BPA-induced Changes Research Articles

A preliminary analysis of the effects of bisphenol A on the plant root growth via changes in endogenous plant hormones

Bisphenol A (BPA) is ubiquitous in the environment worldwide, affecting plant growth and development. Endogenous plant hormones serve as switches that regulate plant growth and development. However, plants have different physiological requirements and environmental adaptive capacities during the different growth stages. Here, we investigated the effects of BPA on soybean (Glycine max L.) root growth at the three growth stages and analyzed the mechanisms underlying the effects of BPA on the root growth by assessing changes in endogenous hormone. The results showed that low concentration of BPA (1.5mgL−1) improved root growth (except at the seed-filling stage), increased indole-3-acetic acid (IAA) content at the first two growth stages, and increased zeatin (ZT) content and decreased gibberellic acid (GA3) content at the seedling stage. But low concentration of BPA caused decreased ethylene (ETH) contents and constant abscisic acid (ABA) content at all three stages. However, BPA at moderate and high concentrations (6.0 and 12.0mgL−1) inhibited root growth, causing the decreased IAA, GA3 and ETH contents and increased ABA content at all three growth stages. The change degrees of above indices were weakened with prolonging the growth stages. After BPA withdrawal, both the root growth and the hormone contents recovered (with the exception of ZT and ETH), and the recovery degrees had negative correlation with the BPA exposure concentration and had positive correlation with the growth stage. Changes in residual BPA content in the roots were also observed at different BPA concentrations and different growth stages. Our results demonstrated the effects of BPA on root growth were related to BPA-induced changes in hormone, which performed differently at various growth stages.

A novel approach to assessing bisphenol-A hazards using an in vitro model system.

BackgroundAlthough the toxicological impacts of the xenoestrogen bisphenol-A (BPA) have been studied extensively, but the mechanism of action is poorly understood. Eventually, no standard method exists for evaluating the possible health hazards of BPA exposure. Considering mice spermatozoa as a potential in vitro model, we investigated the effects of BPA exposure (0.0001, 0.01, 1, and 100 μM for 6 h) on spermatozoa and the related mechanisms of action. The same doses were also employed to evaluate protein profiles of spermatozoa as a means to monitor their functional affiliation to diseases.ResultsOur results demonstrated that high concentrations of BPA negatively affect sperm motility, viability, mitochondrial functions, and intracellular ATP levels by activating the mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and protein kinase-A pathways. Moreover, short-term exposure of spermatozoa to high concentrations of BPA induced differential expressions of 24 proteins. These effects appeared to be caused by protein degradation and phosphorylation in spermatozoa. Proteins differentially expressed in spermatozoa from BPA treatment groups are putatively involved in the pathogenesis of several diseases, mainly cancer, carcinoma, neoplasm, and infertility.ConclusionsBased on these results, we propose that BPA adversely affects sperm function by the activation of several kinase pathways in spermatozoa. In addition, BPA-induced changes in the sperm proteome might be partly responsible for the observed effects in spermatozoa, subsequently involve in the pathogenesis of many diseases. Therefore, we anticipated that current strategy might broadly consider for the health hazards assessment of other toxicological agents.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2979-5) contains supplementary material, which is available to authorized users.

Gestational Exposure to Bisphenol A Affects the Function and Proteome Profile of F1 Spermatozoa in Adult Mice.

Background:Maternal exposure to the endocrine disruptor bisphenol A (BPA) has been linked to offspring reproductive abnormalities. However, exactly how BPA affects offspring fertility remains poorly understood.Objectives:The aim of the present study was to evaluate the effects of gestational BPA exposure on sperm function, fertility, and proteome profile of F1 spermatozoa in adult mice.Methods:Pregnant CD-1 mice (F0) were gavaged with BPA at three different doses (50 μg/kg bw/day, 5 mg/kg bw/day, and 50 mg/kg bw/day) on embryonic days 7 to 14. We investigated the function, fertility, and related processes of F1 spermatozoa at postnatal day 120. We also evaluated protein profiles of F1 spermatozoa to monitor their functional affiliation to disease.Results:BPA inhibited sperm count, motility parameters, and intracellular ATP levels in a dose-dependent manner. These effects appeared to be caused by reduced numbers of stage VIII seminiferous epithelial cells in testis and decreased protein kinase A (PKA) activity and tyrosine phosphorylation in spermatozoa. We also found that BPA compromised average litter size. Proteins differentially expressed in spermatozoa from BPA treatment groups are known to play a critical role in ATP generation, oxidative stress response, fertility, and in the pathogenesis of several diseases.Conclusions:Our study provides mechanistic support for the hypothesis that gestational exposure to BPA alters sperm function and fertility via down-regulation of tyrosine phosphorylation through a PKA-dependent mechanism. In addition, we anticipate that the BPA-induced changes in the sperm proteome might be partly responsible for the observed effects in spermatozoa.Citation:Rahman MS, Kwon WS, Karmakar PC, Yoon SJ, Ryu BY, Pang MG. 2017. Gestational exposure to bisphenol-A affects the function and proteome profile of F1 spermatozoa in adult mice. Environ Health Perspect 125:238–245; http://dx.doi.org/10.1289/EHP378

Bisphenol A exposure alters release of immune and developmental modulators and expression of estrogen receptors in human fetal lung fibroblasts

Bisphenol A (BPA) has been shown to exert biological effects through estrogen receptor (ER)-dependent and ER-independent mechanisms. Recent studies suggest that prenatal exposure to BPA may increase the risk of childhood asthma. To investigate the underlying mechanisms in the actions of BPA, human fetal lung fibroblasts (hFLFs) were exposed to varying doses of BPA in culture for 24hr. Effects of BPA on localization and uptake of BPA, cell viability, release of immune and developmental modulators, cellular localization and expression of ERα, ERβ and G-protein coupled estrogen receptor 30 (GPR30), and effects of ERs antagonists on BPA-induced changes in endothelin-1 (ET-1) release were examined. BPA at 0.01–100μmol/L caused no changes in cell viability after 24hr of exposure. hFLFs expresses all three ERs. BPA had no effects on either cellular distribution or protein expression of ERα, however, at 100μmol/L (or 23μmol/L intracellular BPA) increased ERβ protein levels in the cytoplasmic fractions and GPR30 protein levels in the nuclear fractions. These paralleled with increased release of growth differentiation factor-15, decreased phosphorylation of nuclear factor kappa B p65 at serine 536, and decreased release of ET-1, interleukin-6, and interferon gamma-induced protein 10. ERs antagonists had no effects on BPA-induced decrease in ET-1 release. These data suggest that BPA at 100μmol/L altered the release of immune and developmental modulators in hFLFs, which may negatively influence fetal lung development, maturation, and susceptibility to environmental stressors, although the role of BPA in childhood asthma remains to be confirmed in in vivo studies.

Bisphenol-A affects male fertility via fertility-related proteins in spermatozoa.

The xenoestrogen bisphenol-A (BPA) is a widespread environmental contaminant that has been studied for its impact on male fertility in several species of animals and humans. Growing evidence suggests that xenoestrogens can bind to receptors on spermatozoa and thus alter sperm function. The objective of the study was to investigate the effects of varying concentrations of BPA (0.0001, 0.01, 1, and 100 μM for 6 h) on sperm function, fertilization, embryonic development, and on selected fertility-related proteins in spermatozoa. Our results showed that high concentrations of BPA inhibited sperm motility and motion kinematics by significantly decreasing ATP levels in spermatozoa. High BPA concentrations also increased the phosphorylation of tyrosine residues on sperm proteins involved in protein kinase A-dependent regulation and induced a precocious acrosome reaction, which resulted in poor fertilization and compromised embryonic development. In addition, BPA induced the down-regulation of β-actin and up-regulated peroxiredoxin-5, glutathione peroxidase 4, glyceraldehyde-3-phosphate dehydrogenase, and succinate dehydrogenase. Our results suggest that high concentrations of BPA alter sperm function, fertilization, and embryonic development via regulation and/or phosphorylation of fertility-related proteins in spermatozoa. We conclude that BPA-induced changes in fertility-related protein levels in spermatozoa may be provided a potential cue of BPA-mediated disease conditions.

Sex-specific effects of long-term exposure to bisphenol-A on anxiety- and depression-like behaviors in adult mice

Humans are routinely exposed to low levels of bisphenol A (BPA), an environmental endocrine disruptor, which is widely used in the production of polycarbonate plastics. The effects of perinatal exposure to BPA have been shown to affect various aspects of social behaviors such as anxiety and depression in adult offspring. Because sex hormones play a critical role in neurobehavior in adulthood, it is possible that long-term exposure to BPA has widespread effects on these emotional behaviors in adulthood. In the present study, adult mice were exposed to BPA at dosages of 0.04, 0.4, 4, 40mgkg−1d−1 for 12weeks. A behavioral assay was performed using the open field test (OFT), mirrored maze, the elevated plus maze (EPM), and the forced swim task. The results showed that, after exposure to BPA at 0.4–40mgkg−1d−1, the number of open arm entries and the time spent in them in the elevated plus maze task were reduced in males but increased in females, and thus eliminating or reversing sex differences in these behaviors. BPA at 0.04–40mgkg−1d−1 increased the immobility of male mice in the forced swimming test. Furthermore, BPA (0.4–40mgkg−1d−1) significantly decreased brain level of testosterone in males, but no significant influence was found in serum and the brain levels of estradiol in females. Western blot analysis further indicated that BPA at 0.4, 4, or 40mgkg−1d−1 significantly down-regulated the protein level of estrogen receptor β (ERβ) in the hippocampus of the adult males but not females, and inhibited the protein level of GABA(A)α2 receptor in hippocampus of males but promoted that of females. These results suggest that long-term exposure to BPA sex specifically affects anxiety- and depression-like behaviors in adult mice. Changes in the levels of GABA(A)α2 receptor and ERβ proteins of hippocampus might be associated with BPA-induced changes in these emotional behaviors.

Neither direct nor developmental exposure to bisphenol A alters the severity of experimental inflammatory colitis in mice

Bisphenol A (BPA) is a high production volume endocrine disrupting chemical that is widely used in many consumer products and prevalent in human biological fluids. Recent studies suggest that BPA is active even at low levels, raising concern about its potential harm to human health. Given that the main route of exposure to BPA is oral, via the consumption of BPA-tainted foods and beverages, intestinal tissues could be particularly vulnerable to BPA-induced changes. A novel examination is reported here of whether oral exposure to BPA affects inflammatory bowel disease (IBD), an immune-mediated disease of the colon, using a mouse model of inflammatory colitis. In addition to direct exposure, the possible contribution of maternal BPA exposure to disease later in life is explored. It was found that daily oral exposure to BPA at the US Environmental Protection Agency described oral reference dose (50 µg/kg/day), either via direct oral route or through maternal sources (i.e. developmental exposure), did not significantly alter disease outcomes of body weight, survival, or colonic pathology. These observations suggest that oral BPA exposure, at this dose and for this exposure duration, has minimal influence on aspects of the inflammatory response that regulate immune mediated diseases of the gastrointestinal tract.

Abstract P5-03-06: Bisphenol A and mammary stem cells: implications in breast cancer susceptibility

Abstract It has been speculated that the increasing incidence of breast cancer might be linked to the increased exposure to environmental synthetic estrogens, such as bisphenol A (BPA), which is a most pervasive chemical in modern life as a component of polycarbonate plastics and epoxy resins used widely for food and beverage containers and dental sealants. Perinatal exposure to low, environmentally relevant doses of BPA in rodents resulted in the induction of pre-neoplastic ductal hyperplasia, carcinoma in situ, and increased susceptibility to tumorigenesis. However, the underlying mechanism for these observations is unclear. The murine mammary stem cells (MaSCs) are present in fetal mammary rudiments and could be the putative targets for BPA-induced tumorigenesis. More recently, MaSCs of different lineages have been matched with different subtypes of breast cancer by their specific gene-expression signatures. We thus hypothesize that mammary gland exposed to BPA at a susceptible window may lead to its susceptibility to tumorigenesis through a MaSC and/or stem cell niche mediated mechanism. To test this hypothesis, we exposed 21-day old Balb/C mice to BPA by gavage at 25 µg/kg/day during puberty for 3 weeks, and then isolated primary mammary cells at different time points (6-week, 2 and 4-month) for MaSC quantification using an in vitro mammosphere formation and 3D-ECM sphere differentiation assay as well as the in vivo cleared mammary fat pad regeneration assay. Our findings indicate that low dose BPA exposure at puberty can accelerate puberty onset, increase lateral branches and hyperplasia in adult mammary glands. Further, a single oral dose of DMBA at 30 mg/kg administrated at 2-month old resulted in a 2.4-fold increase in hyperplasia of mammary glands harvested at 4-month old when compared with BPA treated group without DMBA. Most significantly, puberty BPA exposure increased luminal MaSCs during gland development and this resulted in an increase of luminal cells in adult glands. In addition, puberty BPA exposure also altered basal MaSCs in such a way that regenerated glands from these basal MaSCs yielded higher preneoplastic lesion than control basal MaSCs, indicating puberty BPA exposure render basal MaSCs more susceptible to transformation. We also found significant increase of gene expression in steroid hormonal receptors (e.g. ERs and PR) in the stromal compartment (or stem cell niche), which suggest that the changes we observed above for the luminal and basal MaSCs may be caused indirectly through altered stromal environment upon BPA exposure during early life stage. Future studies are necessary to differentiate the effect of BPA exposure on MaSCs or the MaSC niche. In conclusion, our study showed that BPA-induced morphogenesis changes in mammary gland had a stem cell origin. More importantly, our findings suggest that BPA-induced susceptibility of mammary glands to tumorigenesis may also have a stem cell origin. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-06.

Acute and chronic toxic effects of bisphenol a onChlorella pyrenoidosaandScenedesmus obliquus

The acute and chronic toxic effects of Bisphenol A (BPA) on Chlorella pyrenoidosa (C. pyrenoidosa) and Scenedesmus obliquus (S. obliquus) were not well understood. The indoor experiments were carried out to observe and analyze the BPA-induced changes. Results of the observations showed that in acute tests BPA could significantly inhibit the growth of both algae, whereas chronic exposure hardly displayed similar trend. Superoxide dismutase (SOD) and Catalase (CAT) activities of both algae were promoted in all the treatments. Chlorophyll a synthesis of the two algae exhibited similar inhibitory trend in short-term treatments, and in chronic tests C. pyrenoidosa hardly resulted in visible influence, whereas in contrast, dose-dependent inhibitory effects of S. obliquus could be clearly observed. The experimental results indicated that the growth and Chlorophyll a syntheses of S.obliquus were more sensitive in response to BPA than that of C. pyrenoidosa, whereas for SOD andCAT activities, C. pyrenoidosa was more susceptible. This research provides a basic understanding of BPA toxicity to aquatic organisms.

Bisphenol A decreases atrial contractility involving NO‐dependent G‐cyclase signaling pathway

Bisphenol A (BPA) is used in manufacturing plastics. Even though BPA is reported to produce reproductive and behavioral toxicity in experimental animals, the direct effect of BPA on the cardiovascular system is not known. The present study was therefore undertaken to evaluate the effect of BPA, on spontaneously beating rat right atrial preparations. In this study, in vitro isometric contractions of right atria were recorded. Cumulative concentration-response of BPA on atrial contractions was obtained in the absence or presence of antagonists. BPA (0.1-100 μ m) decreased the rate and the force of atrial contractions in a concentration-dependent manner. At 100 μ m, the decreases were >90%. The BPA-induced changes were not blocked by atropine (muscarinic receptor blocker). However, pretreatment with N-ω-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor) or methylene blue (a guanylyl cyclase inhibitor) blocked the BPA-induced changes in rate and force. Nitroglycerine, an NO-donor, decreased the rate and force of atrial contractions. Further, the BPA-induced changes were not due to the solvent (ethanol) used to dissolve it. The present study therefore indicates that BPA decreases the atrial contractility involving NO-dependent G-cyclase signaling mechanisms.

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.