Effects of bisphenol A on the proliferation and cell cycle of HBL-100 cells

Bisphenol A (BPA) is an environmental estrogen that exhibits non-genotoxic carcinogenicity, causing concern globally. The aim was to investigate the effects of BPA on the proliferation and cell cycle of human normal breast cells HBL-100. An improved E-Screen assay was used to study cell proliferation, and flow cytometry was used to study cell cycle phases. Western blot analysis was utilized to detect cell cycle proteins and estrogen receptor α (ERα) expression. The results showed that the highest cell proliferation rate induced by BPA was at 1.0 × 10⁻⁶ mol/L. At 1.0 × 10⁻¹⁰, 1.0 × 10⁻⁸, and 1.0 × 10⁻⁶ mol/L, BPA promoted more cells to enter into G2/M phase and caused an increase in the expression of cyclinD1 and CDK4. After adding ICI182780 into the system, the promoting effects of BPA on cell proliferation and cell cycle change decreased, but these promoting effects were still significantly greater compared with the solvent control (P < 0.05). Regardless of ICI182780 exposure, BPA did not have significant effect on ERα expression. BPA has estrogen-like activity and can stimulate HBL-100 proliferation and cell division through the estrogen receptor pathway. BPA may have other pathways through which it can exert stimulating effects and exhibit non-genotoxic carcinogenicity.     

Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity

Polyphenols present in foods and supplements may contribute to human health by preventing cardiovascular diseases and cancer. Drug–food or drug–herb interactions have recently come into focus but, except for some phytochemicals, few components of food or herbs participate in such interactions. In this study, we systematically evaluated the inhibitory effects of 60 polyphenols and related compounds on human cytochrome P450 (CYP) 3A4 and CYP2C9 activity by in vitro assay to investigate whether some polyphenols induce drug interactions. In addition, the kinetics of potent CYP inhibitors was investigated by Lineweaver–Burk plot analysis. Three coumarins and 12 flavonoids significantly suppressed CYP3A4 or CYP2C9 activities. Lineweaver–Burk plot analysis indicated that apigenin and its dimer amentoflavone and imperatorin displayed a mixed type of inhibition on CYP3A4 or CYP2C9. Among the inhibitors, amentoflavone was the most potent inhibitor of CYP3A4 and CYP2C9 activities with IC₅₀ values of 0.07 and 0.03 μM, respectively. The K_i value of amentoflavone was significantly lower than that of the CYP2C9 inhibition positive control sulfaphenazole. These findings suggest that some dietary polyphenols may have the potential to inhibit the metabolism of clinical drugs.     

Expression and functional characterization of cytochrome P450 26A1, a retinoic acid hydroxylase

Retinoic acid (RA) is a critical signaling molecule that performs multiple functions required to maintain cellular viability. It is also used in the treatment of some cancers. Enzymes in the CYP26 family are thought to be responsible for the elimination of RA, and CYP26A1 appears to serve the most critical functions in this family. In spite of its importance, CYP26A1 has neither been heterologously expressed nor characterized kinetically. We expressed the rCYP26A1 in baculovirus-infected insect cells and purified the hexahistidine tagged protein to homogeneity. Heme incorporation was determined by carbon monoxide difference spectrum and a type 1 spectrum was observed with RA binding to CYP26A1. We found that RA is a tight binding ligand of CYP26A1 with low nM binding affinity. CYP26A1 oxidized RA efficiently (depletion K_m 9.4 ± 3.3 nM and V_max 11.3 ± 4.3 pmoles min⁻¹ pmole P450⁻¹) when supplemented with P450 oxidoreductase and NADPH but was independent of cytochrome b5. 4-Hydroxy-RA (4-OH-RA) was the major metabolite produced by rCYP26A1 but two other primary products were also formed. 4-OH-RA was further metabolized by CYP26A1 to more polar metabolites and this sequential metabolism of RA occurred in part without 4-OH-RA leaving the active site of CYP26A1. The high efficiency of CYP26A1 in eliminating both RA and its potentially active metabolites supports the major role of this enzyme in regulating RA clearance in vivo. These results provide a biochemical framework for CYP26A1 function and offer insight into the role of CYP26A1 as a drug target as well as in fetal development and cell cycle regulation.     

CYP2S1 is negatively regulated by corticosteroids in human cell lines

Cytochrome P450s are monooxygenase proteins involved in the metabolism of both exogenous and endogenous compounds. CYP2S1 can metabolize eicosanoids in the absence of both NADPH and NADPH cytochrome P450 reductase, and can also activate the anticancer agent 1 AQ4N [1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxy anthracene-9,10-dione]. CYP2S1 is mainly expressed in extrahepatic tissues such as the trachea, lung, stomach, small intestine, spleen, skin, breast, kidney and placenta. Furthermore, increased expression of CYP2S1 occurs in several tumors of epithelial origin, making the characterization of CYP2S1 regulation relevant to the treatment of disease. We report that the synthetic glucocorticoid receptor ligand dexamethasone (DEX) represses CYP2S1 expression. The ED₅₀ is between 1 nM and 3 nM and maximal repression is reached by 48 h. Other corticosteroids are also effective at repressing CYP2S1. We show that repression by DEX is mediated by the glucocorticoid receptor and requires histone deacetylase activity.     

Contrasting effects of insulin and cellular differentiation on expression of the novel insulin receptor substrate APS in skeletal muscle

The novel insulin receptor substrate protein APS is highly expressed in insulin-sensitive tissues and plays an important role in insulin-mediated glucose uptake and GLUT4 translocation via the Cbl/CAP pathway. Tyrosine phosphorylation of APS leads to recruitment of c-Cbl and Crk, while overexpression of APS mutant inhibits GLUT4 translocation in response to insulin, but the regulation of APS expression in skeletal muscle has not been previously reported. L6 myoblasts were differentiated in 2% FBS and serum starved for 24 h prior to stimulation for 24 h with either insulin 1 μM (n = 6), rosiglitazone 10 μM (n = 6), resistin 500 nM (n = 6) or the MAP kinase inhibitor PD098059 50 μM (n = 6) for 30 min, followed by insulin 1 μM for 24 h. Semi-quantitative real-time RT-PCR was used to determine the expression of APS mRNA relative to the control gene TF2D. APS expression was markedly upregulated by myoblast differentiation (0.55 ± 0.08 versus 1.14 ± 0.08, p = 0.001), and this effect was augmented by addition of rosiglitazone 10 μM for 24 h to the differentiated myotubes (1.50 ± 0.09, p = 0.025). Insulin caused a 3.1-fold decrease in APS mRNA expression (0.37 ± 0.01 versus 1.14 ± 0.08, p = 0.001), an effect that was attenuated by the MAP kinase inhibitor PD098059 (0.80 ± 0.03, p = 0.001). Exposure to resistin produced a modest decrease (1.4-fold) in myotube expression of APS (0.8 ± 0.09, p = 0.025). In conclusion, this is the first study to show that exposure to insulin markedly reduces the expression of APS in skeletal muscle via a MAP kinase dependent pathway, whereas myocyte differentiation and rosiglitazone increase APS expression. Changes in APS expression may be important in the aetiology and therapeutic reversal of insulin resistance in skeletal muscle.     

Thiomers: Inhibition of cytochrome P450 activity

The aim of the present study was to investigate the potential of different thiolated polymers (thiomers) on the catalytic activity of CYP450s on one hand and to explore new inhibitors for CYP activity on the other hand. Several thiolated polymers including poly(acrylic acid)-cysteine (PAA-cysteine), chitosan-thioglycolic acid (chitosan-TGA), and thiolated PEG-g-PEI copolymer along with brij® 35, myrj® 52 and the well-established CYPP450 inhibitor verapamil were screened for their CYP3A4 and CYP2A6 inhibitory activity, and their IC₅₀ values were determined. Both enzyme inhibition assays were performed in 96-well microtiter plates. 7-Benzyloxy-4-(trifluoromethyl)-coumarin (BFC) and 7-hydroxycoumarin (7-HC) were used as fluorescent substrates in order to determine CYP3A4 and CYP2A6 catalytic activity, respectively. All investigated compounds inhibited CYP3A4 as well as CYP2A6 activity. All tested (thiolated) polymers were found to be more potent inhibitors of CYP3A4 than of CYP2A6 catalytic activity. Apart from verapamil that is a known CYP3A4 inhibitor, brij® 35 and myrj® 52 were explored as potent inhibitors of CYP3A4 and CYP2A6 catalytic activity. Among the tested polymers, the rank order for CYP3A4 inhibition was PAA-cysteine (100 kDa) > brij® 35 > thiolated PEG-g-PEI copolymer (16 kDa) > myrj® 52 > PAA (100 kDa) > PAA-cysteine (450 kDa) > verapamil > PAA (450 kDa) > chitosan-TGA (150 kDa) > chitosan (150 kDa). On the other hand, the rank order of CYP2A6 inhibition was brij® 35 > PAA-cysteine (100 kDa) > chitosan-TGA (150 kDa) > PAA (100 kDa) > thiolated PEG-g-PEI copolymer (16 kDa) > PAA-cysteine (450 kDa) > chitosan (150 kDa) > verapamil > PAA (450 kDa) > myrj® 52. Thus, this study suggests that (thiolated) polymers display a promising potential to inhibit cytochrome P450s activity and might turn out to be potentially valuable tools for improving the oral bioavailability of actively secreted compounds by avoiding intestinal metabolism.     

Binding thermodynamics at the human cannabinoid CB1 and CB2 receptors

The thermodynamic parameters ΔG°, ΔH° and ΔS° of the binding equilibrium of agonists and antagonists at cannabinoid CB₁ and CB₂ receptors were determined by means of affinity measurements at different temperatures and van’t Hoff plots were constructed. Affinity constants were measured on CHO cells transfected with the human CB₁ and CB₂ receptors by inhibition assays of the binding of the cannabinoid receptor agonist [³H]-CP-55,940. van’t Hoff plots were linear for agonists and antagonists in the temperature range 0-30 °C. The thermodynamic parameters for CB₁ receptors fall in the ranges 17 ≤ ΔH° ≤ 59 kJ/mol and 213 ≤ ΔS° ≤ 361 kJ/mol for agonists and −52 ≤ ΔH° ≤ −26 kJ/mol and −12 ≤ ΔS° ≤ 38 kJ/mol for antagonists. The thermodynamic parameters for CB₂ receptors fall in the ranges 27 ≤ ΔH° ≤ 48 kJ/mol and 234 ≤ ΔS° ≤ 300 kJ/mol for agonists and −19 ≤ ΔH° ≤ −17 kJ/mol and 43 ≤ ΔS° ≤ 74 kJ/mol for antagonists. Collectively, these data show that agonist binding is always totally entropy-driven while antagonist binding is enthalpy and entropy-driven, indicating that CB₁ and CB₂ receptors are thermodynamically discriminated. These data could give new details on the nature of the forces driving the CB₁ and CB₂ binding at a molecular level. Enthalpy, entropy, free energy and binding affinity for each ligand to its receptor can all be assessed and therefore the optimal binding profile discovered. Carrying out these binding investigations as early as possible in the discovery process increases the probability that a lead compound will become a successful pharmaceutical compound.     

Bisphenol-A rapidly promotes dynamic changes in hippocampal dendritic morphology through estrogen receptor-mediated pathway by concomitant phosphorylation of NMDA receptor subunit NR2B

Bisphenol-A (BPA) is known to be a potent endocrine disrupter. Evidence is emerging that estrogen exerts a rapid influence on hippocampal synaptic plasticity and the dendritic spine density, which requires activation of NMDA receptors. In the present study, we investigated the effects of BPA (ranging from 1 to 1000 nM), focusing on the rapid dynamic changes in dendritic filopodia and the expressions of estrogen receptor (ER) β and NMDA receptor, as well as the phosphorylation of NMDA receptor subunit NR2B in the cultured hippocampal neurons. A specific ER antagonist ICI 182,780 was used to examine the potential involvement of ERs. The results demonstrated that exposure to BPA (ranging from 10 to 1000 nM) for 30 min rapidly enhanced the motility and the density of dendritic filopodia in the cultured hippocampal neurons, as well as the phosphorylation of NR2B (pNR2B), though the expressions of NMDA receptor subunits NR1, NR2B, and ERβ were not changed. The antagonist of ERs completely inhibited the BPA-induced increases in the filopodial motility and the number of filopodia extending from dendrites. The increased pNR2B induced by BPA (100 nM) was also completely eliminated. Furthermore, BPA attenuated the effects of 17β-estradiol (17β-E₂) on the dendritic filopodia outgrowth and the expression of pNR2B when BPA was co-treated with 17β-E₂. The present results suggest that BPA, like 17β-E₂, rapidly results in the enhanced motility and density of dendritic filopodia in the cultured hippocampal neurons with the concomitant activation of NMDA receptor subunit NR2B via an ER-mediated signaling pathway. Meanwhile, BPA suppressed the enhancement effects of 17β-E₂ when it coexists with 17β-E₂. These results provided important evidence suggesting the neurotoxicity of the low levels of BPA during the early postnatal development of the brain.     

Human hepatic CYP2B6 developmental expression: The impact of age and genotype

Although CYP2B6 is known to metabolize numerous pharmaceuticals and toxicants in adults, little is known regarding CYP2B6 ontogeny or its possible role in pediatric drug/toxicant metabolism. To address this knowledge gap, hepatic CYP2B6 protein levels were characterized in microsomal protein preparations isolated from a pediatric liver bank (N = 217). Donor ages ranged from 10 weeks gestation to 17 years of age with a median age of 1.9 months. CYP2B6 levels were measured by semi-quantitative western blotting. Overall, CYP2B6 expression was detected in 75% of samples. However, the percentage of samples with detectable CYP2B6 protein increased with age from 64% in fetal samples to 95% in samples from donors >10 years of age. There was a significant, but only 2-fold increase in median CYP2B6 expression after the neonatal period (birth to 30 days postnatal) although protein levels varied over 25-fold in both age groups. The median CYP2B6 level in samples over 30 postnatal days to 17 years of age (1.3 pmol/mg microsomal protein) was lower than previously reported adult levels (2.2-22 pmol/mg microsomal protein), however, this likely relates to the median age of these samples, i.e., 10.3 months. CYP2B6 expression did not vary significantly by gender. Furthermore, CYP2B6 levels did not correlate with CYP3A4, CYP3A5.1 or CYP3A7 activity, consistent with different mechanisms controlling the ontogeny and constitutive expression of these enzymes and the lack of significant induction in the pediatric samples.     

Bisphenol-A rapidly enhanced passive avoidance memory and phosphorylation of NMDA receptor subunits in hippocampus of young rats

Bisphenol-A (BPA), an endocrine disruptor, is found to influence development of brain and behaviors in rodents. The previous study indicated that perinatal exposure to BPA impaired learning-memory and inhibited N-methyl-d-aspartate receptor (NMDAR) subunits expressions in hippocampus during the postnatal development in rats; and in cultured hippocampal neurons, BPA rapidly promotes dynamic changes in dendritic morphology through estrogen receptor-mediated pathway by concomitant phosphorylation of NMDAR subunit NR2B. In the present study, we examined the rapid effect of BPA on passive avoidance memory and NMDAR in the developing hippocampus of Sprague-Dawley rats at the age of postnatal day 18. The results showed that BPA or estradiol benzoate (EB) rapidly extended the latency to step down from the platform 1 h after footshock and increased the phosphorylation levels of NR1, NR2B, and mitogen-activated extracellular signal-regulated kinase (ERK) in hippocampus within 1 h. While 24 h after BPA or EB treatment, the improved memory and the increased phosphorylation levels of NR1, NR2B, ERK disappeared. Furthermore, pre-treatment with an estrogen receptors (ERs) antagonist, ICI182,780, or an ERK-activating kinase inhibitor, U0126, significantly attenuated EB- or BPA-induced phosphorylations of NR1, NR2B, and ERK within 1 h. These data suggest that BPA rapidly enhanced short-term passive avoidance memory in the developing rats. A non-genomic effect via ERs may mediate the modulation of the phosphorylation of NMDAR subunits NR1 and NR2B through ERK signaling pathway.     

Changed preference for sweet taste in adulthood induced by perinatal exposure to bisphenol A-A probable link to overweight and obesity

Background

The preference of obesity has risen dramatically worldwide over the past decades. Some latest reports showed significant increase of obesity in men compared to women. Implication of environmental endocrine disruptors has been focused more and more. Numerous studies in vitro and vivo implied metabolic actions of bisphenol A (BPA), however much less consideration is given to the possibility of BPA exposure-induced change in gender-specific behaviors which result in obesity and overweight.

Objectives

To examine whether perinatal exposure to BPA at relative dose to environmental levels can influence sweet preference of male and female rats and consequently lead to alteration in bodyweight.

Methods

Rats perinatally exposed to BPA at doses of 0.01, 0.1 and 1.0 mg/L were tested sweet preference for 0.25%, 0.5% saccharin and 15% sucrose by two-bottle choice (water vs. saccharin/sucrose). The food intake, liquid consumption and bodyweight of each rat were monitored daily. At the end of the test, the fat percentage and tail blood pressure were measured.

Results

Significant sex difference of preference for 0.25% and 0.5% saccharin was shown in control and all BPA-treated groups (p < 0.001, female vs. male). 0.1 and 1.0 mg/L BPA treatment induced the increase of preference for 0.25% saccharin solution in males, but not in females. 0.1 mg/L BPA treatment increased sucrose preference in males at postnatal day (PND) 70 and 140 (p < 0.05 and p < 0.001, compared to control respectively) but decreased sucrose preference in females at PND 140 (p < 0.05, compared to control). The males treated by BPA showed overweight (p < 0.001), high fat percentage (p < 0.001) and tail blood pressure (p < 0.05) than control at PND 140.

Conclusion

Perinatal exposure to a low dose of BPA could increase sweet preference of male rats. Calorie intake may be programmed during early life, leading to changes of body weight depending on the gender. Although further researches concerning the mechanism are required, the results of the present study are particularly important with regards to the more significant increasing prevalence of obesity in men and the environmental endocrine disruptors.     

Estrogenic status modulates the effect of soy on hepatic responses to 7,12-dimethylbenz(a)anthracene (DMBA)

We examined the influence of estradiol (E2) status and soy protein isolate (SPI) intake on the hepatic responses altered by 7,12-dimethylbenz(a)anthracene (DMBA, a polycyclic aromatic hydrocarbon [PAH]). Sprague-Dawley rats were ovariectomized (OVX) at PND50 and infused with E2 or vehicle for 14 d and gavaged with 50 mg/kg DMBA or vehicle 24 h before sacrifice at PND64. Rats were fed an AIN-93G diet made with SPI or casein as sole protein source throughout the study. Basal AhR protein levels were reduced (P < 0.05) by SPI feeding irrespective of the E2 status. However, DMBA increased (P < 0.05) AhR-induced CYP1A1 gene expression in OVX, SPI-fed rats, but reduced (P < 0.05) CYP1A1 in OVX + E2, SPI-fed rats. Chromatin-immunoprecipitation demonstrated lower (P < 0.05) DMBA-mediated recruitment of estrogen receptor alpha to the CYP1A1 promoter by SPI feeding in the presence of E2, suggesting an estrogen-like action of SPI on DMBA-mediated signaling in the absence of E2. Further, microarray analysis (Rat 230-2.0 Affymetrix-GeneChip™) revealed 231 genes common to SPI + DMBA and SPI + E2 + DMBA (normalized to E2) treatments. AhR-activated genes (CYP1A1, CYP1A2, and NQO1) were down-regulated by SPI + E2 + DMBA compared to SPI + DMBA. Unique interactions among SPI, DMBA and E2 altered the expression profile of 316 genes, not observed by either treatment alone. Our data suggest that although E2 status does not effect soy-mediated AhR degradation, it modulates the effects of soy on many genes, including CYP1A1.     

Metabolism of bilirubin by human cytochrome P450 2A6

The mouse cytochrome P450 (CYP) 2A5 has recently been shown to function as hepatic “Bilirubin Oxidase” (Abu-Bakar, A., et al., 2011. Toxicol. Appl. Pharmacol. 257, 14-22). To date, no information is available on human CYP isoforms involvement in bilirubin metabolism. In this paper we provide novel evidence for human CYP2A6 metabolising the tetrapyrrole bilirubin. Incubation of bilirubin with recombinant yeast microsomes expressing the CYP2A6 showed that bilirubin inhibited CYP2A6-dependent coumarin 7-hydroxylase activity to almost 100% with an estimated K_i of 2.23 μM. Metabolite screening by a high-performance liquid chromatography/electrospray ionisation mass spectrometry indicated that CYP2A6 oxidised bilirubin to biliverdin and to three other smaller products with m/z values of 301, 315 and 333. Molecular docking analyses indicated that bilirubin and its positively charged intermediate interacted with key amino acid residues at the enzyme's active site. They were stabilised at the site in a conformation favouring biliverdin formation. By contrast, the end product, biliverdin was less fitting to the active site with the critical central methylene bridge distanced from the CYP2A6 haem iron facilitating its release. Furthermore, bilirubin treatment of HepG2 cells increased the CYP2A6 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A6 compared to cells treated only with CHX. Collectively, the observations indicate that the CYP2A6 may function as human “Bilirubin Oxidase” where bilirubin is potentially a substrate and a regulator of the enzyme.     

In utero exposure to bisphenol-A and its effect on birth weight of offspring

To examine the effect of in utero BPA exposure on the birth weight of offspring, a total of 587 children from families in which parent(s) did or did not have occupational exposure to BPA were examined. Their birth weights were obtained by an in-person interview of the mother. Parental BPA exposure level during the index pregnancy was determined through personal air sampling measurements and exposure history. After controlling for potential confounders, parental exposure to BPA in the workplace during pregnancy was associated with decreased birth weight. The association was stronger for maternal exposure which is statistically significant (P = 0.02). A dose-response relationship was observed with increased BPA exposure levels in pregnancy associated with greater magnitude of decrease of birth weight in offspring (P = 0.003). Our findings provide the new epidemiologic evidence suggesting that in utero exposure to BPA during pregnancy may be associated with decreased birth weight in offspring.     

Involvement of activating ERK1/2 through G protein coupled receptor 30 and estrogen receptor α/β in low doses of bisphenol A promoting growth of Sertoli TM4 cells

Sertoli cells play a pivotal role in supporting proliferation of germ cells and differentiation during spermatogenesis in mammals. Nanomolar concentrations of Bisphenol A (BPA) can significantly stimulate the proliferation of mouse immature Sertoli (TM4) cells. However, mechanisms by which BPA caused these effects were still unclear. In the present study, an inverse U-shaped curve was observed when treating TM4 cells with increasing doses of BPA: 1 to 10 nM BPA significantly stimulated the proliferation of TM4 cells and increased the proportion of cells in S phase; >1 μM BPA caused lesser proliferation of cells. Exposure of TM4 cells to G15 or ICI 182,780, which are specific antagonists of GPR30 and estrogen receptor α/β (ERα/β), respectively, abolished BPA-induced proliferation of cells, which suggests that both GPR30 and ERα/β were involved in the observed effects of BPA. Furthermore, exposure to BPA caused rapid (5 min) activation of ERK1/2 via both GPR30 and ERα/β. Blocking the GPR30/EGFR signal transduction pathway by antagonists suppressed both phosphorylation of ERK and BPA-induced cell proliferation. BPA up-regulated mRNA and protein expression of GPR30 in a concentration-dependent manner. In summary, the results reported here indicated that activating ERK1/2 through GPR30 and ERα/β is involved in low doses of BPA that promoted growth of Sertoli TM4 cells. The GPR30/EGFR/ERK signal is the downstream transduction pathway in BPA-induced proliferation of TM4 Sertoli cells.     

Loss of BRCA1 leads to an increased sensitivity to Bisphenol A

Humans are chronically exposed to the plasticizer, Bisphenol A (BPA), that can adversely affect the normal hormonal regulation of cellular functions by mimicking the actions of estrogen. This biological response to BPA may vary according to an individual's genetic characteristics (e.g., BRCA1 mutations or deletion). In this study, both cell culture and mouse models were used to elucidate whether the loss of BRCA1 function could affect BPA-mediated cell proliferation. In studies using BPA levels comparable to human exposures, we found that loss of BRCA1 enhances BPA-induced cell proliferation in both systems. In vitro, we found that loss of BRCA1 enhances BPA-induced ERα signaling. In vivo, we found that BPA administration stimulates mammary gland epithelial tissue/cell proliferation leading to hyperplasia in Brca1 mutant mice compared to wild-type control mice. These results suggest that the biological responses in BRCA1-deficient cells may depend on environmental exposures, specifically BPA.     

Influence of vitamin C on bisphenol A,nonylphenol and octylphenol induced oxidative damages in liver of male rats

The purpose of this study was to investigate whether bisphenol A (BPA), nonylphenol (NP) and octylphenol (OP) induce oxidative stress in the liver of male rats and co-administration of vitamin C can prevent any possible oxidative stress. Wistar male rats were divided into seven groups (vehicle, BPA, NP, OP, BPA + C, NP + C, OP + C). BPA, OP and NP groups (25 mg kg⁻¹ day⁻¹) were administered orally to rats three times a week for 50 days. In BPA + C, NP + C, OP + C groups, vitamin C (60 mg kg⁻¹ day⁻¹) was administered along with BPA, OP and NP (25 mg kg⁻¹ day⁻¹) treatments. Aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), thiobarbituric acid-reactive substances (TBARS) were increased, glutathione (GSH) levels were decreased in treatment groups. AST, ALT, LDH and TBARS levels were increased whereas GSH levels were decreased in BPA + C, NP + C and OP + C groups compared to BPA, NP, and OP groups, respectively. Hepatic necrosis and congestion were observed in livers of rats treated. In conclusion, the present results demonstrate that BPA, NP, and OP cause oxidative damage by disturbing the balance between ROS and antioxidant defenses system in liver of male rats. Vitamin C co-administration along with BPA, NP, OP aggravates the damage in liver of male rats.