2,6-diethanones and their derivatives as potential agents targeting ERα. Four of the molecules synthesized exhibited preferential cytotoxicity in ERα+ cell line (MCF-7) compared to ERß+ cell line (MDA-MB-231). Molecular dynamics (MD) in combination with molecular mechanics-generalized Born surface area (MM-GBSA) methods could account for binding selectivity. Further cotreatment and E-screen studies with known ER ligands-estradiol (E2 ) and tamoxifen (Tam)-indicated isoform-selective anti-estrogenicity in ERα+ cell line which might be ER-mediated. ERα siRNA silencing experiments further confirmed the ER selective nature of ligands.

Estrogenicity of halogenated bisphenol A: in vitro and in silico investigations.

The binding interactions of bisphenol A (BPA) and its halogenated derivatives (halogenated BPAs) to human estrogen receptor α ligand binding domain (hERα-LBD) was investigated using a combined in vitro and in silico approach. First, the recombinant hERα-LBD was prepared as a soluble protein in Escherichia coli BL21(DE3)pLysS. A native fluorescent phytoestrogen, coumestrol, was employed as tracer for the fluorescence polarization assay. The results of the in vitro binding assay showed that bisphenol compounds could bind to hERα-LBD as the affinity ligands. All the tested halogenated BPAs exhibited weaker receptor binding than BPA, which might be explained by the steric effect of substituents. Molecular docking studies elucidated that the halogenated BPAs adopted different conformations in the flexible hydrophobic ligand binding pocket (LBP), which is mainly dependent on their distinct halogenation patterns. The compounds with halogen substituents on the phenolic rings and on the bridging alkyl moiety acted as agonists and antagonists for hERα, respectively. Interestingly, all the compounds in the agonist conformation of hERα formed a hydrogen bond with His524, while the compounds in the antagonist conformation formed a hydrogen bond with Thr347. These docking results suggested a pivotal role of His524/Thr347 in maintaining the hERα structure in the biologically active agonist/antagonist conformation. Comparison of the calculated binding energies vs. experimental binding affinities yielded a good correlation, which might be applicable for the structure-based design of novel bisphenol compounds with reduced toxicities and for environmental risk assessment. In addition, based on hERα-LBD as a recognition element, the proposed fluorescence polarization assay may offer an alternative to chromatographic techniques for the multi-residue determination of bisphenol compounds.

Characterizing properties of non-estrogenic substituted bisphenol analogs using high throughput microscopy and image analysis.

Animal studies have linked the estrogenic properties of bisphenol A (BPA) to adverse effects on the endocrine system. Because of concerns for similar effects in humans, there is a desire to replace BPA in consumer products, and a search for BPA replacements that lack endocrine-disrupting bioactivity is ongoing. We used multiple cell-based models, including an established multi-parametric, high throughput microscopy-based platform that incorporates engineered HeLa cell lines with visible ERα- or ERß-regulated transcription loci, to discriminate the estrogen-like and androgen-like properties of previously uncharacterized substituted bisphenol derivatives and hydroquinone. As expected, BPA induced 70-80% of the estrogen-like activity via ERα and ERß compared to E2 in the HeLa prolactin array cell line. 2,2' BPA, Bisguaiacol F, CHDM 4-hydroxybuyl acrylate, hydroquinone, and TM modified variants of BPF showed very limited estrogen-like or androgen-like activity (< 10% of that observed with the control compounds). Interestingly, TM-BFP and CHDM 4-hydroxybuyl acrylate, but not their derivatives, demonstrated evidence of anti-estrogenic and anti-androgenic activity. Our findings indicate that Bisguaiacol F, TM-BFP-ER and TM-BPF-DGE demonstrate low potential for affecting estrogenic or androgenic endocrine activity. This suggest that the tested compounds could be suitable commercially viable alternatives to BPA.

Synthesis and characterization of Fullerene modified ZnAlTi-LDO in photo-degradation of Bisphenol A under simulated visible light irradiation.

In this study, ZnAlTi layered double hydroxide (ZnAlTi-LDH) combined with fullerene (C60) was fabricated by the urea method, and calcined under vacuum atmosphere to obtain nanocomposites of C60-modified ZnAlTi layered double oxide (ZnAlTi-LDO). The morphology, structure and composition of the nanocomposites were analyzed by Scanning Electron Microscopy, High-resolution transmission electron microscopy, X-ray diffraction patterns, Fourier transform infrared and specific surface area. The UV-vis diffuse reflectance spectra indicated that the incorporation of C60 expanded the absorption of ZnAlTi-LDO to visible-light region. The photo-degradation experiment was conducted by using a series of C60 modified ZnAlTi-LDO with different C60 weight percentage to degrade Bisphenol A (BPA) under simulated visible light irradiation. In this experiment, the degradation rate of C60 modified ZnAlTi-LDO in photo-degradation of BPA under simulated visible light irradiation was over 80%. The intermediates formed in the degradation of BPA process by using LDO/C60-5% were 4-hydroxyphenyl-2-propanol, 4-isopropenylphenol and Phenol. Photogenerated holes, superoxide radical species, ·OH and singlet oxygen were considered to be responsible for the photodegradation process, among which superoxide radical species and ·OH played a predominant role in the photocatalytic reaction system. C60 modified ZnAlTi-LDO catalysts for photocatalytic reduction shows great potential in degradation of organic pollutants and environmental remediation.

Development of a new colorimetric assay for detection of bisphenol-A in aqueous media using green synthesized silver chloride nanoparticles: experimental and theoretical study.

In the present study, a cost-effective, green and simple synthesis method was applied for preparation of stable silver chloride nanoparticles (AgCl-NPs). The method was done by forming AgCl-NPs from Ag+ ions using aqueous extract of brown algae (Sargassum boveanum) obtained from the Persian Gulf Sea. This extract served as capping agent during the formation of AgCl-NPs. Creation of AgCl-NPs was confirmed by UV-visible spectroscopy, powder X-ray diffraction, energy-dispersive X-ray spectroscopy, and high-resolution transmission electron microscopy, while the morphology and size analyses were characterized using high-resolution transmission electron microscopy and dynamic light scattering. After optimization of some experimental conditions, particularly pH, a simple and facile system was developed for the naked-eye detection of bisphenol-A. Moreover, a theoretical study of AgCl interaction with bisphenol-A was performed at the density functional level of theory in both gas and solvent phases. Theoretical results showed that electrostatic and van der Waal interactions play important roles in complexation of bisphenol-A with AgCl-NPs, which can lead to aggregation of the as-prepared AgCl-NPs and results in color change from specific yellow to dark purple, where a new aggregation band induced at 542 nm appears. The absorbance at 542 nm was found to be linearly dependent on the bisphenol-A concentration in the range of 1 × 10-6-1 × 10-4 M, with limit of detection of 45 nM. In conclusion, obtained results from the present study can open up an innovative application of the green synthesis of AgCl-NPs using brown algae extract as colorimetric sensors.

Study on the uptake and deglycosylation of the masked forms of zearalenone in human intestinal Caco-2 cells.

This study investigated for the first time the intestinal transfer of two modified forms of zearalenone (ZEN), zearalenone-14-glucoside (ZEN14Glc) and zearalenone-16-glucoside (ZEN16Glc), using polarized monolayers of Caco-2 cells. The cells were apically exposed to 40 µM of ZEN14Glc, ZEN16Glc and ZEN, separately. Results showed that, after apical administration, ZEN14Glc and ZEN16Glc can be detected in cellular extracts indicating uptake by intestinal cells. Moreover, the glucosylated forms were cleaved to release ZEN, with a different cleavage ability for the two conjugated isomers. In particular, ZEN16Glc seems to be less prone to deglycosylation compared to ZEN14Glc, probably on account of an increased steric hindrance. We could show that human cytosolic ß-glucosidase is able to cleave ZEN14Glc liberating ZEN, but is unable to cleave ZEN16Glc.All metabolites could cross the cell membrane and be detected in the apical compartment, while ZEN was also found in the basolateral compartment together with the modified mycotoxin form.

3D QSAR studies of hydroxylated polychlorinated biphenyls as potential xenoestrogens.

Mono-hydroxylated polychlorinated biphenyls (OH-PCBs) are found in human biological samples and lack of data on their potential estrogenic activity has been a source of concern. We have extended our previous in silico 2D QSAR study through the application of advance techniques such as docking and 3D QSAR to gain insights into their estrogen receptor (ERα) binding. The results support our earlier findings that the hydroxyl group is the most important feature on the compounds; its position, orientation and surroundings in the structure are influential for the binding of OH-PCBs to ERα. This study has also revealed the following additional interactions that influence estrogenicity of these chemicals (a) the aromatic interactions of the biphenyl moieties with the receptor, (b) hydrogen bonding interactions of the p-hydroxyl group with key amino acids ARG394 and GLU353, (c) low or no electronegative substitution at para-positions of the p-hydroxyl group, (d) enhanced electrostatic interactions at the meta position on the B ring, and (e) co-planarity of the hydroxyl group on the A ring. In combination the 2D and 3D QSAR approaches have led us to the support conclusion that the hydroxyl group is the most important feature on the OH-PCB influencing the binding to estrogen receptors, and have enhanced our understanding of the mechanistic details of estrogenicity of this class of chemicals. Such in silico computational methods could serve as useful tools in risk assessment of chemicals.

Oxidation of organic contaminants by manganese oxide geomedia for passive urban stormwater treatment systems.

To advance cost-effective strategies for removing trace organic contaminants from urban runoff, the feasibility of using manganese oxides as a geomedia amendment in engineered stormwater infiltration systems to oxidize organic contaminants was evaluated. Ten representative organic chemicals that have previously been detected in urban stormwater were evaluated for reactivity in batch experiments with birnessite. With respect to reactivity, contaminants could be classified as: highly reactive (e.g., bisphenol A), moderately reactive (e.g., diuron) and unreactive (e.g., tris(2-chloro-1-propyl)phosphate). Bisphenol A and diuron reacted with birnessite to produce a suite of products, including ring-cleavage products for bisphenol A and partially dechlorinated products for diuron. Columns packed with manganese oxide-coated sand were used evaluate design parameters for an engineered infiltration system, including necessary contact times for effective treatment, as well as the impacts of stormwater matrix variables, such as solution pH, concentration of natural organic matter and major anions and cations. The manganese oxide geomedia exhibited decreased reactivity when organic contaminants were oxidized, especially in the presence of divalent cations, bicarbonate, and natural organic matter. Under typical conditions, the manganese oxides are expected to retain their reactivity for 25 years.

The molecular mechanism of bisphenol A (BPA) as an endocrine disruptor by interacting with nuclear receptors: insights from molecular dynamics (MD) simulations.

Bisphenol A (BPA) can interact with nuclear receptors and affect the normal function of nuclear receptors in very low doses, which causes BPA to be one of the most controversial endocrine disruptors. However, the detailed molecular mechanism about how BPA interferes the normal function of nuclear receptors is still undiscovered. Herein, molecular dynamics simulations were performed to explore the detailed interaction mechanism between BPA with three typical nuclear receptors, including hERα, hERRγ and hPPARγ. The simulation results and calculated binding free energies indicate that BPA can bind to these three nuclear receptors. The binding affinities of BPA were slightly lower than that of E2 to these three receptors. The simulation results proved that the binding process was mainly driven by direct hydrogen bond and hydrophobic interactions. In addition, structural analysis suggested that BPA could interact with these nuclear receptors by mimicking the action of natural hormone and keeping the nuclear receptors in active conformations. The present work provided the structural evidence to recognize BPA as an endocrine disruptor and would be important guidance for seeking safer substitutions of BPA.