Upregulation of Clusterin in Prostate and DNA Damage in Spermatozoa from Bisphenol A-Treated Rats and Formation of DNA Adducts in Cultured Human Prostatic Cells

Department of Health Sciences, University of Genoa, Genoa, Italy.
Toxicological Sciences (Impact Factor: 3.85). 05/2011; 122(1):45-51. DOI: 10.1093/toxsci/kfr096
Source: PubMed


Among endocrine disruptors, the xenoestrogen bisphenol A (BPA) deserves particular attention due to widespread human exposure. Besides hormonal effects, BPA has been suspected to be involved in breast and prostate carcinogenesis, which share similar estrogen-related mechanisms. We previously demonstrated that administration of BPA to female mice results in the formation of DNA adducts and proteome alterations in the mammary tissue. Here, we evaluated the ability of BPA, given with drinking water, to induce a variety of biomarker alterations in male Sprague-Dawley rats. In addition, we investigated the formation of DNA adducts in human prostate cell lines. In BPA-treated rats, no DNA damage occurred in surrogate cells including peripheral blood lymphocytes and bone marrow erythrocytes, where no increase of single-strand DNA breaks was detectable by comet assay and the frequency of micronucleated cells was unaffected by BPA. Liver cells were positive at transferase dUTP nick end labeling assay, which detects both single-strand and double-strand breaks and early stage apoptosis. BPA upregulated clusterin expression in atrophic prostate epithelial cells and induced lipid peroxidation and DNA fragmentation in spermatozoa. Significant levels of DNA adducts were formed in prostate cell lines treated either with high-dose BPA for 24 h or low-dose BPA for 2 months. The BPA-related increase of DNA adducts was more pronounced in PNT1a nontumorigenic epithelial cells than in PC3 metastatic carcinoma cells. On the whole, these experimental findings support mechanistically the hypothesis that BPA may play a role in prostate carcinogenesis and may, potentially, affect the quality of sperm.

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    • "In the adult rat prostate, low-and high-dose BPA exposure has been reported to adversely increase clusterin levels and expression of aromatase , while decreasing levels of 5α-reductase type 1 and 2 (Castro et al. 2013; De Flora et al. 2011; Sánchez et al. 2013). Interestingly, Castro et al. (2013) and De Flora et al. (2011) reported that BPA exposure increased the plasma estradiol to testosterone ratio, which has been implicated in the development of benign prostate hyper plasia (Nicholson et al. 2012; Nicholson and Ricke 2011). Further, gestational exposure to low-dose BPA increased gene expression of androgen receptor, Esr1, aromatase, and estrogen-related receptor γ in the mouse prostate (Arase et al. 2011). "
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    ABSTRACT: Background: In 2007, an expert panel reviewed associations between bisphenol A (BPA) exposure and reproductive health outcomes. Since then, new studies have been conducted on the impact of BPA on reproduction. Objective: In this review, we summarize data obtained since 2007, focusing on a) findings from human and animal studies, b) the effects of BPA on a variety of reproductive end points, and c) mechanisms of BPA action. Methods: We reviewed the literature published from 2007 to 2013 using a PubMed search based on keywords related to BPA and male and female reproduction. Discussion: Because BPA has been reported to affect the onset of meiosis in both animal and in vitro models, interfere with germ cell nest breakdown in animal models, accelerate follicle transition in several animal species, alter steroidogenesis in multiple animal models and women, and reduce oocyte quality in animal models and women undergoing in vitro fertilization (IVF), we consider it an ovarian toxicant. In addition, strong evidence suggests that BPA is a uterine toxicant because it impaired uterine endometrial proliferation, decreased uterine receptivity, and increased implantation failure in animal models. BPA exposure may be associated with adverse birth outcomes, hyperandrogenism, sexual dysfunction, and impaired implantation in humans, but additional studies are required to confirm these associations. Studies also suggest that BPA may be a testicular toxicant in animal models, but the data in humans are equivocal. Finally, insufficient evidence exists regarding effects of BPA on the oviduct, the placenta, and pubertal development. Conclusion: Based on reports that BPA impacts female reproduction and has the potential to affect male reproductive systems in humans and animals, we conclude that BPA is a reproductive toxicant.
    Environmental Health Perspectives 06/2014; 122(8). DOI:10.1289/ehp.1307728 · 7.98 Impact Factor
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    • "According to the present results, short-term BPA administration to castrated rats supplemented with T decreased the mRNA levels of both 5α-R1 and 5α-R2 isozymes in ventral prostate of rats, which had constant levels of circulating T. BPA has been shown to exert endocrine-disrupting effects on reproduction, development, and metabolism [28]. Recent findings linked exposure to BPA with several male reproductive disorders [29–32] and prostate diseases [33, 34]. Our group recently demonstrated that adult exposure to BPA decreased in the rat prostate gland the expression of both 5α-R1 and 5α-R2, as well as the circulating T levels [22]. "
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    ABSTRACT: The development, growth, and function of the prostate gland depend on androgen stimulation. The primary androgen in prostate is 5α-dihydrotestosterone (DHT) which is synthesized from circulating testosterone (T) through the action of 5α-reductase (5α-R). Although 5α-R occurs as five isozymes, only 5α-R1 and 5α-R2 are physiologically involved in steroidogenesis. The endocrine disruptor bisphenol A (BPA) alters sexual organs, including the prostate. Our previous findings indicated that BPA decreased the expression of 5α-R1 and 5α-R2 in rat prostate but also circulating T. Thus, it is unclear whether BPA exerts this effect on 5α-R isozymes by reducing circulating T or by any other mechanism. In this study, we examine the effects of short-term exposure to BPA at doses below 25 μg/Kg/d and above 300 μg/Kg/d of the TDI on mRNA levels of 5α-R1 and 5α-R2 in prostate of adult castrated rats supplemented with T to achieve constant circulating T levels. mRNA levels were measured by absolute quantitative RT-PCR, T levels by RIA, and DHT levels by ELISA. Our results indicated that in castrated rats treated with T BPA at the two doses studied significantly decreased the mRNA levels of both 5α-R isozymes in a dose-dependent manner without modifications in circulating T.
    07/2013; 2013:629235. DOI:10.1155/2013/629235
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    • "BPA has been shown to exert endocrine-disrupting effects on reproduction, development, metabolism, and cancer in humans and other species [5], [6]. Recent findings linked exposure to BPA with several male reproductive disorders [7]–[10] and prostate diseases [11]–[13], although the specific mechanisms of action have yet to be elucidated. Most studies have demonstrated that administration of low-doses of BPA during early life, when tissues are especially sensitive to endocrine disrupting chemicals, significantly affect several aspects of prostate development [14], [15]. "
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    ABSTRACT: The high incidence of prostate cancer (PCa) and benign prostatic hypertrophy (BPH) in elderly men is a cause of increasing public health concern. In recent years, various environmental endocrine disruptors, such as bisphenol A (BPA), have been shown to disrupt sexual organs, including the prostate gland. However, the mechanisms underlying these effects remain unclear. Because androgens and estrogens are important factors in prostate physiopathology, our objective was to examine in rat ventral prostate the effects of adult exposure to BPA on 5α-Reductase isozymes (5α-R types 1, 2, and 3) and aromatase, key enzymes in the biosynthesis of dihydrotestosterone and estradiol, respectively. Adult rats were subcutaneously injected for four days with BPA (25, 50, 300, or 600 µg/Kg/d) dissolved in vehicle. Quantitative RT-PCR, western blot and immunohistochemical analyses showed lower mRNA and protein levels of 5α-R1 and 5α-R2 in BPA-treated groups versus controls but higher mRNA levels of 5α-R3, recently proposed as a biomarker of malignancy. However, BPA treatment augmented mRNA and protein levels of aromatase, whose increase has been described in prostate diseases. BPA-treated rats also evidenced a higher plasma estradiol/testosterone ratio, which is associated with prostate disease. Our results may offer new insights into the role of BPA in the development of prostate disease and may be of great value for studying the prostate disease risk associated with exposure to BPA in adulthood.
    PLoS ONE 02/2013; 8(2):e55905. DOI:10.1371/journal.pone.0055905 · 3.23 Impact Factor
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