Dietary Intervention for Bisphenol A-induced Susceptibility to Prostate Neoplasia

描述（由申请人提供）：在动物模型中，早期接触天然或环境雌激素会导致前列腺癌的发生。流行病学研究提供了令人信服的证据，表明类似的雌激素重编程可能发生在人类妊娠期间。我们已经证明，新生儿短暂暴露于高剂量或低剂量雌二醇会导致成年大鼠前列腺的永久性变化，包括前列腺上皮内瘤变的发生。最近，我们还发现，生命早期暴露于环境相关水平的双酚A（一种普遍存在于塑料和环氧树脂中的环境雌激素）会增加成人前列腺对激素致癌的易感性。我们的工作假设是，在发育过程中，自然、合成或环境雌激素暴露在相关剂量下可能是衰老男性前列腺癌的易感因素，并为这种成人疾病提供了一个发育起源。我们已经确定了DNA甲基化的表观遗传改变是这种发育重编程事件的分子基础。可降解cAMP的磷酸二酯酶4D4 （PDE4D4）基因在新生儿暴露于雌二醇/BPA后发生永久性低甲基化，导致PDE4D4基因表达增加，这可能有助于致癌。这一见解为早期干预提供了一个独特的机会，其目标是逆转该腺体的雌激素重编程。日粮中甲基供体的有效性可直接影响基因甲基化。目前的建议将研究一种干预策略与产妇膳食叶酸补充旨在消除不利的雌激素对前列腺的影响。本研究提出了两个具体目的：目的1：确定在发育早期母体膳食中添加甲基供体是否可以逆转新生儿雌激素诱导的癌前前列腺病变。目的2：确定母体膳食叶酸是否可以逆转雌激素诱导的PDE4D4低甲基化，并增加与致癌相关的表达。我们预测，这些贯穿妊娠期和哺乳期的母亲喂养研究将有效地预防、逆转或延缓成年前列腺癌前病变的发生，这是早期暴露于高雌二醇或环境相关剂量双酚a的功能。如果是这样，这将为目前担心意外接触环境雌激素化合物的孕妇和喂养新生儿的人提供一种有效和简单的干预措施。越来越多的证据表明，许多成人疾病可能有胎儿的起源基础，这可能适用于前列腺，胎儿雌激素暴露和随着年龄增长前列腺癌的风险增加。有证据表明雌激素重编程的表观遗传基础涉及DNA甲基化模式的改变。孕妇在妊娠和哺乳期膳食中补充叶酸和维生素B12等甲基供体可能能够逆转雌激素诱导的前列腺甲基化改变和随后的病理。这些发现将支持孕妇使用膳食补充剂来抵消人类暴露于普遍存在的环境内分泌干扰物（如双酚a）的怀疑致癌潜力。

DESCRIPTION (provided by applicant): Early life exposure to natural or environmental estrogens predisposes to prostate carcinogenesis with aging in animal models. Epidemiology studies provide compelling evidence that similar estrogen reprogramming may occur during gestation in humans. We have shown that brief neonatal exposure to high or low-dose estradiol results in permanent changes in the adult rat prostate including onset of prostatic intraepithelial neoplasia. Recently, we also found that early life exposure to environmentally relevant levels of bisphenol A, a prevalent environmental estrogen found in plastics and epoxy resins, increases the susceptibility of the adult prostate to hormonal carcinogenesis. Our working hypothesis is that natural, synthetic or environmental estrogenic exposures at relevant doses during development may be a predisposing factor to prostatic carcinoma in the aging male and provide a developmental origin for this adult disease. We have identified epigenetic alterations in DNA methylation as a molecular basis for this developmental reprogramming event. The gene for phosphodiesterase 4 D4 (PDE4D4), which degrades cAMP, was permanently hypomethylated following neonatal estradiol/BPA exposure resulting in increased PDE4D4 gene expression which may contribute to carcinogenisis. This insight provides a unique opportunity for early intervention with the goal of reversing estrogenic reprogramming of this gland. Methyl donor availability in the diet can directly influence gene methylation. The present proposal will investigate an intervention strategy with maternal dietary folate supplementation aimed at negating the adverse estrogenic effects on the prostate gland. Two Specific Aims are proposed: Aim 1: Determine whether maternal dietary supplementation with methyl donors during early development can reverse the neonatal estrogen-induced precancerous prostate lesions. Aim 2: Determine whether maternal dietary folate can reverse the estrogen-induced PDE4D4 hypomethylation with increased expression associated with carcinogenesis. We predict that these maternal feeding studies throughout gestation and lactation will effectively prevent, reverse or retard the onset of precancerous lesions in the adult prostate gland as a function of early exposure to elevated estradiol or an environmentally relevant dose of BPA. If such is the case, this will provide an effective and simple intervention for pregnant mothers and those feeding newborns who are currently concerned about unintended exposure to environmental estrogenic compounds. Principal Investigator: Prins, Gail S. Project Narrative There is increasing evidence that a number of adult diseases may have a fetal basis of origin and this may apply to the prostate gland regarding fetal estrogenic exposures and increased risk of prostate cancer with aging. Evidence indicates an epigenetic basis for estrogen reprogramming involving alterations in DNA methylation patterns. Maternal dietary supplementation during gestation and lactation with methyl donors such as folate and vitamin B12 may be capable of reversing the estrogen-induced methylation alterations and subsequent pathology in the prostate gland. Such findings would support the use of dietary supplements in pregnant mothers to counteract human exposures to prevalent environmental endocrine disruptors (e.g. BPA) with suspected carcinogenic potential.