Bisphenol A In Mice Research Articles

Role of Pumpkin and Linseed Oils in Attenuating the Nephrotoxicity of Bisphenol-A in Mice: Biochemical, Genetic and Histopathological studies

Role of Pumpkin and Linseed Oils in Attenuating the Nephrotoxicity of Bisphenol-A in Mice: Biochemical, Genetic and Histopathological studies

Effects of bisphenol-A and folic acid on growth, reproductive development, and DNA methylation in snapdragons (Antirrhinum majus)

Bisphenol-A (BPA), used in the production of polycarbonate plastics, exerts complex effects on the development of organisms and on their epigenomes as a methylation disruptor. BPA is of concern due to its ubiquity in the environment. In contrast, folic acid can promote plant growth and has been shown to correct the methyl-disrupting effects of BPA in mice. We investigated the effects of prolonged exposure to BPA and folic acid on plant height, dry mass, and DNA methylation of floral tissues of Antirrhinum majus L. (snapdragons) from seedling to floral senescence. At low and medium concentrations (5 and 25 mg/L), BPA had a growth-promoting effect early in development and appeared to accelerate floral development compared with the controls. At senescence, plants treated with the low and medium concentrations of BPA had decreased dry mass compared with the controls. Folic acid promoted growth early through mid-vegetative development and also promoted early flowering. In general, the acceleration of floral development associated with the low concentration of BPA and folic acid correlated with higher DNA methylation percentages. These data suggest that prolonged exposure to BPA influences plant growth and floral development, and causes epigenetic modifications that may potentially be alleviated through the application of folic acid, thus suggesting the significance of folic acid for environmental protection.

Crosstalk between BPA and FXRα Signaling Pathways Lead to Alterations of Undifferentiated Germ Cell Homeostasis and Male Fertility Disorders.

SummarySeveral studies have reported an association between the farnesoid X receptor alpha (FXRα) and estrogenic signaling pathways. Fxrα could thus be involved in the reprotoxic effects of endocrine disruptors such as bisphenol-A (BPA). To test this hypothesis, mice were exposed to BPA and/or stigmasterol (S), an FXRα antagonist. Following the exposure to both molecules, wild-type animals showed impaired fertility and lower sperm cell production associated with the alteration of the establishment and maintenance of the undifferentiated germ cell pool. The crosstalk between BPA and FXRα is further supported by the lower impact of BPA in mice genetically ablated for Fxrα and the fact that BPA counteracted the effects of FXRα agonists. These effects might result from the downregulation of Fxrα expression following BPA exposure. BPA and S act additively in human testis. Our data demonstrate that FXRα activity modulates the impact of BPA on male gonads and on undifferentiated germ cell population.

Protective effects of silymarin against bisphenol A-induced hepatotoxicity in mouse liver.

Bisphenol A (BPA) is an endocrine-disrupting chemical released into the environment, with severe consequences for human health, including metabolic syndrome and associated pathological conditions. Due to limited information on BPA-induced hepatotoxicity, the present study focused on investigating the association between BPA-induced toxicity and inflammatory markers in the liver, and how these injuries may be alleviated using the natural agent silymarin, a flavonoid with antioxidant properties obtained from Silybum marianum. Administration of BPA to male CD-1 mice for 10 days caused a significant increase in the number of cells immunopositive for interleukin 6 and tumor necrosis factor-α, pro-inflammatory cytokines that mediate the hepatic inflammatory response. Treatment with 200 mg/kg of silymarin concurrently with BPA for 10 days resulted in a diminished level of pro-inflammatory cytokines and in significantly reduced ultrastructural injuries. Additionally, silymarin was able to restore the significantly decreased glycogen deposits observed following BPA exposure to normal levels, thus favoring hepatic glycogenesis. This study represents the first report of silymarin ability to reduce hepatic lesions and to counteract inflammation caused by BPA in mice. A dose of 200 mg/kg silymarin was sufficient to induce a protective effect against structural and ultrastructural injuries induced by BPA and to lower the levels of pro-inflammatory cytokines observed in murine liver tissue following exposure to BPA.

Pharmacokinetics of bisphenol A in serum and adipose tissue following intravenous administration to adult female CD-1 mice

Bisphenol A (BPA) is an important industrial chemical used as the monomer for polycarbonate plastic and in epoxy resins for use in food can liners. Worldwide biomonitoring studies consistently find high prevalence of BPA conjugates in urine consistent with pervasive exposure at levels typically below 1μg/kgbw/day. The current study used LC/MS/MS to measure serum pharmacokinetics of unconjugated (active) and conjugated (inactive) BPA in adult female CD-1 mice following intravenous (IV) injection, which produces higher serum levels by circumventing the processes of absorption from the GI tract and presystemic metabolism that occur after oral administration. Deuterated BPA (100μg/kgbw) was used to avoid interference by background contamination from trace amounts of native BPA. Additionally, the pharmacokinetics of unconjugated BPA were determined in adipose tissue, a proposed site of action and “depot” for BPA. After IV injection, unconjugated BPA rapidly distributed out of the circulation (t1/2=0.2h) and terminal elimination also proceeded rapidly (t1/2=0.8h). Consistent with the degree of aqueous solubility, lipid/water solubility ratio, and partitioning from blood into adipose tissue in vivo, the levels of unconjugated BPA in mouse adipose tissue rapidly reached a maximal level (0.25h) that did not exceed the serum maximum at the initial sampling time (0.08h). Terminal elimination of unconjugated BPA from adipose tissue (t1/2=7.0h) was similar to that for conjugated BPA in serum (t1/2=6.6h) and <0.01% of the administered dose remained in adipose tissue after 24h. These plasma and tissue kinetics are consistent with rapid equilibria and underscore the non-persistent nature of BPA, particularly when compared with slowly metabolized lipophilic organic pollutants like halogenated dibenzodioxins.

TBTCl (tri-n-butyltin chloride)과 bisphenol A에 의한 단기노출이 등줄쥐의 번식에 미치는 영향

To investigate the effects of short-term treatment with tri-n-butyltin chloride (TBTCl) and bisphenol A (BPA) on the reproduction of striped field mice, the mice were intramuscularly injected with TBTCl or BPA immediately before the reproductive season and examined in the reproductive season after keeping them for 4 months. As a result, there were no differences between the control and the compound-treated groups regarding body weight in both sexes, the residual levels of the compounds in the adult males, and the gonadosomatic index (GSI) and the histological structures with LM and EM of the testes and epididymides in both the adult and young males. The infant mortality and abortion rate, however, were high in the TBTCl-treated groups and BPA-treated groups respectively, compared to the control group. Conclusively, it was suggested that short-term treatment with TBTCl or BPA in mice in the non-reproductive season might have inhibited the development of the uterine embryos or fetuses, although it did not induce accumulations of these compounds or affect the reproductive organs of adult and young (F1) males.

CARDIOVASCULAR HEALTH: Exploring a Potential Link between BPA and Heart Disease

Most people in the United States are exposed to the plastic monomer bisphenol A (BPA), whether in plastic linings in food cans, containers made of hard plastic, or other plastics and foods containing BPA. Exposure to this suspected endocrine disruptor is illustrated by urine samples collected for NHANES (the National Health and Nutrition Examination Survey), for which the Centers for Disease Control and Prevention surveys thousands of adults and children. A new analysis of NHANES data published 13 January 2010 in PLoS ONE adds more evidence for an association between heart disease and higher exposures to BPA, even at the relatively low levels seen in the general population. David Melzer, an epidemiologist at the University of Exeter, United Kingdom, and his colleagues first looked at NHANES data collected from 2003 and 2004; their results, published in the 17 September 2008 issue of JAMA, were the first to show an association between higher levels of BPA metabolites in urine and adverse adult health outcomes, including heart disease. The current analysis considered NHANES data from 2005 and 2006. Although the BPA levels in urine samples from this new group of people were lower by almost a third, the association remained between coronary heart disease and higher urinary BPA. While this study may help inform future research, such cross-sectional studies “should not be used to demonstrate that a particular chemical can cause a particular effect,” said Steven G. Hentges of the Polycarbonate/BPA Global Group of the American Chemistry Council in a 13 January 2010 press release. And indeed, Melzer and his colleagues emphasize that because this study is cross-sectional—a snapshot in time instead of a long-term observational investigation—they cannot say whether BPA contributes to heart disease or if heart disease changes the exposure to or metabolism of BPA in adults. “What would really help is if industry and regulators could support independent studies [to examine] whether high BPA levels are present before any disease started,” Melzer says. “Chasing human [data] is the way forward,” says Richard Sharpe, an endocrinologist from The Queen’s Medical Research Institute in Edinburgh who did not participate in the research. NHANES provides a robust data set, he says, and the repeatability of the association with a second survey group is positive. However, that replication is somewhat incomplete because not all of the associations found with BPA in the first study were found in the second. “The more logical interpretation of the results as they stand at the moment is that they are looking at two variables that are associated with something else,” Sharpe says. Diet, for instance, is a major contributor to heart disease in the United States and also a major source of BPA exposure. “We should remember that heart disease develops over a long period of time,” Sharpe says, “so if BPA is involved causally, a cross-sectional study such as this [PLoS ONE report] cannot show this.” Scott Belcher, a scientist at the University of Cincinnati, says the association in humans is “not super surprising in light of our animal studies and because we already know estrogens are related to various cardiovascular end points.” Belcher’s team reported at the June 2009 Endocrine Society annual meeting that BPA exposure in vitro in muscle cells and in whole hearts from female rodents leads to arrhythmias, and they recently received American Recovery and Reinvestment Act funds from the NIEHS to conduct further research on BPA in mice. Meanwhile, pending the release of an updated toxicology review for BPA, the Food and Drug Administration announced in January 2010 it is “taking reasonable steps to reduce human exposure to BPA in the food supply.”

Prenatal Preview: Early Bisphenol A Exposure May Spawn Late-Life Reproductive Problems

Vol. 117, No. 6 EnvironewsOpen AccessPrenatal Preview: Early Bisphenol A Exposure May Spawn Late-Life Reproductive Problemsis corrected byErrata Angela Spivey Angela Spivey Search for more papers by this author Published:1 June 2009https://doi.org/10.1289/ehp.117-a256aCited by:3AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Scientists increasingly find that exposure to toxicants during critical periods of pre- and perinatal development can have long-lasting effects that increase the risk of reduced fertility, reproductive tumors, and breast cancer later in life. Some animal studies have suggested that very low doses of bisphenol A (BPA) in a range relevant to human exposures can cause abnormalities in the uterus, vagina, and ovary when those exposures occur during early development. To date, however, evidence for a carcinogenic effect of low-dose BPA on the female reproductive tract has been lacking; studies examining carcinogenic susceptibility to BPA have focused only on the mammary and prostate glands. Now a report from researchers at the NIEHS indicates that low prenatal doses of BPA in mice may cause potentially carcinogenic alterations in female reproductive tissues [EHP117:879–885; Newbold et al.].Widespread human exposure to BPA is a cause for concern because of the compound’s chemical similarity to diethylstilbestrol (DES), an antinausea drug that caused harmful reproductive effects in women whose mothers took it during pregnancy. This study used an experimental animal model (the CD-1 mouse) that has been useful in studying the effects of prenatal exposure to DES.On gestational days 9–16, pregnant mice were injected with relatively low dosages of BPA—0.1, 1, 10, 100, or 1,000 μg/kg/day, which are considered by the authors and other researchers to be within an environmentally relevant range. When the dams’ offspring reached late adulthood (16–18 months), their reproductive tissues were evaluated.Some of the BPA-exposed offspring developed both benign and malignant lesions in late adulthood. In the pups that received 1 μg/kg/day, the incidence of benign ovarian cysts was 67%—similar to what the same team had previously observed for neonatal exposure to BPA. In addition, more severe ovarian lesions were found in the groups that received 10, 100, or 1,000 μg/kg/day but not in control animals. The occurrence of progressive proliferative lesions of the oviduct seemed to increase following BPA exposure, similar to effects seen in previous studies following prenatal exposure to DES. Because DES appears to delay the expression of genes that guide the development of the reproductive tract, the authors suggest that molecular “misprogramming” is the most likely reason for both DES- and BPA-induced lesions of the oviduct.Malignant changes in the uterus also were found in exposed mice, although the incidence of those lesions was not statistically different from that seen in controls. In addition, more severe pathologies were observed in exposed animals but not in controls. These included atypical hyperplasia and stromal polyps of the uterus, sarcoma of the uterine cervix, and mammary adenocarcinoma.According to the authors, this study is the first to find both benign and malignant lesions in reproductive tissues of senescent female mice exposed prenatally to BPA over a wide dosage range thought to be relevant to human exposure. The study adds to the growing body of literature showing adverse effects following developmental exposure to low doses of BPA and suggests that exposure during critical periods of fetal development may result in adverse reproductive and carcinogenic changes over the long term.FiguresReferencesRelatedDetailsCited by Beydoun H, Beydoun M, Jeng H, Zonderman A and Eid S (2016) Bisphenol-A and Sleep Adequacy among Adults in the National Health and Nutrition Examination Surveys, Sleep, 10.5665/sleep.5466, 39:2, (467-476), Online publication date: 1-Feb-2016., Online publication date: 1-Feb-2016. Beydoun H, Khanal S, Zonderman A and Beydoun M (2014) Sex differences in the association of urinary bisphenol-A concentration with selected indices of glucose homeostasis among U.S. adults, Annals of Epidemiology, 10.1016/j.annepidem.2013.07.014, 24:2, (90-97), Online publication date: 1-Feb-2014. Dietert R, DeWitt J, Germolec D and Zelikoff J (2010) Breaking Patterns of Environmentally Influenced Disease for Health Risk Reduction: Immune Perspectives, Environmental Health Perspectives, 118:8, (1091-1099), Online publication date: 1-Aug-2010.Related articlesErrata1 August 2009Environmental Health Perspectives Vol. 117, No. 6 June 2009Metrics About Article Metrics Publication History Originally published1 June 2009Published in print1 June 2009 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. 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Functional changes in dopamine D3 receptors by prenatal and neonatal exposure to an endocrine disruptor bisphenol-A in mice.

Bisphenol-A (BPA), one of the most common environmental endocrine disrupters, has been evaluated extensively for toxicity and carcinogenicity. However, little is still known about its action on the central nervous system (CNS). In the previous study, we found that prenatal and neonatal exposure to BPA markedly enhanced the rewarding effect induced by morphine. Here we found that prenatal and neonatal exposure to BPA resulted in the attenuation of dopamine D3 receptor-mediated G-protein activation by 7-OH-DPAT in the mouse limbic forebrain. This treatment also caused a significant decrease in the B(max) value of [(3)H]PD128907, a dopamine D3 receptor ligand, in this area. Under these conditions, no change in dopamine D3 receptor mRNA expression in the limbic forebrain and lower midbrain was observed by prenatal and neonatal exposure to BPA. The present data provide further evidence that prenatal and neonatal exposure to BPA leads to the reduction of functional dopamine D3 receptors without affecting the new synthesis of dopamine D3 receptors in the mouse limbic forebrain.

Prenatal and neonatal exposure to bisphenol-a enhances the central dopamine d1 receptor-mediated action in mice: enhancement of the methamphetamine-induced abuse state

Bisphenol-A (BPA), one of the most common environmental endocrine disrupters, has been extensively evaluated for toxicity in a variety of tests in rodents, including developmental and reproductive toxicity, and carcinogenicity. However, little is known about its action on the CNS. In this report, we show that prenatal and neonatal exposure to BPA in mice leads to the enhancement of the dopamine D1 receptor-dependent rewarding effect induced by a psychostimulant methamphetamine. Furthermore, this treatment with BPA markedly enhanced hyperlocomotion and its sensitization induced by methamphetamine, which reflects extensive abuse associated with sociological and psychiatric problems. We also demonstrated that chronic exposure to BPA produced an up-regulation of dopamine D1 receptor function to activate G-protein in the mouse limbic forebrain, which is thought to be a critical site for the expression of rewarding effects by abuse drugs. Additionally, chronic BPA exposure produced a significant increase in levels of the dopamine D1 receptor mRNA in the whole brain. In contrast, no change in protein levels of methamphetamine-targeted proteins, dopamine transporter or the type 2 vesicle monoamine transporter in the brain was observed by prenatal and neonatal exposure to BPA. The present data provide the first evidence that prenatal and neonatal exposure to BPA can potentiate the central dopamine D1 receptor-dependent neurotransmission, resulting in supersensitivity of methamphetamine-induced pharmacological actions related to psychological dependence on psychostimulants.