Oxidation of Bisphenol A and Related Compounds

Bisphenol A was oxidized to monoquinone and bisquinone derivatives by Fremy’s salt, a radical oxidant, though salcomine and alkali did not catalyze the oxidation by molecular oxygen. Bisphenol A, bisphenol B, and 3,4'-(1-methylethylidene)bisphenol were converted to their monoquinone derivatives in the presence of tyrosinase at 25°C at pH 6.5, but not to the bisquinone derivatives under these conditions.     

Synthesis of fluorescent and photoaffinity-labeled derivatives of bisphenol A and their inhibitory activity toward hypoxic expression of erythropoietin

Bisphenol A derivatives, possessing a fluorescent dye and a photo-reactive group, were synthesized from bisphenol A, and the inhibitory activity of the derivatives was evaluated against hypoxic response. The synthesized derivatives were found to inhibit the hypoxic expression of erythropoietin in Hep3B cells as well as bisphenol A.     

Bisphenol A derivatives act as novel coactivator-binding inhibitors for estrogen receptor β

Bisphenol A and its derivatives are recognized as endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is less well understood. Herein, we sought to identify novel ERβ ligands using a radioligand competitive binding assay to screen a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as both ERα agonists and ERβ antagonists. Docking simulations of these compounds and ERβ suggested that they bound not only to the canonical binding site of ERβ but also to the coactivator binding site located on the surface of the receptor, suggesting that they act as coactivator-binding inhibitors (CBIs). Receptor–ligand binding experiments using WT and mutated ERβ support the presence of a second ligand-interaction position at the coactivator-binding site in ERβ, and direct binding experiments of ERβ and a coactivator peptide confirmed that these compounds act as CBIs. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting critical insight for the future development of ER signaling–based drugs and their potential to function as endocrine disruptors.     

姜黄素对双酚A致小鼠卵巢氧化损伤的保护

本文旨在研究姜黄素(CRC)对双酚A(BPA)诱导的小鼠卵巢氧化损伤的保护作用。将28日龄雌性小鼠分为对照组、姜黄素组、双酚A组和双酚A加姜黄素组,连续灌胃6周。收集卵巢,通过活性氧(ROS)水平的检测、卵巢闭锁卵泡的观察以及3种关键抗氧化酶表达和活性的测定,研究姜黄素对双酚A诱发的卵巢氧化损伤的保护作用及机制。结果显示,与对照组相比,双酚A暴露后明显增加了卵巢的活性氧水平,造成氧化应激,提高了卵巢中有腔卵泡闭锁比例。与双酚A组相比,双酚A和姜黄素共同处理组降低了卵巢的活性氧水平和卵巢中有腔卵泡闭锁比例。双酚A暴露降低了卵巢超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GPx)以及过氧化氢酶(CAT)的表达和活性,姜黄素逆转了双酚A诱导的3种抗氧化酶表达和活性的下降。结果表明,姜黄素可逆转双酚A通过氧化应激造成的卵巢损伤。     

Receptor binding characteristics of the endocrine disruptor bisphenol A for the human nuclear estrogen-related receptor gamma. Chief and corroborative hydrogen bonds of the bisphenol A phenol-hydroxyl group with Arg316 and Glu275 residues

Bisphenol A, 2,2-bis(4-hydroxyphenyl)propane, is an estrogenic endocrine disruptor that influences various physiological functions at very low doses, even though bisphenol A itself is ineffectual as a ligand for the estrogen receptor. We recently demonstrated that bisphenol A binds strongly to human estrogen-related receptor gamma, one of 48 human nuclear receptors. Bisphenol A functions as an inverse antagonist of estrogen-related receptor gamma to sustain the high basal constitutive activity of the latter and to reverse the deactivating inverse agonist activity of 4-hydroxytamoxifen. However, the intrinsic binding mode of bisphenol A remains to be clarified. In the present study, we report the binding potentials between the phenol-hydroxyl group of bisphenol A and estrogen-related receptor gamma residues Glu275 and Arg316 in the ligand-binding domain. By inducing mutations in other amino acids, we evaluated the change in receptor binding capability of bisphenol A. Wild-type estrogen-related receptor gamma-ligand-binding domain showed a strong binding ability (K(D) = 5.70 nm) for tritium-labeled [(3)H]bisphenol A. Simultaneous mutation to Ala at positions 275 and 316 resulted in an absolute inability to capture bisphenol A. However, individual substitutions revealed different degrees in activity reduction, indicating the chief importance of phenol-hydroxyl<-->Arg316 hydrogen bonding and the corroborative role of phenol-hydroxyl<-->Glu275 hydrogen bonding. The data obtained with other characteristic mutations suggested that these hydrogen bonds are conducive to the recruitment of phenol compounds by estrogen-related receptor gamma. These results clearly indicate that estrogen-related receptor gamma forms an appropriate structure presumably to adopt an unidentified endogenous ligand.     

Biodegradation of bisphenol A and its halogenated analogues by <Emphasis Type="Italic">Cunninghamella elegans</Emphasis> ATCC36112

Bisphenol A and its halogenated analogues are commonly used industrial chemicals with strong toxicological effects over many organisms. In this study, metabolic fate of bisphenol A and its halogenated analogues were evaluated with Cunninghamella elegans ATCC36112. Bisphenol A and related analogues were rapidly transformed into several metabolites by C. elegans within 2–4 days. Detailed analysis of metabolites reveals that both phase I and II metabolism occurred in C. elegans. Cytochrome P450-dependent hydroxylation was observed in BPA. However, major reaction with bisphenol A and analogues with 1-2 halogen atoms were the formation of glucose-conjugate, not being inhibited by cytochrome P450 inhibitor. Overall metabolic rates decreased with increasing number of substitution at 2- and 6-position of BPA structures, which may be consequences of limited bioavailability or steric hindrance to conjugate-forming reaction. Information from the current study will provide detailed insights over the fungal metabolism of BPA and analogues.     

环境雌激素双酚A的研究进展

环境荷尔蒙是现代生命科学领域研究的热点之一,如今越来越多的人开始关注这一话题。在我们的生活环境中充斥着各种化学有毒试剂,其中,有一类物质能够模拟或抑制内分泌激素的活动,我们称之为内分泌干扰物。内分泌干扰物有能力改变内分泌系统的结构和功能。双酚A作为一种环境雌激素,属于内分泌干扰物的一种。双酚A被广泛应用于聚碳酸酯塑料和环氧树脂的制造。双酚A具有弱雌激素效应,能够与雌激素受体结合,引起内分泌系统的应答。目前的研究表明,双酚A会透过血胎屏障影响到胚胎发育,会对神经内分泌系统、肝组织功能以及生殖器的发育造成损伤。本文主要综述了环境雌激素双酚A在小鼠发育阶段所引起的诸多不利影响,并对环境荷尔蒙未来的研究方向进行了展望。     

Highly enantioselective hydrolysis of dl-menthyl acetate to l-menthol by whole-cell lipase from Burkholderia cepacia ATCC 25416

Bisphenol A was polymerized by Coprinus cinereus peroxidase in aqueous 2-propanol solution. Various polymerized products with different molecular weights and hydroxyl values were synthesized depending on the reaction compositions (the ratio of aqueous buffer to 2-propanol). Poly(bisphenol A), a polymer of bisphenol A, was mixed with a diazonaphthoquinone derivative to form a new type of photoresist. A thin photoresist film was formed on the silicon wafer and exposed to UV light for different lengths of time. Poly(bisphenol A) having a molecular weight of approximately 3000 yielded sharply contrasted patterns as compared with the other poly(bisphenol A)s having different molecular weights.     

Down-regulation of murine Cyp1a-1 in mouse hepatoma Hepa-1c1c7 cells by bisphenol A

Cultured mouse hepatoma Hepa-1c1c7 cells were treated with either bisphenol A or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or in combination to assess the role of bisphenol A in the process of Cyp1a-1 induction. Treatment of Hepa-1c1c7 cultures with 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) induced Cyp1a-1, as determined by analysis of 7-ethoxyresorufin O-deethylase (EROD) activities. Bisphenol A alone did not affect the activity of Cyp1a-1-specific EROD; in contrast, TCDD-induced EROD activities were markedly reduced in the concomitant treatment of TCDD and bisphenol A in a dose-dependent manner. Treatment with tamoxifen, an antiestrogen that acts through the estrogen receptor, did not affect the suppressive effects of bisphenol A on TCDD-induced EROD activity. TCDD-induced Cyp1a-1 mRNA levels were markedly suppressed in the concomitant treatment of TCDD and bisphenol A consistent with their effects on EROD activity. Transient transfection assay using dioxin-response element (DRE)-linked luciferase revealed that bisphenol A reduced transformation of the aryl hydrocarbons (Ah) receptor to a form capable of specifically binding to the DRE sequence in the promoter of the Cyp1a-1 gene. These results suggest the down-regulation of the Cyp1a-1 gene expression by bisphenol A in Hepa-1c1c7 cells might be antagonism of the DRE binding potential of nuclear Ah receptor but not mediated through estradiol receptor.     

Biological and enzymatic treatment of bisphenol A and other endocrine disrupting compounds: a review

Bisphenol A is predominantly used as an intermediate in the production of polycarbonate plastics and epoxy resins. Traces of bisphenol A released into the environment can reach into the wastewater and soil via application of sewage sludge from wastewater treatment systems that receive water containing bisphenol A, or from leachate from uncontrolled landfills. In this study we have made an effort to review the work on the presence of bisphenol A and other related endocrine disrupting compounds in the environment and their impact on the life of living organisms including human beings. Bisphenol A has several implications on the health of human beings as well it can also affect the growth of plants and animals. Number of physicochemical methods such as adsorption, membrane based filtration, ozonation, fenton, electrochemical and photochemical degradation has been used for the removal of bisphenol A. However, these methods have some inherent limitations and therefore cannot be used for large scale treatment of such pollutants. The alternative procedures have attracted the attention of environmental scientists. Biological methods are looking quite promising and these procedures are helpful in the complete degradation of bisphenol A and related compounds. Several bacterial, fungal, and algal strains and mixed cultures have successfully been employed for the degradation of bisphenol A. Recently, enzymatic methods have attracted the attention of the environmentalists for the treatment of bisphenol A and other endocrine disrupting compounds. Numerous types of oxidoreductases; laccases, tyrosinases, manganese peroxidase, lignin peroxidase, polyphenol oxidases, horseradish peroxidase and bitter gourd peroxidase have exhibited their potential for the remediation of such types of compounds. The cytochrome P 450 monooxygenases and hemoglobin have also participated in the degradation of bisphenol A and other related endocrine disrupting compounds. Various redox mediators, surfactants and additives have also enhanced enzymatic oxidation of bisphenol A and other related endocrine disrupting compounds.     

Low doses of BPF-induced hypertrophy in cardiomyocytes derived from human embryonic stem cells via disrupting the mitochondrial fission upon the interaction between ERβ and calcineurin A-DRP1 signaling pathway

Cell Biology and Toxicology - Bisphenol F (BPF) is a replacement to bisphenol A, which has been extensively used in industrial manufacturing. Its wide detection in various human samples raises...     

The endocrine disruptor nonylphenol preferentially blocks cyclooxygenase-1

The anthropogenic chemicals nonylphenol, bisphenol A, phthalic acid benzyl n-butyl ester, phthalic acid di-n-butyl ester and phthalic acid di(2-ethylhexyl) ester have been shown to possess sex hormone-like activity. To explore the possible actions of these chemicals on the autacoid synthesis in the body, we investigated the effects of nonylphenol, bisphenol A, phthalic acid benzyl n-butyl ester, phthalic acid di-n-butyl ester and phthalic acid di(2-ethylhexyl) ester on the activities of cyclooxygenase-1 and -2. Bisphenol A and all three phthalic acid derivatives had no significant effect on the cyclooxygenase-1 and -2 activities up to 100 microM. On the other hand, nonylphenol exhibited a marked inhibition on the cyclooxygenase-1 activity (10-100 microM nonylphenol, 7-95% inhibition), with no detectable change in the activity of cyclooxygenase-2. The inhibition patterns for the substrate, arachidonic acid, and a cofactor, phenol, were competitive and uncompetitive, respectively. These results suggest that nonylphenol can be a selective inhibitor of cyclooxygenase-1 activity.     

Disruption of the blood-testis barrier integrity by bisphenol A in vitro: Is this a suitable model for studying blood-testis barrier dynamics?

Bisphenol A, an estrogenic environmental toxicant, has been implicated to have hazardous effects on reproductive health in humans and rodents. However, there are conflicting reports in the literature regarding its effects on male reproductive function. In this study, it was shown that in adult rats treated with acute doses of bisphenol A, a small but statistically insignificant percentage of seminiferous tubules in the testes displayed signs of germ cell loss, consistent with some earlier reports. It also failed to disrupt the blood-testis barrier in vivo. This is possibly due to the low bioavailability of free bisphenol A in the systemic circulation. However, bisphenol A disrupted the blood-testis barrier when administered to immature 20-day-old rats, consistent with earlier reports concerning the higher susceptibility of immature rats towards bisphenol A. This observation was confirmed using primary Sertoli cells cultured in vitro with established tight junction-permeability barrier that mimicked the blood-testis barrier in vivo. The reversible disruption of Sertoli cell tight junction barrier by bisphenol A was associated with an activation of ERK, and a decline in the levels of selected proteins at the tight junction, basal ectoplasmic specialization, and gap junction at the blood-testis barrier. Studies by dual-labeled immunofluorescence analysis and biotinylation techniques also illustrated declining levels of occludin, connexin 43, and N-cadherin at the cell–cell interface following bisphenol A treatment. In summary, bisphenol A reversibly perturbs the integrity of the blood-testis barrier in Sertoli cells in vitro, which can also serve as a suitable model for studying the dynamics of the blood-testis barrier.     

Bisphenol‐A Induces Podocytopathy With Proteinuria in Mice

Bisphenol‐A, a chemical used in the production of the plastic lining of food and beverage containers, can be found in significant levels in human fluids. Recently, bisphenol‐A has been associated with low‐grade albuminuria in adults as well as in children. Since glomerular epithelial cells (podocytes) are commonly affected in proteinuric conditions, herein we explored the effects of bisphenol‐A on podocytes in vitro and in vivo. On cultured podocytes we first observed that bisphenol‐A—at low or high concentrations—(10 nM and 100 nM, respectively) was able to induce hypertrophy, diminish viability, and promote apoptosis. We also found an increase in the protein expression of TGF‐β1 and its receptor, the cyclin‐dependent kinase inhibitor p27Kip1, as well as collagen‐IV, while observing a diminished expression of the slit diaphragm proteins nephrin and podocin. Furthermore, mice intraperitoneally injected with bisphenol‐A (50 mg/Kg for 5 weeks) displayed an increase in urinary albumin excretion and endogenous creatinine clearance. Renal histology showed mesangial expansion. At ultrastructural level, podocytes displayed an enlargement of both cytoplasm and foot processes as well as the presence of condensed chromatin, suggesting apoptosis. Furthermore, immunohistochemistry for WT‐1 (specific podocyte marker) and the TUNEL technique showed podocytopenia as well as the presence of apoptosis, respectively. In conclusion, our data demonstrate that Bisphenol‐A exposure promotes a podocytopathy with proteinuria, glomerular hyperfiltration and podocytopenia. Further studies are needed to clarify the potential role of bisphenol‐A in the pathogenesis as well as in the progression of renal diseases. J. Cell. Physiol. 229: 2057–2066, 2014. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.     

Sample clean-up with sol-gel enzyme and immunoaffinity columns for the determination of bisphenol A in human urine

The paper describes the development of a simple and highly selective analytical method for the determination of free and total bisphenol A in urine samples. Free bisphenol A levels can be determined after sample clean-up using sol-gel immunoaffinity columns containing anti-bisphenol A antibodies. In determining total bisphenol A levels, the sample pre-treatment procedure consists of sample preparation using an on-line combination of two sol-gel columns, an enzyme column containing glucuronidase and arylsulfatase, and an immunoaffinity column. Bisphenol A can then be quantified by high-performance liquid chromatography and fluorescence detection. The mean recovery was found to be 78% with a standard deviation of 3.4%, the LOD (S/N=3) was 0.2 ng/ml. The method was applied to determine free and total urinary BPA levels of healthy adults and dialysis patients.     

Mutagenicity of bisphenol A and its suppression by interferon-alpha in human RSa cells

Bisphenol A is used as a monomer in the production of polycarbonate plastic products. The widespread use of bisphenol A has raised concerns about its effects in humans. Since there is little information on the mutagenic potential of the chemical, the mutagenicity of bisphenol A was tested using human RSa cells, which has been utilized for identification of novel mutagens. In genomic DNA from cells treated with bisphenol A at concentrations ranging from 1x10(-7) to 1x10(-5)M, base substitution mutations at K-ras codon 12 were detected using PCR and differential dot-blot hybridization with mutant probes. Mutations were also detected using the method of peptide nucleic acid (PNA)-mediated PCR clamping. The latter method enabled us to detect the mutation in bisphenol A-treated cells at a dose (1x10(-8)M) equivalent to that typically found in the environment. Induction of ouabain-resistant (Oua(R)) phenotypic mutation was also found in cells treated with 1x10(-7) and 1x10(-5)M of bisphenol A. The induction of K-ras codon 12 mutations and Oua(R) mutations was suppressed by pretreating RSa cells with human interferon (HuIFN)-alpha prior to bisphenol A treatment. The cells treated with bisphenol A at the concentration of 1x10(-6)M elicited unscheduled DNA synthesis (UDS). These findings suggested that bisphenol A has mutagenicity in RSa cells as well as mutagens that have been tested in these cells, and furthermore, that a combination of the PNA-mediated PCR clamping method with the human RSa cell line may be used as an assay system for screening the mutagenic chemicals at very low doses.     

Biodegradation of endocrine-disrupting phenolic compounds using laccase followed by activated sludge treatment

Endocrine-disrupting phenolic compounds in the water were degraded by laccase fromTrametes sp. followed by activated sludge treatment. The effect of temperature on the degradation of phenolic compounds and the production of organic compounds were investigated using endocrine-disrupting chemicals such as bisphenol A, 2,4-dichlorophenol, and diethyl phthalate. Bisphenol A and 2,4-dichlorophenol disappeared completely after the laccase treatment, but no disappearance of diethyl phthalate was observed. The Michaelis-Menten type equation was proposed to represent the degradation rate of bisphenol A by the lacasse under various temperatures. After the laccase treatment of endocrine-disrupting chemicals, the activated sludge treatment was attempted and it could convert about 85 and 75% of organic compounds produced from bisphenol A and 2,4-dichlorophenol into H₂O and CO₂, respectively.     

Removal of bisphenol A by polymerization and precipitation method using Coprinus cinereus peroxidase

Bisphenol A was efficiently removed by the polymerization and precipitation method using Coprinus cinereus peroxidase. The removal efficiency was optimal between pH 9–10 and at 40 °C with a molar ratio of H₂O₂ to bisphenol A of about 2. To remove 100 mg bisphenol A l^–1, peroxidase was required 5 U ml^–1 at pH 7 and 25 °C and 3 U ml^–1 at pH 10 and 40 °C.     

Dynamics of action of bisphenol as radical-scavenging antioxidant against lipid peroxidation in solution and liposomal membranes

Probucol is used commercially as an antiatherogenic drug. Bisphenol is formed in vivo as a metabolite of probucol. The structure of bisphenol suggests the antioxidant function but its capacity has not been studied in detail. In the present study, dynamics of the antioxidant action of bisphenol were studied in several model systems and compared with those of probucol and alpha-tocopherol. The reactivity toward radicals and antioxidant activity of bisphenol per se were found to be much smaller than those of alpha-tocopherol or N,N'-diphenyl-p-phenylenediamine (DPPD) but stronger than probucol. However, bisphenol spared alpha-tocopherol in the oxidation of phosphatidylcholine liposomal membranes and it spared DPPD and acted as a synergist against the oxidant of methyl linoleate in solution. These results imply that bisphenol may act as a potent antioxidant in combination with other antioxidants.