Oral Administration Of Bisphenol A Research Articles

Genome-wide transcriptome analysis reveals that Bisphenol A activates immune responses in skeletal muscle

Cumulative human exposure to the environmental toxin, bisphenol A (BPA), has raised important health concerns in recent decades. However, the direct genomic regulation of BPA in skeletal muscles and its clinical significance are poorly understood. Therefore, we conducted a genome-wide transcriptome analysis after daily oral administration of BPA at the lowest observed adverse-effect level (LOAEL, 50 mg/kg) in male mice for six weeks to explore the gene-expression regulations in skeletal muscle induced by BPA. The primary Gene Ontology terms linked to BPA-dependent, differentially expressed genes at LOAEL comprised adaptive-immune response, positive regulation of T cell activation, and immune system process. The gene-set enrichment analysis disclosed increased complement-associated genes [complement components 3 (C3) and 4B, complement factor D, complement receptor 2, and immunoglobulin lambda constant 2] in the group administered with BPA, with a false-discovery rate of <0.05. Subsequent validation analysis conducted in BPA-fed animal skeletal muscle tissue and in vitro experiments confirmed that BPA induced immune activation, as evidenced by increased levels of C3 and C4α proteins in mice, C2C12 myoblasts, and mouse skeletal muscle cells. In addition, BPA markedly upregulated the transcription of tumor necrosis factor-α (Tnfα) in C2C12 myoblasts and mouse skeletal muscle cells, which was substantially inhibited by 5z-7-oxozeanol and parthenolide, providing further evidence of BPA-induced inflammation in muscle cells. Our bioinformatics and subsequent animal and in vitro validations demonstrate that BPA can activate inflammation in skeletal muscle, which could be a risk factor underlying chronic muscle weakness and wastage.

Bisphenol A enhances apoptosis, fibrosis, and biochemical fluctuations in the liver of adult male rats with possible regression after recovery.

Bisphenol A (BPA) is an environmental contaminant that might be harmful. Human exposure to BPA can occur during the fetal and postnatal periods and extends throughout life. This study aimed to estimate the effects of oral administration of BPA on rat liver and assess the possibility of recovery after cessation. Adult male albino rats were orally administered with BPA (50 mg/kg body weight) for 8 weeks, and then one group was left to recover for 4 weeks. Histological, immunohistochemical, biochemical, and quantitative real-time polymerase chain reaction assessments were performed. Loss of hepatic architecture, vascular dilatation congestion, and exudation, as well as cellular vacuolation, fat accumulation, and pyknotic nuclei were detected. Furthermore, inflammatory infiltration, localized metaplasia, and excessive collagen deposition in the portal triad were observed. Expression of Bcl-2-associated X protein and transforming growth factor beta 1 was prominent, denoting apoptosis and fibrosis. After the administration of BPA, serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, cholesterol, triglycerides, and low-density lipoproteins were enhanced. Additionally, total protein, albumin, and high-density lipoproteins decreased. After a recovery for 4 weeks, hepatic cellular and vascular pathologies returned to normal, except for some inflammatory infiltration. Regarding biochemical affection, most of the parameters were directed toward normal during recovery. However, most of them were still significantly different from controls. This explored BPA hepatotoxicity from structural and functional aspects, and the possible spontaneous reversibility was confirmed. However, the precise mechanisms underlying hepatotoxicity or recovery need more in-depth investigations.

Long-term exposure of Bisphenol A impairs metabolism and develop insulin resistance

Bisphenol A (BPA) is a well-recognized endocrine disruptor which has wide applications in current age. This is an industrial compound which is being used in the preparation of juice cans, water containers and various other household plastic products. The main objective of this study was to investigate the mechanism of BPA-induced metabolic pathways disturbance and other key risk factors that can may lead to the development of impaired insulin secretion from β-cells of pancreatic islets and insulin resistance peripheral tissues. The methodology involved the oral administration of BPA in different doses i.e., 50, 500, 2500 and 5000 for 3 months. The predefined BPA induced metabolic risk factors that lead towards the insulin resistance were measured by using ELISA kits. The association of long-term exposure of BPA with, significant reduction (P<0.05) of antioxidant enzymes, such as superoxide dismutase (SOD), glutathione (GSH), catalase (CAT) and, considerable higher levels (P<0.05) of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), can exacerbate the chances of insulin resistance and impaired insulin secretion. Furthermore, we found a significant correlation (P<0.05) between the long-term exposure of BPA and various enzymes that control the metabolism of carbohydrates such as α-glucosidase, glucose-6-phosphatase, hexokinase, α-amylase. The same correlation (P<0.05) was also found to be existed in between the enzymes involved in the biosynthesis of cholesterol such as HMG-CoA reductase and long-term exposure of BPA. It can be concluded that long-term exposure of BPA can disrupt the various metabolic pathways by inducing the oxidative stress which provokes various inflammatory responses that ultimately lead to impair the β-cells of pancreatic islets and insulin resistance peripheral tissues.

Maternal and developmental toxicity of Bisphenol-A in SWR/J mice

Bisphenol-A (BPA), an organic compound with two phenol functional groups, is a widely used industrial plasticizer with known estrogenic properties. It is used in the manufacture of epoxy resins and polycarbonate plastics. This study was designed to evaluate and assess the possible toxicity arising from the oral administration of BPA to pregnant mice. Pregnant SWR/J mice (15 mice/group) were administrated oral doses of BPA (125, 250 and 500 mg/kg/day) over the course of five-day intervals during gestation (D1-5, D6-10 and D11-15), while control groups received only corn oil. The results indicated that BPA was associated with a reduction in the body weight of the pregnant mice from around 2–3 days after administration until the end of gestation. The greatest effects were evident when the BPA was given during the later stages of pregnancy, and with higher doses. They also showed marked reduction in food intake and, to a lesser extent, in water intake. Furthermore, doses of BPA induced a reduction in implantation sites, lower foetal body weight and increased mortality rates. Abortion and foetal resorption rates were not affected by BPA administration, however. The above findings were concluded by discussing the possible mechanisms involved in producing these effects.

Comparison of the renal effects of bisphenol A in mice with and without experimental diabetes. Role of sexual dimorphism

Bisphenol-A (BPA), a chemical -xenoestrogen- used in the production of the plastic lining of food and beverage containers, is present in the urine of almost the entire population. Recent studies have shown that BPA exposure is associated with podocytopathy, increased urinary albumin excretion (UAE), and hypertension. Since these changes are characteristic of early diabetic nephropathy (DN), we explored the renal effects of BPA and diabetes including the potential role of sexual dimorphism. Male and female mice were included in the following animals' groups: control mice (C), mice treated with 21.2 mg/kg of BPA in the drinking water (BPA), diabetic mice induced by streptozotocin (D), and D mice treated with BPA (D + BPA). Male mice form the D + BPA group died by the tenth week of the study due probably to hydro-electrolytic disturbances.Although BPA treated mice did not show an increase in serum creatinine, as observed in D and D + BPA groups, they displayed similar alteration to those of the D group, including increased in kidney damage biomarkers NGAL and KIM-1, UAE, hypertension, podocytopenia, apoptosis, collapsed glomeruli, as well as TGF-β, CHOP and PCNA upregulation. UAE, collapsed glomeruli, PCNA staining, TGF-β, NGAL and animal survival, significantly impaired in D + BPA animals. Moreover, UAE, collapsed glomeruli and animal survival also displayed a sexual dimorphism pattern.In conclusion, oral administration of BPA is capable of promoting in the kidney alterations that resemble early DN. Further translational studies are needed to clarify the potential role of BPA in renal diseases, particularly in diabetic patients.

Rationale and design of a randomized controlled trial examining oral administration of bisphenol A on hepatic glucose production and skeletal muscle insulin sensitivity in adults

Previous observational studies have shown that the endocrine disrupting chemical bisphenol A (BPA) is associated with type 2 diabetes, but few studies have examined direct effects of BPA on human health. The purpose of this study is to determine whether orally administered BPA at the US Environmental Protection Agency (EPA) safe dose of 50 μg/kg body weight has an adverse effect on hepatic glucose production and skeletal muscle insulin sensitivity. Forty, non-habitually active, healthy adults of normal weight will be enrolled. Participants will begin with a 2-day baseline energy balance diet low in bisphenols in which urine and blood will be collected, and standard tests performed to assess the primary outcome measures of hepatic glucose production (via [6,6-2H] glucose infusion) and skeletal muscle insulin sensitivity (via euglycemic hyperinsulinemic clamp technique). Secondary outcome measures are fasting hormones/endocrine factors (insulin, glucose, C-peptide, Pro-insulin, adiponectin, 17-beta-estradiol, free fatty acids) related to the pathogenesis of type 2 diabetes. Participants will then be randomly assigned to a 4-day energy balance diet plus oral administration of BPA at 50 μg/kg body weight (Diet + BPA) or 4-day energy balance diet plus oral administration of placebo (Diet + No BPA); all outcome measures will be reassessed after 4 days. Findings from this study will provide a framework for other studies in this area, and provide much needed experimental evidence using gold standard measures as to whether oral BPA administration over several days poses any risk of type 2 diabetes.

Bisphenol A-induced oxidative damage in the hepatic and cardiac tissues of rats: The modulatory role of sesame lignans.

Bisphenol A (BPA) is an environmental pollutant that is widely produced throughout the world. It is primarily used in the manufacture of polycarbonate plastics, epoxy resins, paints and dental materials. BPA has been reported to promote hepatotoxicity and cardiotoxicity. The antioxidant activity of sesame lignans is well established. The current study assessed the protective efficiency of sesame lignans against BPA-induced hepatotoxicity and cardiotoxicity. Rats were divided into 4 groups: A control group, a BPA-treated group, a sesame lignans-treated group and a sesame lignans and BPA-treated group. Rats were orally administered their respective doses daily [30 mg/kg body weight (BW) BPA and/or 20 mg/kg BW sesame lignans] for 6 weeks. Liver function tests were performed using serum of all groups. Lipid profile and antioxidant status were also measured in liver tissue of the studied groups. The results were confirmed by histopathological examination of liver and heart tissues. The oral administration of BPA was revealed to elicit significant decreases in the activities of hepatic glutathione peroxidase, glutathione reductase, superoxide dismutase and glutathione. It also significantly increased levels of malondialdehyde. Furthermore, BPA-treatment resulted in lipid accumulation, elevated activities of alanine aminotransferase, creatine kinase MB and lactate dehydrogenase, and histological changes of liver and heart tissues. However, the co-administration of sesame lignans and BPA attenuated hepatotoxicity, cardiotoxicity and BPA-induced histological changes. The results of the current study indicated that sesame lignans may be helpful in the development of novel natural drugs to treat hepatic and cardiovascular disorders.

Oral Administration of Bisphenol A Directly Exacerbates Allergic Airway Inflammation but Not Allergic Skin Inflammation in Mice.

Bisphenol A (BPA) is used in various areas of daily life as a major component of plastic products. However, it is also known as a strong endocrine disruptor that affects the human immune system. Studies have indicated that BPA possibly exacerbates allergic diseases such as atopic dermatitis and asthma. The main aim of this study was to elucidate whether BPA is directly involved in the exacerbation of allergic inflammation. Initially, in vivo experiments with mouse models of allergic inflammation induced by Th2 type hapten toluene-2, 4-diisocyanate (TDI) was performed. Mice were subjected to oral administration of BPA 48, 24, and 4 h before challenge with TDI. Dermal challenge of TDI onto the ear auricle was performed for the allergic dermatitis model, and intratracheal challenge of TDI was performed for the allergic airway inflammation model. In the allergic dermatitis model, ear-swelling response was significantly downregulated by high doses of BPA. The opposite reaction was observed in the allergic airway inflammation model, including significant exacerbation of red coloration in the lung, local cytokine levels, and total IgE levels in serum by BPA administration. To confirm the in vivo results, in vitro experiments with human epidermal keratinocytes (HEKs) and bronchial epithelial (BEAS-2B) cells were carried out. Significant enhancement of cytokine release from BEAS-2B cells but not HEKs in the BPA-treated group supported the in vivo observations. Our results imply that exposure to BPA directly exacerbates allergic airway inflammation but not allergic dermatitis.

Melatonin ameliorates bisphenol A-induced perturbations of the prostate gland of adult Wistar rats.

Bisphenol A (BPA) is an endocrine disrupting chemical (EDC) that has been demonstrated to induce alterations in reproductive organs while melatonin (ML), an antioxidant, present in plants and animals, is capable of protecting against EDC-induced alterations. Adult male Wistar rats (average weight, 240 + 10 g) were divided into four groups of ten animals each: Rats in group I (control) received oral 0.2 ml 1% dimethyl sulfoxide (DMSO)/99% canola oil as vehicle; group II received intra-peritoneal 10 mg/kg BW/day ML. Group III received oral BPA dissolved in DMSO and solubilized in canola oil at 10 mg/kg BW/day. Group IV were treated with same dose of BPA as group III with a concomitant intra-peritoneal 10 mg/kg BW/day ML. All treatments lasted for 14 days. BPA significantly increased the prostatic index of the rats while ML ameliorated it. BPA significantly increased serum levels of estrogen as well as prostate-specific antigen but decreased serum testosterone in the rats while concomitant treatment with ML ameliorated these alterations. Also, BPA caused vascular congestion, hyperplasia (functional, reactive and atypical) of prostatic epithelium as well as tubular atrophy the rats while ML attenuated the observed lesions. Decreased localization of αSmooth muscle actin, vimentin and S100 proteins were observed in the BPA-treated rats while these decreases were ameliorated by ML. The present study has shown that sub-acute oral administration of BPA induced alterations in prostatic index, serum hormone levels, down-regulated protein localization and induced morphological lesions of the prostate gland in rats while concomitant treatment with intra-peritoneal ML ameliorated these conditions. Hence, low dose of ML can protect against BPA-induced toxicity of the prostate gland of rats.

EFFECT OF VITAMIN C AND THYMOQUINONE ON EXPERIMENTALLY BISPHENOL A INDUCED HEPATO - RENAL TOXICITY IN ADULT MALE ALBINO RATS

Background: Bisphenol-A (BPA) is the building block of polycarbonate plastics, a hard plastic used to make numerous consumer products, including most baby bottles and water bottles. Objective: Assessing the adverse effect of oral administration of BPA on liver and kidney of adult male albino rats and evaluation of the role of vitamin C and thymoquinone (TQ) in alleviating the possible detrimental effects of BPA. Material and Methods: Fifty six adult male albino rats of local strain were housed in 14 suitable metal cages(20 ×32× 20 cm for every 4 rats).They were divided into seven equal groups : The 1st group was served as a control group, the 2nd group was treated with bisphenol-A, the 3 rd group was normal and treated with vitamin C alone ,the 4 th group was normal and treated with thymoquinone alone, the 5 th group was administered by bisphenol-A and treated with vitamin C, the 6 th group was administered by bisphenol-A and treated with thymoquinone and the 7 th group was administered by bisphenol-A and treated with both vitamin C and thymoquinone. All animals were treated for four weeks. Results: Administration of bisphenol-A (50mg/Kg body weight orally) to rats resulted in an increase in alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea , creatine, and hepatic and renal MDA level, and decreased reduced glutathione (GSH) and superoxide dismutase (SOD) contents of the liver and kidney as compared to control group. In contrast, the administration of vitamin C (500 mg/ kg body weight) and/ or thymoquinone(10 mg /kg body weight) to bisphenol-A treated rats attenuated the toxicity of bisphenol. This alleviation was more pronounced in the bisphenol-A group treated with both vitamin C and thymoquinone. Conclusion: BPA has detrimental effect on liver and kidney of adult male albino rats. It supported the possibility that the synergistic effect of thymoquinone and vitamin C played a notable role in protecting the liver and kidney against BPA-induced toxicity and oxidative stress in male rats.

Melatonin protects oocyte quality from Bisphenol A-induced deterioration in the mouse.

Bisphenol A (BPA) has been reported to adversely affect the mammalian reproductive system in both sexes. However, the underlying mechanisms regarding how BPA disrupts the mammalian oocyte quality and how to prevent it have not been fully defined. Here, we document that BPA weakens oocyte quality by impairing both oocyte meiotic maturation and fertilization ability. We find that oral administration of BPA (100μg/kg body weight per day for 7days) compromises the first polar body extrusion (78.0% vs 57.0%, P<.05) by disrupting normal spindle assembly, chromosome alignment, and kinetochore-microtubule attachment. This defect could be remarkably ameliorated (76.7%, P<.05) by concurrent oral administration of melatonin (30mg/kg body weight per day for 7days). In addition, BPA administration significantly decreases the fertilization rate of oocytes (87.2% vs 41.1%, P<.05) by reducing the number of sperm binding to the zona pellucida, which is consistent with the premature cleavage of ZP2 as well as the mis-localization and decreased protein level of ovastacin. Also, the localization and protein level of Juno, the sperm receptor on the egg membrane, are strikingly impaired in BPA-administered oocytes. Finally, we show that melatonin administration substantially elevates the in vitro fertilization rate (63.0%, P<.05) by restoring above defects of fertilization proteins and events, which might be mediated by the improvement of oocyte quality via reduction of ROS levels and inhibition of apoptosis. Collectively, our data reveal that melatonin has a protective action against BPA-induced deterioration of oocyte quality in mice.

Effects of chronic ingestion of Bisphenol A on gut contractility in rats

Background: Bisphenol A (BPA) is a plastic toxin widely used in manufacturing of plastic containers. It is known to produce a variety of toxic effects on body functions including reproduction, metabolism, and development. Despite the fact that the gastrointestinal tract is chronically exposed to food containing BPA, its effect on the gut motility is poorly understood. Aims and Objectives: The present study attempted to assess the small and large gut contractility in vitro in male rats fed with BPA-mixed food for 28 days. Materials and Methods: This study was carried out in 8 adult male albino rats of 150-200 g weight. One group (4 rats) was subjected to daily oral administration of BPA (50 μg/kg/day) for 28 days. Another group of 4 rats was Sham-fed and served as control. With the help of organ bath preparations and computerized data acquisition system, in vitro isometric contraction (spontaneous and agonist-induced) was recorded from small gut (distal ileum) and large gut (mid colon) segments. Results: Recordings of spontaneous contractions revealed significantly (P < 0.05) decreased contractile tension in small gut and a decrease in both tension and frequency in large gut of the BPA-fed group of rats. Conclusion: Chronic exposure of BPA depresses spontaneous and agonist-induced contractility of small and large gut of rats.

Impact of prenatal and postnatal exposure to bisphenol A on female rats in a two generational study: Genotoxic and immunohistochemical implications.

Environmental xenoestrogen contaminant bisphenol A (BPA), widely used as a monomer in the manufacture of epoxy, polycarbonate plastics and polystyrene resins. However, exposure to BPA has raised concerns, and the negative impacts of its exposure on reproduction have been controversial. The purpose of this work was directed to assess the potential adverse effects of BPA on dam rats and their first generation females in a comparative toxicological study. Fifteen pregnant female rats were classified into three equal groups; first group was orally administered corn oil and served as control (group1), second and third groups were orally administered BPA at dose levels of 50 and 200 mg/kg b.wt respectively (groups 2 & 3). The administration was carried out daily from zero day through the gestation period (21 days) until the last day of the lactation period (21days) and was extended after weaning for three months, in which female off springs of first generation (F1) of the three groups of dams were classified into; F1control group (group 4), F1 group treated with low dose of BPA (group 5) and F1 group treated with high dose of BPA (group 6) which continued in daily oral administration of BPA at the same previously mentioned doses for three months. The results elucidated a clear marked DNA fragmentation in the ovary of both dam and F1 female groups especially at higher examined concentration. Also, the data demonstrated a significant increase in the serum levels of GGT, ALP, glucose, total cholesterol, triglycerides, LDH and also in the serum level of estrogen hormone. Meanwhile, our study recorded a significant decrease in total protein, catalase, GST, HDL and FSH hormone in both treated dam and F1 female groups which was more significantly decreased in F1 female rats. Moreover, our experiment illustrated up-regulation in the immunoexpression of ERβ in ovary, uterus and liver of dam and F1 female groups. The histopathological investigation showed degeneration in the epithelial lining of ovarian follicles, submucosal leukocytic infiltration and increase in vaculation of hepatic cells with proliferation of kupffer cells. The lesions were more sever in groups 3 & 6 of both dam and their F1 females. Our data speculated that long- term exposure to BPA at 50 and 200 mg/kg.b.wt. depicted total genomic damage, significant alterations in liver enzymes, lipid profile, antioxidant enzymes and reproductive hormones with up-regulation in the expression of ERβ which were more significantly perturbed in group 3 and group 6 of both dam and F1 female rats.

Thymoquinone attenuates toxicity and oxidative stress induced by bisphenol A in liver of male rats.

Bisphenol A (BPA) is a fairly ubiquitous compound which has a great concern to human health. The current study was designed to (1) Assess the adverse effect of oral administration of BPA on liver of male rats and (2) Evaluate the role of thymoquinone (TQ), the major bioactive ingredient in the oil of Nigella sativa seed, in alleviating the possible detrimental effects of BPA on the liver. Rats were divided into control group administered olive oil, BPA group administered 10 mg BPA kg(-1) day(-1), TQ group administered 10 mg TQ kg(-1) day(-1) and BPA-TQ group administered the same previous doses of both BPA and TQ. After 24 h of the last dose, rats were decapitated and blood and liver were collected to determine some oxidative stress and biochemical parameters. Bisphenol A elicited a significant elevation in lipid peroxidation concomitant with depletion of antioxidant defense system in hepatic tissue. It also induced liver dysfunction as indicated by altered liver function markers and biochemical parameters. The administration of TQ attenuated the BPA-induced oxidative stress, alleviated the antioxidative system and improved to a large extent the liver functioning. This data clearly indicates that TQ has the potential to be a protective agent against oxidative stress and liver injury.

Detrimental effects of bisphenol A on development and functions of the male reproductive system in experimental rats.

Bisphenol A (BPA) is widely used in manufacturing industries. It is commonly detected in the environment and was reported to exert oestrogenic effects which may be harmful to the reproductive system. The present study was carried out to observe the effects of oral administration of BPA on the development of the reproductive organs and plasma sex hormone levels in prepubertal male Sprague-Dawley (SD) rats. Prepubertal male SD rats (n=8 in each group) were administered BPA in the doses of 1, 5, 10 and 100 mg/kg BW (body weight) via oral gavage for a period of 6 weeks. The control animals received the vehicle for BPA (Tween 80 in distilled water). Following 6 weeks of BPA exposure, the rats exhibited less evidence of spermatogenesis. There was seminiferous epithelial damage which included disruption of intercellular junctions and sloughing of germ cells into the seminiferous tubular lumen. Furthermore, the lumina of the seminiferous tubules and the epididymis of these animals were filled with immature germ cells and cellular debris. This damage may lead to the significant reduction in the seminiferous tubular diameter in BPA-treated animals. These findings were associated with the significant lower plasma testosterone and 17β-oestradiol levels. There was no significant difference between the body weight gain, the absolute as well as relative testis weight or epididymal weight of BPA-treated animals when compared to the control animals. The findings provided further evidence of the detrimental effects of BPA on the male reproductive system.

Effects of perinatal bisphenol A exposure during early development on radial arm maze behavior in adult male and female rats

Previous work has shown that exposure to bisphenol A (BPA) can affect anxiety behavior. However, no studies have examined whether administration of this endocrine disruptor during the perinatal period has the potential to induce alterations in cognitive behavior in both adult males and females as assessed in an appetitive task. The goal of the current study was to determine whether exposure to different doses of BPA during early development alters performance on the 17-arm radial maze in adulthood in Long–Evans rats. Oral administration of corn oil (vehicle), 4μg/kg, 40μg/kg, or 400μg/kg BPA to the dams occurred daily throughout pregnancy, and the pups received direct oral administration of BPA between postnatal days 1–9. Blood was collected from offspring at weaning age to determine levels of several hormones (thyroxine, thyroid stimulating hormone, follicle stimulating hormone, luteinizing hormone). One male and one female from each litter were evaluated on the 17-arm radial maze, a working/reference memory task, in adulthood. Results indicated that after exposure to BPA at both 4 and 400μg/kg/day, rats of both sexes had decreased levels of FSH at weaning. There were no significant effects of BPA on performance on the radial arm maze in males or females. In conclusion, exposure to BPA during early development had modest effects on circulating hormones but did not affect performance on a spatial learning and memory task.

The effect of bisphenol A on some oxidative stress parameters and acetylcholinesterase activity in the heart of male albino rats

Bisphenol A (BPA) is an endocrine disrupting chemical used on a wide range in industry. Several studies reported that BPA may cause cardiovascular disorders in humans and animals. The present study aims to investigate the effect of BPA on the heart of adult male rats. The rats received a daily oral administration of BPA (25mg/kg for 6weeks and 10mg/kg for 6 and 10weeks). It was found that BPA at the two studied doses induced a significant increase in malondialdehyde, and a significant decrease in catalase after 6weeks. Moreover, a significant decrease in reduced glutathione and acetylcholinesterase (AchE) activity was observed after treatment with the two doses of BPA throughout the studied time intervals. The two doses (25 and 10mg/kg) resulted in a significant decrease in nitric oxide (NO) levels after 6 and 10weeks, respectively. A significant increase in body weight gain occurred in all animals after BPA treatment. These results suggest that BPA has cardiotoxic effects which are mediated by the oxidative stress resulting from the overproduction of free radicals, the deficiency of NO and the inhibition of AchE leading to cholinergic activation. The obesity promoting effect of BPA may also participate in the observed cardiovascular disturbances.

Low dose bisphenol A impairs spermatogenesis by suppressing reproductive hormone production and promoting germ cell apoptosis in adult rats

Bisphenol A (BPA), an estrogenic chemical, has been shown to reduce sperm count; however, the underlying mechanisms remain unknown. Herein, we show that oral administration of BPA (2 µg/kg) for consecutive 14 days in adult rats (BPA rats) significantly reduced the sperm count and the number of germ cells compared to controls. The serum levels of testosterone and follicle-stimulating hormone (FSH), as well as the level of GnRH mRNA in BPA rats were lower than those of control rats. Testosterone treatment could partially rescue the reduction of germ cells in BPA rats. Notably, the number of apoptotic germ cells was significantly increased in BPA rats, which was insensitive to testosterone. Furthermore, the levels of Fas, FasL and caspase-3 mRNA in the testicle of BPA rats were increased in comparison with controls. These results indicate that exposure to a low dose of BPA impairs spermatogenesis through decreasing reproductive hormones and activating the Fas/FasL signaling pathway.

Similarity of Bisphenol A Pharmacokinetics in Rhesus Monkeys and Mice: Relevance for Human Exposure

ObjectiveDaily adult human exposure to bisphenol A (BPA) has been estimated at < 1 μg/kg, with virtually complete first-pass conjugation in the liver in primates but not in mice. We measured unconjugated and conjugated BPA levels in serum from adult female rhesus monkeys and adult female mice after oral administration of BPA and compared findings in mice and monkeys with prior published data in women.MethodsEleven adult female rhesus macaques were fed 400 μg/kg deuterated BPA (dBPA) daily for 7 days. Levels of serum dBPA were analyzed by isotope-dilution liquid chromatography–mass spectrometry (0.2 ng/mL limit of quantitation) over 24 hr on day 1 and on day 7. The same dose of BPA was fed to adult female CD-1 mice; other female mice were administered 3H-BPA at doses ranging from 2 to 100,000 μg/kg.ResultsIn monkeys, the maximum unconjugated serum dBPA concentration of 4 ng/mL was reached 1 hr after feeding and declined to low levels by 24 hr, with no significant bioaccumulation after seven daily doses. Mice and monkeys cleared unconjugated serum BPA at virtually identical rates. We observed a linear (proportional) relationship between administered dose and serum BPA in mice.ConclusionsBPA pharmacokinetics in women, female monkeys, and mice is very similar. By comparison with approximately 2 ng/mL unconjugated serum BPA reported in multiple human studies, the average 24-hr unconjugated serum BPA concentration of 0.5 ng/mL in both monkeys and mice after a 400 μg/kg oral dose suggests that total daily human exposure is via multiple routes and is much higher than previously assumed.

Pharmacological Modulation of Genome and Proteome Alterations in Mice Treated with the Endocrine Disruptor Bisphenol A

Among endocrine disruptors, the xenoestrogen bisphenol A (BPA) is of particular interest due to the very high production and widespread environmental contamination. We recently demonstrated that the oral administration of BPA to mice results in the formation of DNA adducts not only in liver but also in mammary tissue. The present study aimed at evaluating the modulation of BPA-related DNA adducts and proteome alterations by the chemopreventive agents budesonide (BUD) and phenethyl isothiocyanate (PEITC). Swiss ICR (CD-1) mice received, for 8 days, BPA with the drinking water and either chemopreventive agent with the diet. We measured DNA adducts by (32)P postlabeling and 656 proteins by antibody microarray. BPA induced the formation, with similar patterns, of DNA adducts in liver and in mammary tissue. Moreover, BPA dysregulated 13 proteins in mammary tissue, mostly in the sense of upregulation, including estrogen receptor-beta and proteins involved in cell proliferation, inhibition of apoptosis, tissue remodeling, inflammation, stress response, and glutathione synthesis. PEITC significantly inhibited the formation of BPA-induced DNA adducts, but only at the highest dose tested, and BUD was totally ineffective. The chemopreventive agents modulated a variety of BPA-induced changes in proteome profiles. However, as shown by both hierarchical cluster analysis and principal component analysis, BUD and especially PEITC were not able to restore the physiological situation in BPA-treated mice. Therefore, the in vivo use of proteome analysis proves to be a sensitive tool for the early prediction not only of protective effects but also of adverse effects of chemopreventive agents.