DNA damage caused by bisphenol A and estradiol through estrogenic activity

GeneCare Research Institute Co. Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-0063, Japan.
Biological & Pharmaceutical Bulletin (Impact Factor: 1.78). 03/2006; 29(2):206-10. DOI: 10.1248/bpb.29.206
Source: PubMed

ABSTRACT Evidence exists that raises concern about genotoxic effects induced by estrogen: oxidative stress caused by estrogen-derived oxidants, DNA adducts formed by estrogen metabolites and estrogen-induced chromosomal aberration. Estrogen receptors (ER) participate in some of these genotoxic effects by estrogen. In this study, we showed the effects of bisphenol A (BPA), an endocrine-disrupting chemical eliciting weak estrogenic activity, and of 17beta-estradiol (E2), on DNA damage in ER-positive MCF-7 cells by Comet assay. Higher concentrations of BPA, more than 1000 times of E2, were needed to induce the same levels of effects by E2. Immunofluorescence microscopy showed that gammaH2AX, an early marker of DNA breaks, increased after treatment with E2 or BPA in MCF-7 cells. gammaH2AX foci colocalized with Bloom helicase, which is considered to be responsible for the repair of DNA damage after treatment with E2 or BPA. Interestingly, DNA damage was not as severe in ER-negative MDA-MB-231 cells as in MCF-7 cells. The ER antagonist ICI182780 blocked E2 and BPA genotoxic effects on MCF-7 cells. These results together suggest that BPA causes genotoxicity ER dependently in the same way as E2.

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Available from: Akira Shimamoto, Jan 06, 2014
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    • "ROS are scavenged by the endogenous antioxidant defense system, including superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH-Px) in cells. The phenolic compound such as BPA is known to cause abnormalities, DNA damage, and genotoxicity [14] in the liver of rats and mice [3]. Therefore, it has been established that the early environmental stress during developmental stages could cause persistent changes in mitochondrial activity of nonhuman primates [15], which highlights the influence of early exposure for development of disease later in life. "
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    ABSTRACT: Oxidative stress mechanisms are involved in hepatotoxicity. The liver is reported to be affected by bisphenol A (BPA) in animals studies, and has been also reported to possess hepatic toxicity. This study aimed to examine association between liver health status and the effects of BPA on the antioxidant defense systems and liver biomarkers. BPA (0, 2, 10, 50 mg/kg) body weight was mixed in corn oil and intra-peritoneally administered every forty-eight hours for 30 days in dose dependent manner. There was no significant difference between the body weight and weight of rat liver in BPA-treated groups and control groups. The study results show that the levels of malondialdehyde (MDA) and hydrogen peroxide (H2O2) increased after exposure to BPA. However, the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were significantly (P<0.001, P<0.05 and P<0.001 respectively) decreased at 50 mg/kg dosage. Liver markers activities such as Lactate dehydrogenase (LDH), Glutamic-oxalacetic transaminase (GOT) and Glutamic-pyruvic transaminase (GPT) were significantly increased, while γ-Glutamyltransferase (γ-GT) activity was decreased. BPA exposure increased activity of liver biomarkers indicating liver hyperactivity. Analysis of the liver section provided essential evidence of liver apoptosis. Moreover, BPA may lead to induced toxic response of liver oxidative system.
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    • "Additionally the ability of BaP not only to induce teratogenic and genetic damage in its own right, but also to enhance or inhibit the embryo toxic and genotoxic potential of the other compounds was evaluated by exposure to binary mixtures. BPA causes genotoxicity ER dependently (Iso et al., 2006) and it has aneuploidogenic properties (Tayama et al., 2008). The potential endocrine disruption of this chemical is particularly of concern by the observed reduction in the NOEC value from one generation to the next in multi-generation studies (CSTEE, 2002). "
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    ABSTRACT: Genotoxic effects on fauna after waterborne pollutant exposure have been demonstrated by numerous research programmes. Less effort has been focused on establishing relationship between genotoxicity and long-term responses at higher levels of biological organization. Taking into account that embryos may be more sensitive indicators of reproductive impairment than alterations in fertility, we have developed two assays in multiwell plates to address correlations between embryo toxicity and genotoxicity. The potential teratogenicity was assessed by analyzing abnormal development and mortality of Physa acuta at embryonic stage. Genotoxicity was measured by the micronucleus (MN) test using embryonic cells. Our results showed that linkage between genotoxicity and embryo toxicity depends on mechanisms of action of compounds under study. Embryo toxic responses showed a clear dose-related tendency whereas no clear dose-dependent effect was observed in micronucleus induction. The higher embryo toxicity was produced by benzo(a)pyrene exposure followed by fluoxetine and bisphenol A. Vinclozolin was the lower embryo toxic compound. Binary mixtures with BaP always resulted in higher embryo toxicity than single exposures but antagonistic effects were observed for MN induction. Benzo(a)pyrene produced the higher MN induction at 0.04 mg/L, which also produced clear embryo toxic effects. Fluoxetine did not induce cytogenetic effects but 0.25mg/L altered embryonic development. Bisphenol A significantly reduced hatchability at 0.5mg/L while MN induction appeared with higher treatments than those that start causing teratogenicity. Much higher concentration of vinclozolin (5mg/L) reduced hatchability and induced maximum MN formation. In conclusion, while validating one biomarker of genotoxicity and employing one ecologically relevant effect, we have evaluated the relative sensitivity of a freshwater mollusc for a range of chemicals. The embryo toxicity test is a starting point for the development of a life cycle test with freshwater snails even for undertaking multigeneration studies focused on transgenerational effects.
    Ecotoxicology and Environmental Safety 03/2012; 80:152-60. DOI:10.1016/j.ecoenv.2012.02.029 · 2.48 Impact Factor
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    • "Notably, a 100-fold increase in Stra8 was demonstrated in the mouse fetal ovary coincident with the onset of meiosis (14.5 dpc), and a 50-fold increase in Nalp5 was observed when oocytes progressed to the primordial follicle (Fowler et al., 2009; Lawson et al., 2010). Previous studies described that BPA could affect genes involved in differentiation, cell growth, apoptosis and DNA repair (Naciff et al., 2002; Yamada et al., 2002; Lemmen et al., 2004; Daftary and Taylor, 2006; Iso et al., 2006; Miyamoto et al., 2006; Iso et al., 2007). In this sense, this compound could affect gene expression of the ovary and uterus. "
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    ABSTRACT: Bisphenol A (BPA) is a 'weak' endocrine disruptor. The effect of BPA on human reproduction is controversial but has been related to meiotic anomalies, recurrent spontaneous abortion, abnormal karyotypes, the diminishing of oocyte survival, delay in meiotic progression and an elevated rate of MLH1 foci in vitro. The aim of this study is to characterize the gene expression of human fetal oocytes in culture as well as to evaluate the effect of BPA in cultured human oocytes. To accomplish our objective, 12 ovaries from 6 euploid fetuses were used. The ovarian fetal tissue was cultivated in two groups: control group and BPA group (BPA30 µM). The cultures were analyzed at T0 and after 7 (T7), 14 (T14) and 21 (T21) days of culture. Evaluation of gene expression was performed by real-time PCR (RT-PCR), with the evaluated genes being: Smc1β, Sycp1 (pairing-synapsis), Spo11, Rpa, H2ax, Mlh1 and Blm [double-strand break (DSBs) generation, signaling and repair], Erα, Erβ and Errγ (estrogen receptors), Stra8 and Nalp5 (markers of meiotic progression). Oocytes from ovaries cultured and treated with BPA show changes in the expression of Spo11, H2ax and Blm genes, with a significant increase from 3- to 5-fold (P≤ 0.05). Finally, Rpa, showed a 100-fold increment (P≤ 0.01). Erα, Erβ and Errγ genes showed a BPA up-regulation of 2-4-fold in all of the culture times (P≤ 0.05). Oocytes exposed to BPA showed an up-regulation of genes involved in DSB generation, signaling and repair except by Mlh1. Thus, BPA can modify the gene expression pattern, which may explain the effects of BPA on female germ cells.
    Molecular Human Reproduction 11/2011; 18(4):171-83. DOI:10.1093/molehr/gar074 · 3.48 Impact Factor
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