Developmental exposure to bisphenol A increases prostate cancer susceptibility in adult rats: epigenetic mode of action is implicated

Department of Urology, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Fertility and sterility (Impact Factor: 4.59). 03/2008; 89(2 Suppl):e41. DOI: 10.1016/j.fertnstert.2007.12.023
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Similar to the testes, male accessory sex glands are also vulnerable to environmental endocrine disruptors with adverse effects in adulthood. The developing prostate gland isparticularlysensitivetoestrogens,andhigh-dose exposures duringacriticaldevelopmentalwindowresultsinintraepithe- lial prostatic neoplasia (PIN) in adult rodent models. Bisphenol A (BPA), a ubiquitous environmental contaminant leached from plastics and expoxy resins, has estrogenic activity. Although neonatal exposure to environmentally relevant doses of BPA produced no prostate pathology in the adult rat, we asked whether it would sensitize the adult prostate to estrogenic exposures. Relative estrogen levels rise in the aging male and adult estrogen exposures can be carcinogenic to the prostate gland. To test this possibility, newborn rats were exposed to a low dose of BPA (10 mg/kg body weight) or to a low dose (0.1 mg/kg body weight) or high dose 2.5 mg/kg body weight) of estradiol (E) on days 1, 3, and 5 of life. In adulthood (day 90), the animals were given prolonged E exposure with normal levels of testoster- one (T) via T þ E implants or empty capsules for 16 weeks. Prostates were examined histologically at 7 months. Rats treated neonatally to high-dose E with or without adult T þ E had a high PIN incidence and score. Although low-dose neonatal E exposure alone mildly increased the PIN incidence/score, neonatal BPA alone had no pathologic alteration in the aged prostate. However, rats exposed neonatally to BPA followed by T þ E in adulthood showed a significantly higher PIN incidence and score compared with controls, rats exposed only to BPA neonatally, or those given only T þ E in adulthood (1). The PIN incidence and lesions in rats given BPA with adult T þ E appeared similar to rats treated neonatally with high-dose E. Thus, the present findings suggest that an environmentally relevant dose of BPA may increase the susceptibility of the prostate gland to carcinogenesis following additional adult exposures. To determine whether neonatal exposures to estradiol or BPA may be mediated through epigenetic mechanisms, we screened these prostate tissues for global DNA methylation changes. Over 30 gene candidates were cloned that showed consistent methylation changes as a result of neonatal E or BPA exposures. Phosphodisesterase type 4, variant 4 (PDE4D4), the enzyme involved in degrading cAMP and regulating the cellular levels of this key cell-signaling molecule, was identified as a novel imprinted gene (1) .I n normal prostates, the 50 CpG island of PDE4D4 is gradually hypermethylated, and the gene is silenced with aging. Following neonatal BPA or estradiol exposure, PDE4D4 showed early and persistent hypomethylation of its 50 CpG island resulting in elevated PDE4D4 gene expression in the adultprostates.HPCAL,agenethatdrivescAMPproduction, exhibited a specific methylation and expression alteration in neonatal BPA animals with aging. Together, these findings indicate that the prostate epigenome is permanently altered by early exposures to BPA, resulting in changes in gene expression. We hypothesize that this epigenetic alteration may be a molecular underpinning that leads to heightened predisposition to prostate carcinogenesis with aging.

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Available from: Gail S. Prins, Aug 27, 2014
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    • "BPA has been detected in the human placenta (Schonfelder et al., 2002), cord blood (Wan et al., 2010), amitotic fluid (Ikezuki et al., 2002; Yamada et al., 2002), fetal liver (Cao et al., 2012) and breast milk (Sun et al., 2004), making exposure of human neonates and infants a very real concern. According to studies, BPA is estrogen mimic compound resulted in an array of health impacts including prostate and breast cancer (Prins et al., 2008; Pupo et al., 2012). The adverse effects of BPA are largely related to its estrogenic activity (Hiroi et al., 1999; Kurosawa et al., 2002). "
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    ABSTRACT: Bisphenol A (BPA) is an endocrine disrupting compound widely spread in our living environment. It is a contaminant with increasing exposure to it and exerts both toxic and estrogenic effects on mammalian cells. Due to the limited information concerning the effect of BPA on the liver, the present study was designed to assess hepatic tissue injury induced by early life exposure to BPA in female rat offspring. Rat dams (n = 9) were gavaged with 0.5 and 50 mg of BPA/kg b.w./day throughout lactation until weaning. The sham group received olive oil for the same duration while the control group did not receive any injection. The liver tissue was collected from female pups at different pubertal periods (PND50, 90 and 110) to evaluate oxidative stress biomarkers, extent of DNA damage and histopathological changes. Our results indicated that early life exposure to BPA significantly increased oxidative/nitrosative stress, decreased antioxidant enzyme activities, induced DNA damage and chronic severe inflammation in the hepatic tissue in a time dependent manner. These data suggested that BPA causes long-term adverse effects on the liver, which leads to deleterious effects in the liver of female rat offspring.
    08/2015; 71. DOI:10.1016/j.jobaz.2015.01.006
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    • "Among EDCs, xenoestrogens are a subgroup of hormonally active compounds that interfere with the estrogenic signaling pathway. They can either affect the levels of endogenous hormone (Prins et al., 2008; Tabb and Blumberg, 2006), or mimic estrogen action and bind with different affinities to the estrogen receptors ERα or ERβ, that function as ligand-activated transcriptional factors, and modify the pattern of expression of specific target genes (Bulzomi and Marino, 2011). Xenoestrogens have been extensively used not only in agriculture but also in the manufacture of materials, products and goods like resins, textiles, plastics, cosmetics, flame retardants or insulators. "
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    ABSTRACT: Background: Prenatal exposure to endocrine disrupting compounds (EDCs) has previously shown to alter epigenetic marks. Objectives: In this work we explore whether prenatal exposure to mixtures of xenoestrogens has the potential to alter the placenta epigenome, by studying DNA methylation in retrotransposons as a surrogate of global DNA methylation. Methods: The biomarker total effective xenoestrogen burden (TEXB) was measured in 192 placentas from participants in the longitudinal INMA Project. DNA methylation was quantitatively assessed by bisulfite pyrosequencing on 10 different retrotransposons including 3 different long interspersed nuclear elements (LINEs), 4 short interspersed nuclear elements (SINEs) and 3 human endogenous retroviruses (HERVs). Associations were tested using linear mixed-effects regression models and sex interaction was evaluated. Results: A significant sex interaction was observed for AluYb8 (p-value for interaction <0.001, significant at Bonferroni corrected p-value threshold of 0.0025). Boys with the highest TEXB-alpha levels of exposure (third tertile) presented on average a decrease of 0.84% in methylation compared to those in the first tertile (p-value < 0.001), while no significant effects were found in girls (p-value = 0.134). Conclusions: Our findings suggest that boys may be more susceptible to the effect of exposure to xenoestrogens during prenatal development, producing shifts in DNA methylation of certain sensitive genomic repetitive sequences in a tissue important for fetal growth and development.
    Environment International 06/2014; 71C:81-87. DOI:10.1016/j.envint.2014.06.006 · 5.56 Impact Factor
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    • "The effects of neonatal BPA exposure on reproductive organs in mice depended on the level of BPA, 2 mg/kg increased the adult prostate weight [60] and 10 mg/kg disrupted prostate development [61]. Exposure of rats to 10 mg/kg BPA increased susceptibility to prostate carcinogenesis in adults [62]. Male rats exposed to BPA have lower sperm counts and testosterone levels with a significant effect on fertility [53, 63]. "
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    ABSTRACT: Phenols are uremic toxins of intestinal origin formed by bacteria during protein metabolism. Of these molecules, p-cresol is the most studied and has been associated with renal function impairment and vascular damage. Bisphenol A (BPA) is a molecule with structural similarity with phenols found in plastic food and beverage containers as well as in some dialyzers. BPA is considered an environmental toxicant based on animal and cell culture studies. Japanese authorities recently banned BPA use in baby bottles based on observational association studies in newborns. BPA is excreted in urine and uremic patients present higher serum levels, but there is insufficient evidence to set cut-off levels or to link BPA to any harmful effect in CKD. However, the renal elimination and potential exposure during dialysis warrant the monitoring of BPA exposure and the design of observational studies in which the potential health risks of BPA for end-stage renal disease patients are evaluated.
    International Journal of Nephrology 07/2013; 2013(114):437857. DOI:10.1155/2013/437857
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