Inhibitory Effect Of Bisphenol A Research Articles

Distinct inhibitory strength of bisphenol A analogues on human and rat 11β-hydroxysteroid dehydrogenase 1: 3D quantitative structure-activity relationship and in silico molecular docking analysis

Bisphenol A (BPA) analogues are developed to replace BPA usage. However, their effects on 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) are largely unknown. The inhibitory effects of BPA and 10 BPA analogues with the substituents on the bridge moiety on human and rat 11β-HSD1 were explored in human and rat liver microsomes. The strength of inhibiting human 11β-HSD1 was bisphenol FL (IC50, 3.87 μM) > bisphenol Z (6.86 μM) > bisphenol AF (9.42 μM) > bisphenol C (16.14 μM) > bisphenol AP (32.14 μM) = bisphenol B (32.34 μM) > 4,4′-thiodiphenol (67.35 μM) > BPA (297.35 μM) > other BPA analogues (ineffective at 100 μM). The strength of inhibiting rat 11β-HSD1 was bisphenol Z (IC50, 14.44 μM) > 4,4′-thiodiphenol (19.01 μM) > bisphenol B (20.13 μM) > bisphenol F (22.10 μM) > bisphenol E (33.04 μM) > bisphenol AF (49.67 μM) > bisphenol C > (56.97 μM) > bisphenol AP (62.71 μM) >bisphenol FL (96.31 μM) > other BPA analogues (ineffective at 100 μM). Bisphenol A, AF, AP, B, C, F, FL, Z, and 4,4′-thiodiphenol bind to the active sites of human and rat 11β-HSD1. Regression of LogP and molecular weight with IC50 values revealed distinct inhibitory pattern (negative correlation for human 11β-HSD1 vs. positive correlation for rat enzyme). Regression of the lowest binding energy with IC50 values revealed a significant positive regression. 3D QSAR pharmacophore analysis showed one hydrogen bond acceptor and two hydrogen bond donors for human 11β-HSD1. In conclusion, most BPA analogues are more potent inhibitors of human and rat 11β-HSD1 enzymes and there is structure-dependent and species-dependent inhibition.

Does (\u2009\u2212)-epigallocatechin-3-gallate protect the neurotoxicity induced by bisphenol A in vivo?

Bisphenol A (BPA) is one of the chemicals that is firmly accompanied by hippocampal neuronal injury. As oxidative stress appears to be a major contributor to neurotoxicity induced by BPA, antioxidants with remarkable neuroprotective effects can play a valuable protective role. Around the world, ( −)-epigallocatechin-3-gallate (EGCG) was one of the most popular antioxidants that could exert a beneficial neuroprotective role. Here, we examined the potential efficiency of EGCG against neurotoxicity induced by BPA in the hippocampal CA3 region of the rat model. This study revealed that EGCG was unable to abrogate the significant decrease in circulating adiponectin level and hippocampal superoxide dismutase activity as well as an increase in hippocampal levels of nitric oxide and malondialdehyde. Notably, EGCG failed to antagonize the oxidative inhibitory effect of BPA on hippocampal neurotransmission and its associated cognitive deficits. In addition, the histopathological examination with immunohistochemical detection of caspase-3 and NF-kB/p65 emphasized that EGCG failed to protect hippocampal CA3 neurons from apoptotic and necrotic effects induced by BPA. Our study revealed that EGCG showed no protective role against the neurotoxic effect caused by BPA, which may be attributed to its failure to counteract the BPA-induced oxidative stress in vivo. The controversial effect is probably related to EGCG’s ability to impede BPA glucuronidation and thus, its detoxification. That inference requires further additional experimental and clinical studies.Graphical abstract

Leaching of BPA from Baby Feeding Bottle, Aluminium Can and Thermal Printed Paper: Application of Acridine Orange Oxidation Inhibition Method to Estimate BPA

The potential of leaching Bisphenol-A (BPA) from plastic baby feeding bottles, aluminum cans, and thermal printed receipts was investigated under the aquatic condition at high temperatures. BPA is often used to manufacture cross-linked epoxy resin to coat food cans to prevent direct contact with metals and plastic materials. BPA leached from consumer product was analyzed using UV-Visible Spectrophotometer based on the inhibitory effect of BPA on acridine orange oxidation, as a function of change in temperature and time of contact of water with the samples. The proposed method of BPA estimation method was found to be significant and useful for aquatic conditions without any extraction and/or derivatization. The detection limit of BPA under the current experimental setup was 0.1 ng/ml. The results of BPA leached from baby feeding PET bottles, aluminum can with epoxy resin lining, and thermal paper were 87±10 ng/bottles, 68±5 ng/bottle, and 110±15 ng/receipt under the current experimental conditions.

Effect of induced rumination on cortisol habituation to repeated acute stress

The peri-implantation period of pregnancy is critical for conceptus development, implantation, and signaling for establishment of pregnancy. This study evaluated the effects of bisphenol A (BPA) on proliferation, adhesion, and migration of porcine trophectoderm (pTr2) cells, expression of transporters of arginine and synthesis of amino acids. All concentrations of BPA decreased proliferation and adhesion of pTr2 cells after 96 h compared to the control group. Lower concentrations of BPA (1 × 10−9, 1 × 10-8, 10-7M) increased (P < 0.05), but higher concentrations of BPA (1 × 10-5, 1 × 10-4 M) decreased migration of pTr2 cells. BPA increased expression of SLC7A1 mRNA at lower concentrations (1 × 10−9 to 1 × 10-6M) and SL7A6, another cationic acid transporter, at higher concentrations (1 × 10-5, 1 × 10-4 M). BPA also down-regulated the expression of IGF1 and IGF1 receptor at concentrations of 1 × 10-7 to 1 × 10-4 M compared to the control group. The expression of mRNAs for aquaporins (AQP) 3 and 4 were reduced at all concentrations of BPA, but at lower concentrations of BPA, (1 × 10−9 to 1 × 10-8M) expression of AQP9 mRNA increased and the expression of AQP11 was not affected by BPA (P > 0.05). There was an inhibitory effect of BPA on the release of synthesis of asparagine, threonine, taurine, tryptophan, and ornithine into the culture medium by pTr2 cells. Collectively, BPA adversely affected the expression of transporters for cationic amino acids like arginine, as well as AQPs, IGF1, and IGF1R associated with proliferation, migration, and adhesion of pTr2 cells. Those adverse effects would likely increase pregnancy losses during the peri-implantation period of pregnancy.

Effects of Bisphenol A on expression of genes related to amino acid transporters, insulin- like growth factor, aquaporin and amino acid release by porcine trophectoderm cells

The peri-implantation period of pregnancy is critical for conceptus development, implantation, and signaling for establishment of pregnancy. This study evaluated the effects of bisphenol A (BPA) on proliferation, adhesion, and migration of porcine trophectoderm (pTr2) cells, expression of transporters of arginine and synthesis of amino acids. All concentrations of BPA decreased proliferation and adhesion of pTr2 cells after 96 h compared to the control group. Lower concentrations of BPA (1 × 10−9, 1 × 10-8, 10-7M) increased (P < 0.05), but higher concentrations of BPA (1 × 10-5, 1 × 10-4 M) decreased migration of pTr2 cells. BPA increased expression of SLC7A1 mRNA at lower concentrations (1 × 10−9 to 1 × 10-6M) and SL7A6, another cationic acid transporter, at higher concentrations (1 × 10-5, 1 × 10-4 M). BPA also down-regulated the expression of IGF1 and IGF1 receptor at concentrations of 1 × 10-7 to 1 × 10-4 M compared to the control group. The expression of mRNAs for aquaporins (AQP) 3 and 4 were reduced at all concentrations of BPA, but at lower concentrations of BPA, (1 × 10−9 to 1 × 10-8M) expression of AQP9 mRNA increased and the expression of AQP11 was not affected by BPA (P > 0.05). There was an inhibitory effect of BPA on the release of synthesis of asparagine, threonine, taurine, tryptophan, and ornithine into the culture medium by pTr2 cells. Collectively, BPA adversely affected the expression of transporters for cationic amino acids like arginine, as well as AQPs, IGF1, and IGF1R associated with proliferation, migration, and adhesion of pTr2 cells. Those adverse effects would likely increase pregnancy losses during the peri-implantation period of pregnancy.

Urinary bisphenol A versus serum bisphenol A concentration and ovarian reproductive outcomes among IVF patients: Which is a better biomarker of BPA exposure?

Bisphenol A (BPA) is an endocrine-disrupting compound (EDC) that is used widely in commercial products in the production of polycarbonate plastics for baby and water bottles, epoxy resins for lacquer lining of food and beverage cans and water pipes, dental sealants, dental composites and thermal receipts paper. There is inhibitory effect of BPA on nuclear estrogen (E2) production in granulosa cells of developing follicles that disrupt normal development to the antral follicles via suppression of E2 in granulosa cells of developing follicles during the menstrual cycle followed by reduction in the number of oocytes retrieved in in-vitro fertilization (IVF) patients. Several studies corroborate an inverse association between serum and/or urinary BPA concentration and the IVF outcome: Peak E2 levels and the number of oocytes retrieved. Upon oral ingestion, 99.5% of unconjugated parent BPA (free BPA) is metabolized to either BPA glucuronide (BPA-G) or BPA sulfate (BPA-S). The unconjugated BPA can bind to the estrogen receptors (ER) while conjugated BPA (biologically inactive BPA) do not bind the estrogen receptor (ER). The challenge is to assess the relationship between BPA exposure among infertile patients with respect to follicular response and health during IVF. The establishment of temporal sequence between BPA exposure and infertility would be the research question to answer: Which route is a better biomarker? The advantages of urine BPA collection would provide pragmatic advantages for clinicians in order to practice cost-effective medicine. However, unconjugated BPA measurement (compared to total BPA) introduces challenges in measurement accuracy since unconjugated BPA requires higher magnitude of limit of detection (LOD) with higher risk of contamination from the medical equipment. The difference in route of BPA assessment could introduce bias in the interpretation of results in terms of the association between BPA levels and the number of oocytes. Fujimoto et al. and Bloom et al. analyzed the relationship between serum BPA and IVF outcome in infertile women. It may sound hypothetically justified due to utilizing serum unconjugated BPA, this strategy is not successful in choosing a practical biomarker of BPA exposure due to toxicokinetic properties of BPA metabolism and excretion in humans.

Kinetic study of the effect of bisphenol A on the rates of organic matter removal, decay and biomass generation in a membrane bioreactor

This study analyzed the effect of bisphenol A (BPA) on the kinetic behavior of the heterotrophic biomass of a membrane bioreactor (MBR) treating municipal wastewater in order to determine possible variations in the rates of organic matter removal, decay and biomass generation. Four operation phases were analyzed in the steady state at different values of hydraulic retention time (6–10h), mixed liquor suspended solids (4000–7000mgL−1), temperature (12.1–31.1°C), and sludge retention time (9.81–21.67day). A respirometric procedure was used to model the kinetic behavior of heterotrophic biomass contained in the MBR in absence and presence of BPA, and a multivariable statistical analysis was applied to determine the effect of the variables on the substrate degradation rate for organic matter removal (rsu,H), decay coefficient for heterotrophic biomass (bH), and net heterotrophic biomass growth rate (ŕx,H). The results showed that there was no inhibitory effect of BPA on heterotrophic biomass, with higher values of rsu,H and ŕx,H, and lower values of bH in presence of BPA. Heterotrophic biomass from phase 2 showed the highest values of rsu,H (190.22mgO2L−1h−1), bH (0.1304day−1) and ŕx,H (170.68mgVSSL−1h−1) in presence of BPA due to its higher temperature (31.1°C).

Bisphenol A suppresses glucocorticoid target gene (ENaCγ) expression via a novel ERβ/NF-κB/GR signalling pathway in lung epithelial cells.

We previously demonstrated that prenatal exposure to Bisphenol A (BPA) disrupts fetal lung maturation likely through the glucocorticoid signalling pathway, but the precise molecular mechanisms remain obscure. Given that BPA diminished the expression of epithelial sodium channel-γ (ENaCγ), a well-known glucocorticoid receptor (GR) target gene, in fetal lungs, we used this GR target gene to delineate the molecular pathway through which BPA exerts its effects on lung cells. The A549 lung epithelial cell line was used as an in vitro model system. As a first step, we validated our in vitro cell model by demonstrating a robust concentration-dependent suppression of ENaCγ expression following BPA exposure. We also showed that both dexamethasone and siRNA-mediated knockdown of GR expression blocked/abrogated the inhibitory effects of BPA on ENaCγ expression, suggesting that BPA repressed ENaCγ expression via inhibition of GR activity. Given the well-known antagonistic interactions between the pro-inflammatory transcriptional factor NF-κB and GR, we then showed that BPA inhibited GR activity through the activation of NF-κB. Lastly, since BPA is known to function as a pro-inflammatory factor via the estrogen receptor β (ERβ), we provided evidence that BPA signals through ERβ to activate the NF-κB signalling pathway. Taken together, these findings demonstrate that BPA acts on ERβ to activate the NF-κB signalling pathway, which in turn leads to diminished GR activity and consequent repression of ENaCγ expression in lung epithelial cells. Thus, our present study reveals a novel BPA signalling pathway that involves ERβ, NF-κB and GR.

Bisphenol A suppresses Th1-type immune response in human peripheral blood mononuclear cells in vitro

Bisphenol A (BPA) is a widely used plasticizer, which came into focus because of its genotoxic and sensitizing potential. Besides its toxic properties, BPA is also well-known for its antioxidant chemical properties.This in vitro study investigated the interference of BPA with interferon-γ (IFN-γ)-induced tryptophan breakdown and neopterin production in human peripheral blood mononuclear cells (PBMC). The pro-inflammatory cytokine IFN-γ induces the conversion of the essential amino acid tryptophan into kynurenine via the enzyme indoleamine-2,3-dioxygenase (IDO-1). In parallel, GTP-cyclohydrolase produces neopterin, a marker of immune activation. A model system of phytohaemagglutinin (PHA)-stimulated PBMC was used to assess potential immunomodulatory properties of BPA.Treatment of cells with BPA [12.5–200μM] resulted in a significant and dose-dependent suppression of mitogen-induced tryptophan breakdown and neopterin formation along with a decrease of IFN-γ levels. Similar but less pronounced effects were observed in unstimulated cells.We postulate that the inhibitory effects of BPA on both T-cell activation and IDO-1 activity that we describe here may be critical for immune surveillance and is likely to influence T helper (Th) type 1/Th2 balance. Such immunosuppressive effects likely contribute to counteract inflammation. Further studies are required to address the in vivo relevance our in vitro findings.

Inhibitory Effects of Bisphenol-A on Neural Stem Cells Proliferation and Differentiation in the Rat Brain Are Dependent on Wnt/β-Catenin Pathway.

Neurogenesis, a process of generation of new neurons, occurs throughout the life in the hippocampus and sub-ventricular zone (SVZ). Bisphenol-A (BPA), an endocrine disrupter used as surface coating for packaged food cans, injures the developing and adult brain. However, the effects of BPA on neurogenesis and underlying cellular and molecular mechanism(s) are still unknown. Herein, we studied the effect(s) of prenatal and early postnatal exposure of low dose BPA on Wnt/β-catenin signaling pathway that controls different steps of neurogenesis such as neural stem cell (NSC) proliferation and neuronal differentiation. Pregnant rats were treated with 4, 40, and 400 μg BPA/kg body weight orally daily from gestational day 6 to postnatal day 21. Both in vivo and in vitro studies showed that BPA alters NSC proliferation and differentiation. BPA impaired NSC proliferation (5'-bromo-2'-deoxyuridine (BrdU(+)) and nestin(+) cells) and neuronal differentiation (BrdU/doublecortin(+) and BrdU/neuronal nuclei (NeuN(+)) cells) in the hippocampus and SVZ as compared to control. It significantly altered expression/protein levels of neurogenic genes and the Wnt pathway genes in the hippocampus. BPA reduced cellular β-catenin and p-GSK-3β levels and decreased β-catenin nuclear translocation, and cyclin-D1 and TCF/LEF promoter luciferase activity. Specific activation and blockage of the Wnt pathway suggested involvement of this pathway in BPA-mediated inhibition of neurogenesis. Further, blockage of GSK-3β activity by SB415286 and GSK-3β small interfering RNA (siRNA) attenuated BPA-induced downregulation of neurogenesis. Overall, these results suggest significant inhibitory effects of BPA on NSC proliferation and differentiation in the rat via the Wnt/β-catenin signaling pathway.

Bisphenol A Modulates Calcium Currents and Intracellular Calcium Concentration in Rat Dorsal Root Ganglion Neurons

The endocrine-disrupting chemical bisphenol A (BPA) is used to manufacture plastics including food containers, and it may leach into these containers. Consumption of BPA that has leached out of plastics may be harmful as recent research highlighted that BPA can induce alterations in the nervous system. In the present work, we studied the effects of BPA on Ca²⁺ channels in dorsal root ganglion (DRG) neurons. Using whole-cell patch-clamp recordings, we found that I(Ca) could be reduced by BPA in a concentration-dependent manner. Additionally, BPA shifted the activation curve of calcium currents toward a depolarizing direction and increased the slope factor of the curve. The inactivation curve for the currents was also assessed, and the curve shifted toward the depolarizing direction, although it was not significant. Moreover, inhibitory effects of BPA on the increments of intracellular Ca²⁺ concentrations ([Ca²⁺](i)) induced by 50 mM KCl were observed in DRG neurons using a laser scanning confocal microscopy assay. Further work revealed that the PKA and PKC pathways may be involved in the inhibitory effects of BPA since the PKA antagonist GÖ-6983 and the PKC antagonist H-89 significantly alleviated the inhibitory effects of BPA on I(Ca). As such, the results of the present study provide direct evidence that BPA decreases I(Ca) and impairs calcium homeostasis, which may be involved in any toxic effects of BPA on DRG neurons.

Estrogenicity of Bisphenol A: A Concentration-Effect Relationship on Luteinizing Hormone Secretion in a Sensitive Model of Prepubertal Lamb

The model of the prepubertal ovariectomized lamb was selected as a sensitive model to characterize the estrogenic effects of bisphenol A (BPA) on the hypothalamo-pituitary axis (HPA). In a first experiment, the disrupting effect of BPA and of 17-beta estradiol (E2), administered as a constant 54-h iv infusion, on luteinizing hormone (LH) pulsatility was quantified. The results showed that the inhibitory effect of BPA and E2 on LH secretion appeared to follow a dual mechanism: a rapid (about 1 h) suppressive effect for high exposure and an effect observed with a period of latency (about 48 h) probably of genomic origin and observed for lower E2 and BPA levels. For E2, the disrupting dose was 0.14 microg/(kg x d), corresponding to a plasma concentration of 2 pg/ml; for BPA, the lowest observed disrupting plasma concentration was 38 ng/ml, a value only 10-fold higher than the human plasma concentration routinely reported in biomonitoring surveys. In a second experiment, we showed that after 7 weeks of BPA treatment, there was no BPA accumulation and no evidence of an alteration in the HPA responsiveness to BPA. Finally, our results showed that directly considering plasma concentrations, the ratio of the BPA disrupting plasma concentration in lambs over the observed human plasma concentration is only 10, whereas if the dose is considered, it could be concluded that the BPA disrupting dose in lamb is conservatively 50-fold higher than the currently recommended Tolerable Daily Intake of 50 microg/(kg x d).

Determination of bisphenol A using a flow injection inhibitory chemiluminescence method

A new flow injection chemiluminescence (CL) method has been developed for the determination of bisphenol A (BPA), based on the inhibitory effect of BPA on the chemiluminescence reaction between luminol and potassium hexacyanoferrate. Under optimum conditions, the decrease in CL emission intensity was linear with BPA concentration in the range 8.0 x 10(-7)-1.2 x 10(-5) mol/L, and the detection limit was 3.1 x 10(-7) mol/L. The relative standard deviation (RSD) of 11 replicate measurements was 2.6% for 2.0 x 10(-6) mol/L BPA (n = 11). The sampling frequency was calculated to be ca. 120/h. This method has been successfully used to determine the content of BPA in aqueous solution of polycarbonate materials. A brief discussion on the possible chemiluminescence reaction mechanism is presented.

Complexation of Bisphenol A with Calix[6]arene‐Polymer Conjugates

AbstractSodium calix[6]arenehexasulfonic acid (SCX6) was introduced into polymer molecules by the cross‐linking of SCX6 with epichlorohydrin (PolySCX6) or by the covalent binding of carboxymethylated SCX6 to an amino group‐carrying vinyl polymer (Poly(SCX6HMA‐co‐AAm)). The complexation of bisphenol A (BPA) with the SCX6 group in the polymers was examined fluorimetrically using acridine red (AR) as a probe. From the inhibitory effect of BPA on the complexation of AR with the SCX6 group in the polymers, the association constant (Kassoc) of BPA with the SCX6 group was evaluated and the value for BPA with the SCX6 group in Poly(SCX6HMA‐co‐AAm) was much larger than that with the non‐conjugated SCX6, probably because of the support of hydrophobic interactions between the guest and the hydrocarbon moieties in the polymer (polymer main chain and hexamethylene groups introduced for the conjugation of SCX6). The Kassoc value for bisphenol B (BPB) with a non‐conjugated SCX6 was larger than those for bisphenol A and bisphenol F, because of the higher hydrophobicity of BPB among the bisphenols examined. Thermodynamic parameters indicated that the inclusion of BPA into the cavity of sodium propyloxycalix[6]arenehexasulfonic acid (SPCX6) was enthalpy driven, and the entropy change was largely negative (−92 J · mol−1 · K−1). This is probably because of a tight fit of guest molecules in the SPCX6 cavity, resulting in the loss of freedom of both the SPCX6 and the guest molecules. The entropy change for the complexation of BPA with the SCX6 group in the polymer was less negative, probably because of a partial release of water molecules around the SCX6 group upon the complexation. The effect of the structure of guest and host molecules on the complexation was also examined.Chemical structure of various calix[6]arenes: R = H, sodium calix[6]arenehexasulfonic acid; R = C3H7, sodium propyloxycalix[6]arenehexasulfonic acid; R = C4H9, sodium butyloxycalix[6]arenehexasulfonic acid; R = C6H13, sodium hexyloxycalix[6]arenehexasulfonic acid.magnified imageChemical structure of various calix[6]arenes: R = H, sodium calix[6]arenehexasulfonic acid; R = C3H7, sodium propyloxycalix[6]arenehexasulfonic acid; R = C4H9, sodium butyloxycalix[6]arenehexasulfonic acid; R = C6H13, sodium hexyloxycalix[6]arenehexasulfonic acid.

Reproductive effects of long-term exposure to Bisphenol A in the fathead minnow (Pimephales promelas).

Bisphenol A (BPA), a high-volume chemical used to make polycarbonate plastic, epoxy resins, and other chemicals has been reported to be weakly estrogenic. To investigate the effects of long-term exposure to Bisphenol A, a multigeneration study was conducted in which fathead minnows (Pimephales promelas) were exposed to water concentrations of BPA in the range from 1 to 1280 micrograms/L. In this paper, we report the growth and reproductive effects of BPA on sexually mature adults in the F0 generation (after 43, 71, and 164 d of exposure) and the effects on hatchability in the F1 generation. Mean measured concentrations of BPA in the water for all doses, over a 164-d exposure period, were between 70% and 96% of nominal. An inhibitory effect of BPA on somatic growth (length and weight) occurred in adult male fish exposed to 640 and 1280 micrograms/L (after 71 and 164 d). BPA induced vitellogenin synthesis (VTG; a biomarker for estrogen exposure) in males at concentrations of 640 and 1280 micrograms/L after 43 d and 160 micrograms/L after 71 d. In females, plasma VTG concentrations were elevated above controls only after 164-d exposure to 640 micrograms/L. Inhibition of gonadal growth (as measured by the gonadosomatic index) occurred in both males and females at concentrations of 640 and 1280 micrograms/L after 164 d. In males, a concentration of 16 micrograms/L altered the proportion of sex cell types in the testis, suggesting inhibition of spermatogenesis. Concentrations of BPA that induced VTG synthesis and affected gonadal development were lower than those that resulted in discernible effects on reproductive output. Egg production was inhibited at a BPA concentration of 1280 micrograms/L, and hatchability in the F1 generation was reduced at a BPA concentration of 640 micrograms/L (there were not enough eggs spawned in the 1280 micrograms/L group for hatchability studies to be conducted). The results demonstrate that BPA acts as a weak estrogen to fish when administered via the water, with effects on breeding at and above 640 micrograms/L.