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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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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 SiO 2 nanoparticles (NPs) and BPA. In this study, fluorescent ultra-small SiO 2 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 SiO 2  NPs and BPA exposure., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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.

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., Competing Interests: Declaration of competing interest The authors of this article declare that they have no conflict of interests., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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, 17β-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.

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 (q m ) 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., VB 1 and VE), and minerals (i.e., Fe 2+ and Ca 2+ ) 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.

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.

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 [ 3 H]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.

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/β), 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 ERβ agonistic activities, with bisphenol AF (BPAF) being the most potent. On the other hand, BPAF and BPP showed ERα and ERβ antagonistic activities. Interestingly, their ER activities demonstrated a preference toward ERβ. 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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.

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 ERβ 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 ERβ+ 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 (E 2 ) 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., (© 2017 John Wiley & Sons A/S.)

In this study, ZnAlTi layered double hydroxide (ZnAlTi-LDH) combined with fullerene (C 60 ) was fabricated by the urea method, and calcined under vacuum atmosphere to obtain nanocomposites of C 60 -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 C 60 expanded the absorption of ZnAlTi-LDO to visible-light region. The photo-degradation experiment was conducted by using a series of C 60 modified ZnAlTi-LDO with different C 60 weight percentage to degrade Bisphenol A (BPA) under simulated visible light irradiation. In this experiment, the degradation rate of C 60 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/C 60 -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. C 60 modified ZnAlTi-LDO catalysts for photocatalytic reduction shows great potential in degradation of organic pollutants and environmental remediation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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 ERβ-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 ERβ 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.

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.

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 β-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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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., (Published by Elsevier Ltd.)

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.

A novel 8-electrode array as stir bar was designed for selective extraction of trace level exogenous estrogens from food samples, followed by liquid desorption and HPLC-photodiode array detection. The array consisted of 8 screen-printed electrodes and each electrode was modified with Fe3O4@meso-/macroporous TiO2 microspheres and molecularly imprinted film (m-TiMIF). The fabrication of the imprinted film coating was very simple without organic solvents and chemical grafting. Both bisphenol A (BPA) and diethylstilbestrol (DES) were employed as templates in m-TiMIF fabrication in order to enrich both targets simultaneously. Interestingly, the imprinted stir bar array showed higher extraction capacity and selectivity for BPA and DES than the non-imprinted counterpart. Meanwhile, it exhibited fast adsorption and desorption kinetics due to increased mass transport in the ultra-thin film. Importantly, the m-TiMIF coating was robust enough for at least 20 uses without obvious alteration in extraction performance. The main parameters affecting the extraction efficiency, including stir speeding, sample pH, ionic strength, extraction time, desorption solvent and time, were optimized. Under optimal experimental conditions, the limits of detection (S/N=3) of the developed method were 0.28 and 0.47 μg L(-1) for BPA and DES respectively, with enrichment factors of 32.6 and 52.8-fold. The linear ranges were 3.0-1500 μg L(-1) and 4.0-1500 μg L(-1) for BPA and DES, respectively. The m-TiMIF-coating conferred better recovery and selectivity, compared with the commercial stir bar coating. The new method was successfully applied to assess BPA and DES in pork and chicken samples with satisfactory recovery., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Over the last two decades, nonylphenols (NPs) have become to be known as a priority hazardous substance due primarily to its estrogenicity and ubiquitous occurrence in the environment. Nonylphenols are commonly treated as a single compound in the evaluation of their environmental occurrence, fate and transport, treatment or toxicity. However, technical nonylphenols (tNPs) are in fact a mixture of more than 100 isomers and congeners. Recent studies showed that some of these isomers behaved significantly differently in occurrence, estrogenicity and biodegradability. The most estrogenic isomer was about 2 to 4 times more active than tNP. Moreover, the half lives of the most recalcitrant isomers were about 3 to 4 times as long as those of readily-biodegradable isomers. Negligence of NP's isomer specificity may result in inaccurate assessment of its ecological and health effects. In this review, we summarized the recent publications on the analysis, occurrence, toxicity and biodegradation of NP at the isomer level and highlighted future research needs to improve our understanding of isomer-specificity of NP., (Copyright © 2014. Published by Elsevier Ltd.)

The present study investigates the in vitro phase I metabolism of cis-zearalenone (cis-ZEN) in rat liver microsomes and human liver microsomes. cis-ZEN is an often ignored isomer of the trans-configured Fusarium mycotoxin zearalenone (trans-ZEN). Upon the influence of (UV-) light, trans-ZEN isomerizes to cis-ZEN. Therefore, cis-ZEN is also present in food and feed. The aim of our study was to evaluate the in vitro phase I metabolism of cis-ZEN in comparison to that of trans-ZEN. As a result, an extensive metabolization of cis-ZEN is observed for rat and human liver microsomes as analyzed by HPLC-MS/MS and high-resolution MS. Kinetic investigations based on the substrate depletion approach showed no significant difference in rate constants and half-lives for cis- and trans-ZEN in rat microsomes. In contrast, cis-ZEN was depleted about 1.4-fold faster than trans-ZEN in human microsomes. The metabolite pattern of cis-ZEN revealed a total of 10 phase I metabolites. Its reduction products, α- and β-cis-zearalenol (α- and β-cis-ZEL), were found as metabolites in both species, with α-cis-ZEL being a major metabolite in rat liver microsomes. Both compounds were identified by co-chromatography with synthesized authentic standards. A further major metabolite in rat microsomes was monohydroxylated cis-ZEN. In human microsomes, monohydroxylated cis-ZEN is the single dominant peak of the metabolite profile. Our study discloses three metabolic pathways for cis-ZEN: reduction of the keto-group, monohydroxylation, and a combination of both. Because these routes have been reported for trans-ZEN, we conclude that the phase I metabolism of cis-ZEN is essentially similar to that of its trans isomer. As trans-ZEN is prone to metabolic activation, leading to the formation of more estrogenic metabolites, the novel metabolites of cis-ZEN reported in this study, in particular α-cis-ZEL, might also show higher estrogenicity.

Humic substance (HS) in sediment can affect hydrophobic organic compound distribution, transportation, bioavailability, and toxicity. This study investigated the HS (BKHS) extracted from sediment and separated it into low molecular humic (LMHS, <1kDa) and high molecular humic substances (HMHS, 1kDa-0.45μm). Nonylphenol (NP), octylphenol (OP), and bisphenol A (BPA) have a significant sorption capacity for HMHS and BKHS solutions. They are xenoestrogenic endocrine-disrupting compounds that are widely produced and discharged to the environment. The log KHS values of the BKHS and HMHS solutions were between 4.74-5.09Lkg-C(-1) and 4.57-5.09Lkg-C(-1), respectively. However, the three compounds were not sorbed by the LMHS solution. The average values of SUVA254 for HMHS and LMHS were 4.29 and 1.31Lm(-1)mg-C(-1) and the average values of A250-400 for HMHS and LMHS were 18.1 and 4.51nmcm(-1), respectively. The HMHS peak position in the fluorescence excitation/emission matrix at longer wavelengths corresponded to the peak position of LMHS, which indicates that the HMHS had a higher degree of humification than the LMHS. The results suggested that the KHS value's dominant factor was the degree of HS humification., (Copyright © 2014 Elsevier B.V. All rights reserved.)

We measured serum dBPA in non-pregnant and pregnant female rhesus monkeys, fetuses and amniotic fluid. dBPA was administered by a daily oral bolus or sc implantation of Silastic capsules; both resulted in daily average serum unconjugated dBPA concentrations of <1ng/ml. We observed lower serum concentrations of unconjugated dBPA in pregnant females relative to pre-pregnancy values, and generally lower concentrations in fetal serum than in maternal serum. Differences in pharmacokinetics of dBPA were evident between pre-pregnancy, early and late pregnancy, likely reflecting changes in maternal, fetal and placental physiology. The serum ratio of conjugated to unconjugated dBPA after continuous sc release of dBPA was similar to values reported in human biomonitoring studies and markedly lower than with oral administration, suggesting oral bolus exposure is not an appropriate human exposure model. We report elsewhere that there were numerous adverse effects on fetuses exposed to very low serum dBPA in these studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: We compared the pharmacokinetic (PK) profiles of diethylstilbestrol orally dissolving film (DES ODF) and DES-capsule as well as assessing the safety, local tolerability, taste, and disintegration time of DES ODF., Materials and Methods: Twelve healthy male volunteers receiving a single administration of 2.0 mg of DES ODF or DES-capsule were included in the study. The tolerability, taste, and time to dissolution of DES ODF were assessed after dosing. Safety assessments included adverse events, hematology and biochemistry tests, urinalysis, vital signs, and electrocardiography., Results: The PK parameters of DES ODF were all greater than those of DEScapsule. The Cmax values were 5.64 ± 1.1 and 3.4 ± 1.93 ng/mL for DES ODF and DES-capsule, respectively. Assessment of bioequivalence was based on the 90% CIs of the treatment ratios of the log-transformed Cmax, AUC0-t, and AUC0-∞ (DES ODF to DES-capsule), with the mean values being 1.93 (141 - 264), 1.24 (98 - 156), and 1.59 (121 - 207), respectively, indicating that DES ODF had a significantly high bioavailability. The mean DES ODF disintegration time was 14 ± 5 minutes. DES ODF was well tolerated and no serious adverse events or clinically relevant changes were observed., Conclusions: The DES ODF is well tolerated and better absorbed in comparison with DES-capsule.

Bisphenol A (BPA) is a well-known endocrine disruptor with adverse oestrogen-like effects eliciting adverse effects in humans and wildlife. For this reason it is necessary to set up an efficient removal of BPA from wastewaters, before they are discharged into surface waters. The aim of this study was to compare the efficiency of BPA removal from aqueous samples with photolytic, photocatalytic, and UV/H₂O₂ oxidation. BPA solutions were illuminated with different bulbs (halogen; 17 W UV, 254 nm; and 150 W UV, 365 nm) with or without the TiO₂ P-25 catalyst or H₂O₂ (to accelerate degradation). Acute toxicity and oestrogenic activity of treated samples were determined using luminescent bacteria (Vibrio fischeri), water fleas (Daphnia magna), zebrafish embryos (Danio rerio), and Yeast Estrogen Screen (YES) assay with genetically modified yeast Saccharomyces cerevisiae. The results confirmed that BPA is toxic and oestrogenically active. Chemical analysis showed a reduction of BPA levels after photolytic treatment and 100 % conversion of BPA by photocatalytic and UV/H₂O₂ oxidation. The toxicity and oestrogenic activity of BPA were largely reduced in photolytically treated samples. Photocatalytic oxidation, however, either did not reduce BPA toxic and oestrogenic effects or even increased them in comparison with the baseline, untreated BPA solution. Our findings suggest that chemical analysis is not sufficient to determine the efficiency of advanced oxidation processes in removing pollutants from water and needs to be complemented with biological tests.

A novel analytical method employing solid-phase extraction (SPE) coupled with ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous determination of 30 hormones in anti-ageing functional foods (capsules, powders and tablets). The analytes were extracted with acetic acid-acetonitrile (1-99 v/v), methanol and acetone, respectively. The extract was purified using a combined column, followed by analyte detection with electrospray ionisation in positive- or negative-ion modes. The results indicated that the 30 compounds had good linear correlations in the range of 1-1000 μg kg⁻¹, and the correlation coefficients were above 0.99. The limits of detection (LOD) and limits of quantification (LOQ) were 0.03-2 and 0.1-5 μg kg⁻¹, respectively. The average recovery of 30 compounds at the three spiked levels varied from 74.7% to 124.1%, and the relative standard deviation (RSD) was 2.4-15.0%. This method was applied to the analysis of hormones in 14 real samples of which seven hormones (such as estrone, dienestrol) were detected in four samples, but the remainder of the hormones were not detected. The developed method is sensitive, efficient, reliable and applicable to real samples.

Bisphenol-A (BPA) is one of the highest-volume chemicals produced worldwide and the widespread exposure of individuals to BPA is suspected to affect a variety of physiological functions, including reproduction, development, and metabolism. Its estrogenic activity has been well documented in the last 15 years. In addition to estrogen receptors, BPA has been also shown to bind to and activate the estrogen-related receptor γ and pregnane X receptor and inhibit the androgen receptor. Halogenated BPAs were also shown to activate the peroxisome proliferator-activated receptor γ and inhibit thyroid hormone receptors. In this chapter, we review recent studies shedding light on the structural and molecular mechanisms by which BPA and its halogenated derivatives interfere with nuclear hormone receptor signaling. These data provide guidelines for the development of safer substitutes devoid of hormonal activity and may help environmental risk assessment., (© 2014 Elsevier Inc. All rights reserved.)

Breast cancer is one of the most high-profile malignant diseases in modern society. Among postmenopausal women affected by the disease, a substantial portion has breast tumors that are estrogen-receptor positive. A common therapeutic intervention for this type of cancer is through endocrine therapy. Endocrine agents can act by either diminishing the availability or inhibiting the binding of estrogens to ER. Aromatase catalyzes the conversion of androgens to estrogens in the final step of the biosynthesis of estrogens and is therefore an attractive therapeutic target for inhibition. 3DQSAR pharmacophore modeling studies were undertaken for biphenyl derivatives as aromatase inhibitors in JEG-3 cell lines. A four-point pharmacophore with two H-bond acceptors and two aromatic rings as pharmacophoric features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R² = 0.977 for training set molecules. The generated model showed excellent predictive power, with a correlation coefficient of Q² = 0.946 for an external test set. The 3D-QSAR plots illustrated insights into the structure activity relationship of these compounds which may help in the design and development of potent biphenyl derivatives as new aromatase inhibitors.

A simple and cost-effective pre-treatment procedure was developed for six resorcylic acid lactones (RALs) in feed using dispersive solid phase extraction (dSPE) with multi-walled carbon nanotubes (MWCNTs). The sample was analysed after purification by ultra-high performance liquid chromatography-negative electrospray ionisation tandem mass spectrometry (UHPLC-ESI-MS/MS). After extraction with acetonitrile/water (80:20, v/v) and dilution with water, a dSPE procedure was carried out with MWCNTs. The pH value of the extract, the extraction time for MWCNTs, the type and amount of MWCNTs and the type of eluent were optimised to increase the sample throughput and the sensitivity. The samples were quantified using the internal standard zearalenone-D6. The absolute recoveries of the target compounds from feed samples were most efficient when using 100mg of MWCNTs with an outer diameter of less than 8nm and a length of 10-30μm, and ethyl acetate was shown to be the most suitable solvent for desorbing the target compounds from the MWCNTs. The mean recoveries from fortified swine mixed feed samples ranged from 95.3% to 107.2% and had relative standard deviations lower than 10%; the limits of detection and quantification for RALs were in the ranges of 0.20-0.29μg/kg and 0.54-0.78μg/kg, respectively., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Magnetic molecularly imprinted polymers (M-MIPs) for bisphenol A (BPA) and its structural analogues have been prepared by a multi-step swelling and polymerization method using uniformly-sized magnetic particles as a shape template. Binding experiments and Scatchard analyses revealed that two classes of binding sites were formed on M-MIP(BPA). The retention and molecular-recognition properties of M-MIPs for BPA and its structural analogues were evaluated using a mixture of phosphate buffer and acetonitrile or a mixture of water and acetonitrile as a mobile phase by LC. M-MIPs for BPA and [²H₁₆]BPA (BPA-d₁₆), M-MIP(BPA) and M-MIP(BPA-d16), showed almost the same imprinting factors for BPA, while M-MIP for bisphenol B (2,2-bis(4-hydroxyphenyl)butane, BPB), M-MIP(BPB), gave the moderate imprinting factor for BPA. Furthermore, M-MIP(BPB) was applied for the selective extraction and determination of BPA in environmental water samples. The concentration of BPA in river water samples was determined to be 68 ng/L., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Dispersive liquid-liquid microextraction combined with capillary zone electrophoresis-UV detection was developed for analyzing triclosan (TCS) and bisphenol A (BPA) in water, beverage, and urine samples. The factors influencing microextraction efficiencies, such as the kind and volume of extraction and dispersive solvent, the extraction time, and the salt effect, were optimized. A background electrolyte composed of 8 mM sodium tetraborate at pH 9.8 was used as the running buffer. Detection was performed at 214 nm. Under the optimum conditions (sample volume, 5.0 mL; extraction solvent, tetrachloroethane, 22.0 microL; dispersive solvent, tetrahydrofuran, 1.0 mL; extraction time, fewer than 5 s; and without salt addition), the enrichment factors were 110.2 and 82.0 for TCS and BPA, respectively. The linear range was 0.02-2 microg/mL with correlation coefficients of 0.9966-0.9969. LODs were in the range of 4.0-8.0 ng/mL. The environmental water, beverage, and urine samples (at spiking levels of 0.1 and 0.4 microg/mL) were successfully analyzed by the proposed method; the recoveries compared to previous methods were in the range of 81.2-103.3%. As a result, this method can be successfully applied for the rapid and convenient determination of TCS and BPA in water, beverage, and urine samples.

The release of Bisphenol A (BPA) from polycarbonate baby bottles into food and food simulants is reviewed in the perspective of the current intensive discussions on the risks of this substance. Potential factors that have been reported to influence the release of BPA are reviewed. Unlike most polymers polycarbonate is hydrolyzed under alkaline conditions by scale formation, residual alkaline detergents and boiled water. Data suggest that brushing of the bottle did not raise the release of BPA. Claims that used bottles release more BPA than new bottles and that mineral composition of the aqueous food simulant affect release could not be substantiated. There are indications that aminolysis of polycarbonate by milk and ethanolysis of polycarbonate by 50% ethanol might take place under relevant test conditions. The relatively few migration data following the test conditions of European food contact material legislation, comply with the specific migration limit. Two test conditions were identified that reflect real use and exposure, and might cause higher release of BPA compared to the test conditions of European food contact material legislation. Further detailed studies are necessary to verify whether these two exposure scenarios are more severe.

Wastewater treatment plant (WWTP) effluents are considered to be a major source for the release in the aquatic environment of endocrine-disrupting compounds (EDCs). Ozone has proved to be a suitable solution for polishing secondary domestic effluents. In this work, the performance of a full-scale ozonation plant was investigated in order to assess the removal efficiency of four target EDCs: nonylphenol, nonylphenol monoethoxylate, nonylphenol diethoxylate and bisphenol A. The studied system was the tertiary treatment stage of a municipal WWTP which receives an important industrial (textile) load. Chemical analyses showed that the considered substances occurred with a significant variability, typical of real wastewaters; based on this, ozonation performance was carefully evaluated and it appeared to be negatively affected by flow-rate increase (during rainy days, with consequent contact time reduction). Moreover, EDCs' measured removal efficiency was lower than what could be predicted based on literature data, because of the relatively high residual content of biorefractory compounds still present after biological treatment.

The kinetics for reaction between bisphenol A (BPA) and permanganate was examined over pH range of 5.0-9.9 and the estrogenic activity of aqueous BPA solution after oxidation was assessed by yeast two-hybrid assay. Reaction kinetics follows the second-order rate law, with the apparent second-order rate constant of 15.1 ± 1.1 M(-1)s(-1) at pH 6.0 and 25°C and the activation energy of 48.7 kJ/mol. The kinetics exhibits pH dependency and the specific rate constants related to speciation of BPA are 50 ± 28 M(-1)s(-1), 9.6 (±0.6) × 10(3) M(-1)s(-1) and 1.4 (±0.1) × 10(4) M(-1)s(-1) for BPA, BPA(-) and BPA(2-), respectively. The results of the estrogenic/antiestrogenic activity test show that there is a hysteresis for the removal of estrogenic activity of aqueous BPA solution at pH 7.3. Removal of BPA is completed in 10 min, but complete removal of estrogenic activity requires a further 20 min.

The sequestration/inactivation of the oestrogenic mycotoxin zearalenone (ZEA) by two adsorbents--yeast cell wall extract (YCW) and hydrated sodium calcium aluminosilicate (HSCAS)--was studied in three laboratory models: (1) an in vitro model was adapted from referenced methods to test for the sequestrant sorption capabilities under buffer conditions at two pH values using liquid chromatography coupled to a fluorescence detector for toxin quantification; (2) a second in vitro model was used to evaluate the sequestrant sorption stability according to pH variations and using ³H-labelled ZEA at low toxin concentration; and (3) an original, ex vivo Ussing chamber model was developed to further understand the transfer of ZEA through intestinal tissue and the impact of each sequestrant on the mycotoxin bioavailability of ³H-labelled ZEA. YCW was a more efficient ZEA adsorbent than HSCAS in all three models, except under very acidic conditions (pH 2.5 or 3.0). The Ussing chamber model offered a novel, ex vivo, alternative method for understanding the effect of sequestrant on the bioavailability of ZEA. The results showed that compared with HSCAS, YCW was more efficient in sequestering ZEA and that it reduced the accumulation of ZEA in the intestinal tissue by 40% (p < 0.001).

4,4'-Thiodiphenol (TDP) is a bisphenol derivative, and there has been no report on TDP removal by any plants or pure bacterial cultures. The removal of TDP by Portulaca oleracea cv., a floricultural herbal plant, was examined with a hydroculture system, and 97% of TDP was removed after 4 days culture., (Copyright © 2012 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

A xenoestrogen and known endocrine disruptor, bisphenol A (BPA) binds the human estrogen-related receptor-gamma (ERRγ) with high affinity (Kd ≈ 5.5 nM). It is likely that BPA undergoes oxidative biotransformation by hypochlorite/hypochlorous acid ((-)OCl/HOCl) and peroxynitrite (PN) and the products formed in these reactions may serve as secondary estrogens and contribute to the toxicodynamics of BPA. Therefore, in the present study we have examined the formation of chlorinated and nitrated BPA in reactions of BPA with (-)OCl/HOCl and PN(+CO(2)) performed around the neutral pH. We have identified four major products in these reactions and they include 3-chloro-BPA (CBPA), 3,3'-dichloro-BPA (DCBPA), 3-nitro-BPA (NBPA) and 3,3'-dinitro-BPA (DNBPA). Towards understanding the toxicodynamics and estrogenic activity of BPA in biological systems, we have performed molecular docking of BPA, CBPA, DCBPA, DNBPA and NBPA onto the ERRγ using AutoDock 4.2 software and compared the binding energies with those of estradiol, the natural ligand. Based on the genetic algorithm, the three best conformations were selected and averaged for each ligand and a detailed analysis of molecular interactions based on free energies of binding (kcal/mol) was computed. The results indicate the following rank order of binding to ERRγ: BPA (-8.78 ± 0.06) > CBPA (-8.53 ± 0.41) > NBPA (-7.36 ± 0.74) > DCBPA (-5.24 ± 0.17) > DNBPA (-4.95 ± 0.78) > estradiol (-4.94 ± 1.04). The docking studies revealed that the OH group of one of the phenyl rings forms a hydrogen bond with Glu275/Arg316, while the OH group of other phenyl ring was bound to Asp346. These results suggest that both BPA and its putative chlorinated and nitrated metabolites have strong binding affinity compared to estradiol., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Bisphenol A (BPA) is a common industrial chemical that has been associated with a variety of biological disorders. From the unborn to the elderly, BPA affects every demographic of the population; however, its potential long-term effects on prenatal and prepubescent development have led to concern about its use in the field of pediatrics. Because BPA is omnipresent in modern society, the use of BPA derivatives (such as Bis-GMA and Bis-DMA) in dental materials in general, and acrylic resins in particular, will be increasingly examined as research continues to implicate BPA in a number of biological disorders.

To find the multi-target-directed compounds for the treatment of Alzheimer's disease (AD), we synthesized 7-(4-(diethylamino)butoxy)-5-hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one, a novel 7-O-modified genistein derivative (GS-14), and investigated its acetylcholinesterase (AChE) inhibitory effect, estrogenic activity and neuroprotective effect. GS-14 acted as a selective AChE inhibitor in vitro, with an IC₅₀ value of 0.17 μM and showed no inhibition activity against butyrylcholinesterase (BuChE). The Lineweaver-Burk plot revealed that GS-14 was a non-competitive AChE inhibitor with a K(i) value of 0.23 μM and the molecular docking model indicated that GS-14 interacted with the peripheral anionic site (PAS) of AChE. The MCF-7 proliferation assay demonstrated that GS-14 possessed estrogenic activity and GS-14 exhibited a high specificity for estrogen receptor β (ERβ) with a dissociation constant (K(i)) of 2.86 nM compared with that of 1.01 μM for estrogen receptor α (ERα) in the molecular docking study. GS-14 also possessed a neuroprotective effect and showed the best protective effect against the β-amyloid protein-induced injury on SH-SY5Y cells at a concentration of 1 nM. Considering its AChE-inhibition activity, estrogenic activity and neuroprotective effect, GS-14 may be a potential multi-target agent for the treatment of AD.

Curcumin, a polyphenol derived from the rhizome turmeric, has potential as an anticancer agent. We synthesized an amphipathic/surfactant pegylated curcumin (curcumin-PEG) designed for parenteral administration. Objectives of these investigations were to assess side-effects of a therapeutic regimen of curcumin-PEG in a preclinical model. Intraperitoneal (ip) tumor burdens were reduced in athymic female mice grafted with human SKOV-3 ovarian adenocarcinoma cells and injected intravenously (iv) with curcumin-PEG. There were no gross anatomical or histopathological effects detected in non-reproductive organs. Uteri (luminal fluid imbibition) and ovaries (decreased folliculogenesis) were affected by treatment. Curcumin-PEG ip hastened the onset of puberty in immature female mice. Live births were reduced in mature females housed with males and treated iv with curcumin-PEG; mating (vaginal plugs) was not affected. Accessory gland weights, testicular testosterone concentrations, and spermatogenesis were diminished in mature male mice following iv curcumin-PEG. Estrogenic/antiandrogenic and pregnancy-disrupting effects of a water soluble/bioavailable curcumin were demonstrated., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Several studies reported that natural and synthetic estrogens are the major contributors to the estrogenic activity associated with the effluents of wastewater treatment plants. The ability of the enzyme laccase to degrade these compounds in batch experiments has been demonstrated in previous studies. Nevertheless, information is scarce regarding in vitro degradation of estrogens in continuous enzymatic bioreactors. The present work constitutes an important step forward for the implementation of an enzymatic reactor for the continuous removal of estrone (E1) and estradiol (E2) by free laccase from Myceliophthora thermophila. In a first step, the effect of the main process parameters (pH, enzyme level, gas composition (air or oxygen) and estrogen feeding rate) were evaluated in fed-batch bioreactors. E1 and E2 were oxidized by 94.1 and 95.5%, respectively, under the best conditions evaluated. Thereafter, an enzymatic membrane reactor (EMR) was developed to perform the continuous degradation of the estrogens. The configuration consisted of a stirred tank reactor coupled with an ultrafiltration membrane, which allowed the recovery of enzyme while both estrogens and degradation products could pass through it. The highest removal rates at steady state conditions were up to 95% for E1 and nearly complete degradation for E2. Furthermore, the residual estrogenic activity of the effluent was largely reduced up to 97%., (Copyright © 2012 Elsevier B.V. All rights reserved.)

17β-estradiol (E2), the most potent estrogen in humans, known to be involved in the development and progession of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-HSD1, which catalyses the reduction of the weak estrogen estrone (E1) to E2, is often overexpressed in breast cancer and endometriotic tissues. An inhibition of 17β-HSD1 could selectively reduce the local E2-level thus allowing for a novel, targeted approach in the treatment of EDD. Continuing our search for new nonsteroidal 17β-HSD1 inhibitors, a novel pharmacophore model was derived from crystallographic data and used for the virtual screening of a small library of compounds. Subsequent experimental verification of the virtual hits led to the identification of the moderately active compound 5. Rigidification and further structure modifications resulted in the discovery of a novel class of 17β-HSD1 inhibitors bearing a benzothiazole-scaffold linked to a phenyl ring via keto- or amide-bridge. Their putative binding modes were investigated by correlating their biological data with features of the pharmacophore model. The most active keto-derivative 6 shows IC₅₀-values in the nanomolar range for the transformation of E1 to E2 by 17β-HSD1, reasonable selectivity against 17β-HSD2 but pronounced affinity to the estrogen receptors (ERs). On the other hand, the best amide-derivative 21 shows only medium 17β-HSD1 inhibitory activity at the target enzyme as well as fair selectivity against 17β-HSD2 and ERs. The compounds 6 and 21 can be regarded as first benzothiazole-type 17β-HSD1 inhibitors for the development of potential therapeutics.

The mycotoxin zearalenone (ZEN) is a secondary metabolite of fungi which is produced by certain species of the genus Fusarium and can occur in cereals and other plant products. Reporter gene assays incorporating natural steroid receptors and the H295R steroidogenesis assay have been implemented to assess the endocrine disrupting activity of ZEN and its metabolites α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL). α-ZOL exhibited the strongest estrogenic potency (EC(50) 0.022±0.001 nM), slightly less potent than 17-β estradiol (EC(50) 0.015±0.002 nM). ZEN was ~70 times less potent than α-ZOL and twice as potent as β-ZOL. Binding of progesterone to the progestagen receptor was shown to be synergistically increased in the presence of ZEN, α-ZOL or β-ZOL. ZEN, α-ZOL or β-ZOL increased production of progesterone, estradiol, testosterone and cortisol hormones in the H295R steroidogenesis assay, with peak productions at 10 μM. At 100 μM, cell viability decreased and levels of hormones were significantly reduced except for progesterone. β-ZOL increased estradiol concentrations more than α-ZOL or ZEN, with a maximum effect at 10 μM, with β-ZOL (562±59 pg/ml)>α-ZOL (494±60 pg/ml)>ZEN (375±43 pg/ml). The results indicate that ZEN and its metabolites can act as potential endocrine disruptors at the level of nuclear receptor signalling and by altering hormone production., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

A general proposal for predicting the joint effect of endocrine disrupting chemicals by examining binding energy models was developed in this study. 2,2-bis(4-hydroxyphenyl)propane (BPA) and 11 of its analogs were chosen, and the estrogenic activity of each compound was measured by determining its EC50 value using a recombinant gene yeast assay. Binding energies (BEs) were calculated using Surflex-Docking software. The analysis of the relationship between EC50 values and BEs showed that there is a linear correlation between the BEs and EC50 values. Furthermore, the analysis of the given binary and quaternary mixtures of BPA and three of its analogs showed that the joint effects of the mixtures were affected by the proportions of the chemicals in each mixture and their relative binding energy. The correlation between the joint effects of mixtures and the binding energy of the individual compounds has been described using one formula, which can be used to predict the joint effects of other mixtures.

The accuracy, repeatability, and reproducibility characteristics of a method for measuring levels of zearalenone (ZON) in botanical root products, soybeans, grains, and grain products were determined by an AOAC single-laboratory validation procedure. Replicates of 10 test portions of each powdered root product (black cohosh, ginger, ginseng), brown rice flour, brown rice grain, oat flour, rice bran, soybeans, and wheat flour at each spiking level (ZON at 0, 50, 100, and 200 microg/kg) were analyzed on 3 separate days. Test samples were extracted with methanol-water (75 + 25, v/v). The extracts were centrifuged or filtered, diluted with phosphate-buffered saline (PBS) containing 0.5% Tween 20, and filtered; the filtrates were applied to an immunoaffinity column containing antibodies specific for ZON. After the column was washed with methanol-PBS (15 + 85, v/v) containing 0.5% Tween 20 and then with water, the toxin was eluted from the column with methanol, and the eluate was diluted with water. The eluate containing the toxin was then subjected to RPLC with fluorescence detection. All commodities that were found to contain ZON at < 10 microg/kg were used for the recovery study. The average within-day and between-days recoveries of ZON added at levels of 50-200 microg/kg ranged from 82 to 88% and from 81 to 84%, respectively, for all test commodities. The total average of within- and between-day SD and RSDr values for all test commodities ranged from 2.5 to 7.3 microg/kg and from 4.6 to 6.2%, respectively. HorRat values were <1.3 for all matrixes examined. The tested method was found to be acceptable for the matrixes examined.

The objectives of this study were to determine the structural characteristics of perfluoroalkyl acids (PFAAs) that confer estrogen-like activity in vivo using juvenile rainbow trout (Oncorhynchus mykiss) as an animal model and to determine whether these chemicals interact directly with the estrogen receptor (ER) using in vitro and in silico species comparison approaches. Perfluorooctanoic (PFOA), perfluorononanoic (PFNA), perfluorodecanoic (PFDA), and perfluoroundecanoic (PFUnDA) acids were all potent inducers of the estrogen-responsive biomarker protein vitellogenin (Vtg) in vivo, although at fairly high dietary exposures. A structure-activity relationship for PFAAs was observed, where eight to ten fluorinated carbons and a carboxylic acid end group were optimal for maximal Vtg induction. These in vivo findings were corroborated by in vitro mechanistic assays for trout and human ER. All PFAAs tested weakly bound to trout liver ER with half maximal inhibitory concentration (IC(50)) values of 15.2-289 μM. Additionally, PFOA, PFNA, PFDA, PFUnDA, and perlfuorooctane sulfonate (PFOS) significantly enhanced human ERα-dependent transcriptional activation at concentrations ranging from 10-1000 nM. Finally, we employed an in silico computational model based upon the crystal structure for the human ERα ligand-binding domain complexed with E2 to structurally investigate binding of these putative ligands to human, mouse, and trout ERα. PFOA, PFNA, PFDA, and PFOS all efficiently docked with ERα from different species and formed a hydrogen bond at residue Arg394/398/407 (human/mouse/trout) in a manner similar to the environmental estrogens bisphenol A and nonylphenol. Overall, these data support the contention that several PFAAs are weak environmental xenoestrogens of potential concern.

Glucuronidation constitutes an important pathway in the phase II metabolism of the mycotoxin zearalenone (ZEN) and the growth promotor α-zearalanol (α-ZAL, zeranol), but the enzymology of their formation is yet unknown. In the present study, ZEN, α-ZAL and four of their major phase I metabolites were glucuronidated in vitro using hepatic microsomes from steer, pig, rat and human, intestinal microsomes from humans, and eleven recombinant human UDP-glucuronosyltransferases (UGTs). After assigning chemical structures to the various glucuronides by using previously published information, the enzymatic activities of the various microsomes and UGT isoforms were determined together with the patterns of glucuronides generated. All six compounds were good substrates for all microsomes studied. With very few exceptions, glucuronidation occurred preferentially at the sterically unhindered phenolic 14-hydroxyl group. UGT1A1, 1A3 and 1A8 had the highest activities and gave rise to the phenolic glucuronide, whereas glucuronidation of the aliphatic hydroxyl group was mostly mediated by UGT2B7 with low activity. Based on these in vitro data, ZEN, α-ZAL and their metabolites must be expected to be readily glucuronidated both in the liver and intestine as well as in other extrahepatic organs of humans and various animal species.

The thermal decomposition of poly(bisphenol A carbonate) (PoC) results in the formation of the endocrine disruptor bisphenol A (BPA). In the present work, we investigated the kinetics of the thermal decomposition of PoC, and the subsequent decomposition of BPA, under pyrolysis conditions and in the presence of oxygen by using infrared image furnace-ion attachment mass spectrometry. The decomposition of PoC obeyed Arrhenius kinetics, which allowed us to determine the activation energy (E(a)) for thermal decomposition to BPA from Arrhenius plots. From the selected ion monitoring curves for BPA, E(a) for thermal decomposition in a nitrogen atmosphere was calculated to be 133.2 kcal mol(-1), whereas E(a) for oxidative thermal decomposition was calculated to be approximately 35% lower (86.5 kcal mol(-1))., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)