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

Flora, Silvio De; Micale, Rosanna T.; Maestra, Sebastiano La; Izzotti, Alberto; D’Agostini, Francesco; Camoirano, Anna; Davoli, Serena; Troglio, Maria Giovanna; Rizzi, Federica; Davalli, Pierpaola; Bettuzzi, Saverio

doi:10.1093/toxsci/kfr096

Cited by 60 publications

(39 citation statements)

References 40 publications

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“…BPA exposure was previously shown to cause DNA damage in human sperm[7] and murine sperm[43]. The transcripts of some DNA damage-associated genes are abundant in human sperm [39].…”

Section: Resultsmentioning

confidence: 99%

Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men

Zheng

Zhou

et al. 2017

PLoS ONE

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Environmental BPA exposure has been shown to impact human sperm concentration and motility, as well as rodent spermatogenesis. However, it is unclear whether BPA exposure is associated with alteration in DNA hydroxymethylation, a marker for epigenetic modification, in human sperm. A genome-wide DNA hydroxymethylation study was performed using sperm samples of men who were occupationally exposed to BPA. Compared with controls who had no occupational BPA exposure, the total levels of 5-hydroxymethylcytosine (5hmc) increased significantly (19.37% increase) in BPA-exposed men, with 72.69% of genome regions harboring 5hmc. A total of 9,610 differential 5hmc regions (DhMRs) were revealed in BPA-exposed men relative to controls, which were mainly located in intergenic and intron regions. These DhMRs were composed of 8,670 hyper-hMRs and 940 hypo-hMRs, affecting 2,008 genes and the repetitive elements. The hyper-hMRs affected genes were enriched in pathways associated with nervous system, development, cardiovascular diseases and signal transduction. Additionally, enrichment of 5hmc was observed in the promoters of eight maternally expressed imprinted genes in BPA-exposed sperm. Some of the BPA-affected genes, for example, MLH1, CHD2, SPATA12 and SPATA20 might participate in the response to DNA damage in germ cells caused by BPA. Our analysis showed that enrichment of 5hmc both in promoters and gene bodies is higher in the genes whose expression has been detected in human sperm than those whose expression is absent. Importantly, we observed that BPA exposure affected the 5hmc level in 11.4% of these genes expressed in sperm, and in 6.85% of the sperm genome. Finally, we also observed that BPA exposure tends to change the 5hmc enrichment in the genes which was previously reported to be distributed with the trimethylated Histone 3 (H3K27me3, H3K4me2 or H3K4me3) in sperm. Thus, these results suggest that BPA exposure likely interferes with gene expression via affecting DNA hydroxymethylation in a way partially dependent on trimethylation of H3 in human spermatogenesis. Our current study reveals a new mechanism by which BPA exposure reduces human sperm quality.

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“…BPA exposure was previously shown to cause DNA damage in human sperm[7] and murine sperm[43]. The transcripts of some DNA damage-associated genes are abundant in human sperm [39].…”

Section: Resultsmentioning

confidence: 99%

Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men

Zheng

Zhou

et al. 2017

PLoS ONE

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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 hyperplasia (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).…”

Section: Male Urinary Tractmentioning

confidence: 99%

Bisphenol A and Reproductive Health: Update of Experimental and Human Evidence, 2007–2013

Peretz

Vrooman

Ricke

et al. 2014

Environ Health Perspect

475

301

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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.Citation: Peretz J, Vrooman L, Ricke WA, Hunt PA, Ehrlich S, Hauser R, Padmanabhan V, Taylor HS, Swan SH, VandeVoort CA, Flaws JA. 2014. Bisphenol A and reproductive health: update of experimental and human evidence, 2007–2013. Environ Health Perspect 122:775–786; http://dx.doi.org/10.1289/ehp.1307728

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“…The levels of hydrogen peroxide (H 2 O 2 ) and lipid peroxidation were also increased in testes and spermatozoa of BPA-treated animals. In another study, testicular antioxidant enzymes were impaired by a very low-dose (viz., 0.005 mg/kg bwt/day) of BPA following 45 days of exposure (De Flora et al 2011 ;D'Cruz et al 2012 a, b). BPA also decreased antioxidant enzyme activities and induced lipid peroxidation in both epididymides and sperm cells (Chitra et al 2003a ) (Fig.…”

Section: Effects Of Bisphenol a On The Testicular And Epididymal Antimentioning

confidence: 99%

“…1: spermatogonium; 2: preleptotene spermatocyte; 3: pachytene spermatocyte; 4: round spermatid; 5: elongated spermatid; 6 and 7: spermatozoa, before and after capacitation, respectively. Abbreviations: BTB blood-testis barrier, E2 estradiol, LC Leydig cell, FSH follicle-stimulating hormone, GnRH gonadotropin-releasing hormone, SC Sertoli cell, T testosterone (De Flora et al 2011). Meeker et al ( 2010 also studied human male partners of subfertile couples seeking treatment from the Vincent Andrology Lab at Massachusetts General Hospital, and observed increased DNA damage in sperm, and reduced semen quality that were associated with BPA exposure (Fig.…”

Section: Effects Of Bisphenol a On Sperm Functionmentioning

confidence: 99%

Adverse Effects of Bisphenol A on Male Reproductive Function

Manfo

Jubendradass

Nantia

et al. 2013

Reviews of Environmental Contamination and Toxicology

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BPA is a ubiquitous environmental contaminant, resulting mainly from manufacturing,use or disposal of plastics of which it is a component, and the degradation of industrial plastic-related wastes. Growing evidence from research on laboratory animals, wildlife, and humans supports the view that BPA produces an endocrine disrupting effect and adversely affects male reproductive function. To better understand the adverse effects caused by exposure to BPA, we performed an up-to-date literature review on the topic, with particular emphasis on in utero exposure, and associated effects on spermatogenesis, steroidogenesis, and accessory organs.BPA studies on experimental animals show that effects are generally more detrimental during in utero exposure, a critical developmental stage for the embryo. BPA has been found to produce several defects in the embryo, such as feminization of male fetuses, atrophy of the testes and epididymides, increased prostate size, shortening of AGD, disruption of BTB, and alteration of adult sperm parameters (e.g.,sperm count, motility, and density). BPA also affects embryo thyroid development.During the postnatal and pubertal periods and adulthood, BPA affects the hypothalamic-pituitary-testicular axis by modulating hormone (e.g., LH and FSH,androgen and estrogen) synthesis, expression and function of respective receptors(ER, AR). These effects alter sperm parameters. BPA also induces oxidative stress in the testis and epididymis, by inhibiting antioxidant enzymes and stimulating lipid peroxidation. This suggests that employing antioxidants may be a promising strategy to relieve BPA-induced disturbances.Epidemiological studies have also provided data indicating that BPA alters male reproductive function in humans. These investigations revealed that men occupationally exposed to BPA had high blood/urinary BPA levels, and abnormal semen parameters. BPA-exposed men also showed reduced libido and erectile ejaculatory difficulties; moreover, the overall BPA effects on male reproduction appear to be more harmful if exposure occurs in utero. The regulation of BPA and BPA-related products should be reinforced, particularly where exposure during the fetal period can occur. The current TDI for BPA is proposed as 25 and 50 1-1g/kg bwt/day (European Food Safety Authority and Health Canada, respectively). Based on the evidence available, we believe that a TDI value of 5 1-1g/kg bwt/day is more appropriate (the endpoint is modulation of rat testicular function). Certain BPA derivatives are being considered as alternatives to BPA. However, certain of these related products display adverse effects that are similar to those of BPA. These effects should be carefully considered before using them as final alternatives to BPA in plastic production.

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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

Cited by 60 publications

References 40 publications

Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men

Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men

Bisphenol A and Reproductive Health: Update of Experimental and Human Evidence, 2007–2013

Adverse Effects of Bisphenol A on Male Reproductive Function

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