Mosaic of Drosophila Behavior Due to Bisphenol-A Exposure: From Hyperactivity to Aversion

Serum unconjugated bisphenol A concentrations in women may adversely influence oocyte quality during in vitro fertilization

Getting Big on BPA: Role for BPA in Obesity?

The adolescence period, marked by sexual and brain maturation, has shown sensitivity to various environmental disruptors. Exposure to the xenoestrogen bisphenol A (BPA) is known to alter physiological and behavioral responses although its role at this critical period remains largely unknown. Recent research further suggests biochemical and genomic effects of BPA to be mitigated by various natural compounds, while effects on behavior have not been examined. This study aimed to characterize (1) the effects of dietary BPA during adolescence on endogenous corticosterone (CORT) secretion, emotional behavior, and testosterone (T) in adulthood, and (2) the impact of combined exposure to BPA with hop extracts (Hop), a phytoestrogen with anxiolytic properties. To do so, four groups of male Wistar rats [postnatal day (PND) 28] were administered corn oil (control), BPA (40 mg/kg), hops (40 mg/kg), or BPA-hops by oral gavage for 21 days (PND 28–48). Blood droplets collected on PND 28, 48, and 71 served to measure CORT and T changes. As adults, rats were tested in the elevated plus maze (EPM), the social interaction test, and the forced swim test. Our findings demonstrated elevated anxiety and a trend toward depressive-like behaviors in BPA- compared to hops-exposed rats. However, BPA intake had no impact on basal CORT levels, or adulthood T secretion and sociability. Of note, BPA's anxiogenic effect manifested through decreased EPM open arm entries was abolished by hops co-supplementation. Together, our observations suggest the adolescence period to be less sensitive to deleterious effects of BPA than what has been reported upon gestational and perinatal exposure.

Introduction: Endocrine disrupting chemicals (EDC) are either synthetic or natural compounds in the environment that can interfere with endocrine functions. Exposure to EDCs during development is a major concern, and the health consequences may be permanent or long-lasting. Bisphenol A (BPA) is known to be an EDC and prenatal BPA exposure has been related to differences in children’s brain microstructure, leading to differences in children’s behavioral symptoms. Moreover, high BPA exposure during pregnancy is related to increased behavioral problems throughout childhood. In our study, we aimed to evaluate the effects of BPA exposure in zebrafish embryos, focusing on locomotor activities and biochemical parameters. Methods: Zebrafish embryos were exposed to 1μg/L and 10 μg/L BPA until 72 hpf. At the end of exposure period, locomotor activities were determined and acetylcholinesterase (AChE), glutathione S-transferase (GST) and superoxide dismutase (SOD) activities were determined using spectrophotometric methods. Results: Concentration-dependent changes were determined in GST and SOD activities, indicating increased response to oxidative stress due to BPA toxicity. AChE acitivity alterations and locomotor activity changes pointed out the importance of concentration in the neurotoxic effects of BPA in zebrafish embryos. Conclusion: The results of our study pointed out that new studies are needed to examine the effects of BPA, especially on cognitive and locomotor functions.

Bisphenol A (BPA) may be released in the oral cavity after sealant placement: A critical summary of Kloukos D, Pandis N, Eliades T. In vivo bisphenol-a release from dental pit and fissure sealants: a systematic review. J Dent 2013;41(8):659-667.

Bisphenol A (BPA) has shown an ability to disrupt endocrine signaling in some human and animal model studies, raising suspicions that it may be a factor in the development of endocrine-related disorders, including breast cancer.1 Animal studies appear to support that suspicion, but the precise molecular mechanisms by which BPA exposure may lead to cancer in humans are poorly understood.2,3 Previous studies have connected BPA exposure to molecular events in breast cells that are characteristic of cancer development.4 A new study reported in this issue of EHP implicates a gene further upstream of previously demonstrated mechanisms.5 BPA is used in a wide variety of products, including polycarbonate plastics, food and beverage containers, and coated papers (e.g., thermal receipts). Given the many sources of BPA, ongoing exposures are common, and most people carry low (nanomolar) concentrations of the compound in their bodies.6 Compared with ethanol-treated control cells (top left), treatment with BPA (top right) accelerated cell proliferation, as shown by “spheroids” of cells in a 3D culture system. This effect was eliminated when c-Myc was silenced (bottom ... However, it’s difficult to determine the implications of those exposures for humans, because there is essentially no unexposed human population for comparison. BPA also has a short half-life in the human body, with most excreted within a day.7 Consequently, researchers have turned to in vitro cell culture systems to investigate cellular-level effects of BPA in a controlled manner.4 These investigations have led to numerous hypotheses about mechanisms by which BPA could harm breast tissue, but the conclusions are viewed with caution partly because experiments have often used much higher concentrations of BPA than have been measured in humans.1 Within the context of in vitro studies, BPA has been shown to disrupt cell signaling,1,4 which normally requires specific chemical messengers being at the right place at the right time to induce a wide array of downstream effects.8 These disruptions may alter the signals and the cellular processes they control, including those involved in cancer, such as the proliferation, mobility, growth, and programmed death of cells.8 Many of the endocrine-disrupting properties of BPA observed so far have been attributed to interaction with estrogen receptor alpha (ERα), and it is well known that BPA can induce proliferation of ERα-positive breast tumor cells.1 However, studies are lacking on the tumorigenic properties of BPA that may be unrelated to ER interactions. In the current study, the researchers therefore used three breast cancer cell lines that lacked ERα and a fourth that expressed it to investigate effects of BPA exposure at nanomolar concentrations.5 The researchers found that cells exposed to BPA had enhanced expression of the cancer-promoting protein c-Myc. In addition, BPA treatment was associated with higher levels of DNA-damaging reactive oxygen species, more DNA damage, and greater cell proliferation. Blocking transcription of the c-Myc gene (in other words, reducing production of the c-Myc protein) prevented these effects. The researchers concluded that c-Myc plays a key role in mediating BPA’s potential for inducing breast cancer at environmentally relevant levels.5 “This study is important for showing that BPA has very significant effects on breast health,” says study coauthor Mickey Hu, an associate professor of obstetrics and gynecology at Stanford Medical School. “Finding c-Myc as a target of BPA actually is a very important step for us to know how to prevent an adverse effect of BPA on human health.” Hu cautions, however, that the findings should not be construed as saying that BPA will definitely cause breast cancer. “We cannot one hundred percent say that if you are exposed to BPA, you will develop breast cancer—that’s not true. There are a lot of genes involved in cancer development, and it’s a lot more complicated than what we saw [in this study],” he says. Shanaz Dairkee, a senior scientist at the California Pacific Medical Center Research Institute, who studies the mechanistic effects of BPA and other estrogenic chemicals on healthy human breast cells in vitro,4,9 is intrigued by the effects induced within ERα-negative breast cells, since it suggests an impact on other tissues as well. But Dairkee, who was not involved in the study, also notes that while numerous studies have found estrogenic chemicals to alter molecular, cellular, or tissue integrity, the jury is still out regarding their classification as carcinogens. Using experimental models to demonstrate an unequivocal role of environmental chemicals in human carcinogenesis “will require a data matrix incorporating a broader range of doses, population-based live test samples, and cancer end points than is currently out there,” she says.

Bisphenol A: An endocrine disruptor with widespread exposure and multiple effects

Dear Editor, Bisphenol A (BPA) (C15H16O2; 2,2-bis(4-hydroxyphenyl) propane) is a synthetic xenoestrogen produced in large quantities to synthesize polycarbonate plastics. Unconjugated BPA is found in thermal paper receipts where it is present as a colour-developing additive. This unconjugated form found in thermal paper receipts can enter the body through inhalation or dermal contact and is a serious hazard for occupational groups since it can cause endocrine disruption. Furthermore, BPA is associated with cardiovascular and reproductive diseases and insulin resistance.1 The presence of BPA in thermal receipts has detrimental effects, especially on occupational groups, but has received little public scrutiny. Distinct molecular pathways have been identified by studies on BPA exposure. BPA mimics estrogen, causing endocrine disruption; its (BPA) estrogenic potency for non-nuclear estrogen receptors (ER) is similar to estradiol, causing cell function changes at concentrations of 1 picomolar (PM). Estrogen-related receptor Gamma (ERR Gamma) has also been shown to be stimulated by BPA.2,3 Studies show implicated in BPA-induced breast cancer through ERR Gamma-dependent signalling pathway.3 Furthermore, BPA can also damage DNA, causing carcinogenesis and teratogenesis.2 According to studies, the BPA intake of occupational workers through thermal paper receipts was 0.95 Mug/kg bw/day, which was considerably larger than the BPA exposure of the college-age population at 0.05 Mug/kg bw/day.3 This dermal transfer is ten times higher if the skin is humid or greasy.4 Moreover, BPA concentration in urine samples of six recruited volunteers simulating cashiers was found to be three times higher after they had handled thermal papers.3 In women, BPA has been shown to cause polycystic ovarian syndrome and adverse pregnancy outcomes. Male workers exposed to BPA exhibited lower sex drive, increased problems with erections and ejaculation, and diminished sexual satisfaction.3 A strong correlation was demonstrated between urinary BPA levels and the risk of diabetes in numerous studies. High urinary and serum BPA concentrations were also tied to cardiovascular diseases.5 It is long overdue for the world to recognize the hazardous effects of BPA through dermal absorption, especially among the occupational groups. Workers should be educated regarding the adverse effects of BPA and should be advised to handle thermal paper receipts with proper precautions. workers should be educated to wear gloves and wash their hands thoroughly after handling receipts. In addition, less harmful alternatives to BPA should be used and a gradual shift towards electronic receipts.

Bisphenol A (BPA), a xenoestrogen commonly used in plastics, may act as an endocrine disruptor, which indicates that BPA might be a public health risk. The present study aimed to investigate the effect of BPA on 17β-estradiol (E2)-mediated protection against liver ischemia/reperfusion (I/R) injury, and to identify the underlying mechanisms using a rat model. A total of 56 male Sprague Dawley rats were randomly divided into the following seven groups: i) Sham; ii) I/R; iii) Sham + BPA; iv) I/R + BPA; v) I/R + E2; vi) I/R + E2 + BPA; and vii) I/R + E2 + BPA + losartan [LOS; an angiotensin II (Ang II) type I receptor (ATIR) antagonist]. A rat model of hepatic I/R injury was established by inducing hepatic ischemia for 60 min followed by reperfusion for 24 h. When ischemia was induced, rats were treated with vehicle, E2, BPA or LOS. After 24 h of reperfusion, blood samples and hepatic tissues were collected for histopathological and biochemical examinations. The results suggested that 4 mg/kg BPA did not significantly alter the liver function, or Ang II and AT1R expression levels in the Sham and I/R groups. However, 4 mg/kg BPA inhibited E2-mediated hepatic protection by enhancing hepatic necrosis, and increasing the release of alanine transaminase, alkaline phosphatase and total bilirubin (P<0.05). Moreover, BPA increased serum and hepatic Ang II levels, as well as AT1R protein expression levels in the E2-treated rat model of liver I/R injury (P<0.05). LOS treatment reversed the negative effects of BPA on hepatic necrosis and liver serum marker levels, although it did not reverse BPA-mediated upregulation of serum and hepatic Ang II levels, or hepatic AT1R expression. Therefore, the present study suggested that BPA disrupted E2-mediated hepatic protection following I/R injury, but did not significantly affect healthy or I/R-injured livers; therefore, the mechanism underlying the effects of BPA may be associated with upregulation of the Ang II/AT1R signaling pathway.

Bisphenol A (BPA), a candidate endocrine disruptor (ED), is considered to bind to estrogen receptors and to regulate expressions of estrogen responsive genes. It has also shown evidence of affecting the reproductive, immunological and nervous systems of mammalian embryos. However, the effects of BPA on placentae, a central organ of feto-maternal interlocution, are still unclear. To reveal the mechanisms of BPA effects on placentae in mammals, we compared the mRNA expression of 20 nuclear receptors between placentae of vehicle controls and those of orally BPA exposed pregnant mice by a DNA microarray technique. In murine placentae, mRNAs of 11 nuclear receptors were not detected. However, greater than 1.5 fold changes in mRNA expression of nine nuclear receptors between vehicle control and BPA treated mice were noted. Moreover, remarkable changes in mRNA expression of six non-nuclear receptor proteins were induced by BPA exposure. There were various differences in the effects of BPA on the expression of these mRNAs between the placentae with male embryos and those with female embryos. Such embryo-sex dependent differences are interesting and important pointers to understanding of the endocrine disrupting effect of BPA. The present data indicate that BPA affects the expression of nuclear receptor mRNAs in placentae and may disrupt the physiological functions of placentae.

Endocrine disrupting chemicals (EDCs) are common pollutants in the environment and can induce disruption of the endocrine and immune systems. The present study evaluated the effects of selected common environmental EDCs on secretion of inflammatory biomarkers by RAW264.7 cells. The EDCs investigated were Estradiol (E2), 5α-dihydrotestosterone (DHT), and Bisphenol A (BPA). To evaluate if the effects caused by EDCs were modulated by steroid hormone receptors, antagonists of estrogen and androgen receptors were used. The steroid receptor antagonists used were Tamoxifen, an estrogen receptor antagonist, and Flutamide, an androgen receptor antagonist. Secretion of biomarkers of inflammation, namely nitric oxide (NO) and interleukin 6 (IL-6), were monitored. The NO was determined using Griess reaction and IL-6 was measured by enzyme linked immunosorbent assay (ELISA). Although 5 μg/mL E2, DHT, and BPA were not toxic to RAW264.7 cell cultures, the same treatments significantly (p < 0.001) reduced both NO and IL-6 secretion by lipopolysaccharide (LPS)-stimulated RAW264.7 cell cultures. The suppression of NO and IL-6 secretion indicate inhibition of inflammation by DHT, E2, and BPA. The inhibitory effects of DHT, E2 and BPA are partially mediated via their cellular receptors, because the effects were reversed by their respective receptor antagonists. Flutamide reversed the effects of DHT, while Tamoxifen reversed the effects of E2 and BPA. In conclusion, E2, BPA, and DHT inhibit the synthesis of inflammation biomarkers by LPS-stimulated RAW264.7 cells. The inhibitory effects of EDCs can be partially reversed by the addition of an estrogen receptor antagonist for E2 and BPA, and an androgenic receptor antagonist for DHT. The inhibition of inflammatory response in stimulated RAW264.7 cells may be a useful bioassay model for monitoring estrogenic and androgenic pollutants.

Purpose: Bisphenol A (BPA) is used in the manufacture of plastics and belongs to a family of compounds called endocrine disrupting chemicals (EDCs). Because of extensive use of BPA in the manufacture of consumer goods and products, humans are exposed to levels of BPA which may cause adverse effects on endocrine-sensitive organs. Here, we evaluated the effects of BPA on the proliferation of breast cancer cells and the effect of BPA on tumor cell radioresponse.Materials/Methods: Proliferation was evaluated in estrogen-sensitive (MCF-7) and estrogen-insensitive (MDA-MB-231) human breast cancer lines that were treated for 72 hour with BPA (0.1µM; environmentally relevant concentration). The effect on radiation sensitivity was evaluated using clonogenic survival assays after exposure to various dose of BPA (0.1, 1, and 10 µM-) followed by irradiation (IR). DNA damage was evaluated using phosphorylated histone H2AX (γH2AX) and the neutral comet assay. BPA induced cell cycle changes were evaluated by staining of phosphor-H3 and flow cytomety. To investigate the mechanism of BPA±IR induced cell growth, we explored the activation of Akt and mitogen-activated protein kinase (MAPK) after treatments.Results: Exposure of BPA at low-dose (0.1µM) for 72 hour resulted in an increase survival rate in MCF-7 cancer cell (150 ± 19% of control) with more limited effects on MDA-MB-231 cancer cell (123 ± 17% of control). Exposure of MCF-7 to BPA for 72 hour before radiation resulted in an increase in radioresistance with dose-reduction factors at a surviving fraction of 0.1 of 1.23 and 1.31 with BPA 0.1µM, 10µM, respectively. BPA had no effect on the number of cells in each phase of the cell cycle nor on the activation of the G2 cell cycle checkpoint after IR. As a measure of DNA double strand breaks, γH2AX were determined as a function of time after the BPA±IR treatments. BPA also significantly decreased γH2AX expression at 24 hours after IR. Expression of phosphorylated Akt and phosphorylated mitogen-activated protein kinase (MAPK) increased with BPA± IR but decreased with IR alone at 24 hr.Conclusions: These results suggest that BPA can enhance phosphorylation of Akt and MAPK possibly leading to a resistance to radiation-induced cell death after IR. Further studies are needed to determine the clinical relevance of these findings. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6073.

Effects of perinatal exposure to low dose of bisphenol A on anxiety like behavior and dopamine metabolites in brain

Bisphenol A (BPA), a chemical widely used to manufacture plastics, is estrogenic and capable of disrupting sex differentiation. However, recent in vitro studies have shown that BPA can also antagonize T(3) activation of the T(3) receptor. The difficulty in studying uterus-enclosed mammalian embryos has hampered the analysis on the direct effects of BPA during vertebrate development. This study proposed to identify critical T(3) pathways that may be disrupted by BPA based on molecular analysis in vivo. Because amphibian metamorphosis requires T(3) and encompasses the postembryonic period in mammals when T(3) action is most critical, we used this unique model for studying the effect of BPA on T(3)-dependent vertebrate development at both the morphological and molecular levels. After 4 d of exposure, BPA inhibited T(3)-induced intestinal remodeling in premetamorphic Xenopus laevis tadpoles. Importantly, microarray analysis revealed that BPA antagonized the regulation of most T(3)-response genes, thereby explaining the inhibitory effect of BPA on metamorphosis. Surprisingly, most of the genes affected by BPA in the presence of T(3) were T(3)-response genes, suggesting that BPA predominantly affected T(3)-signaling pathways during metamorphosis. Our finding that this endocrine disruptor, well known for its estrogenic activity in vitro, functions to inhibit T(3) pathways to affect vertebrate development in vivo and thus not only provides a mechanism for the likely deleterious effects of BPA on human development but also demonstrates the importance of studying endocrine disruption in a developmental context in vivo.

Transgenerational effect of parental obesity and chronic parental bisphenol A exposure on hormonal profile and reproductive organs of preadolescent Wistar rats of F1 generation: A one-generation study