Dietary Intervention for Bisphenol A-induced Susceptibility to Prostate Neoplasia

描述(由申请人提供)：在动物模型中，早年接触天然或环境雌激素易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，表明在人类怀孕期间可能会发生类似的雌激素重新编程。我们已经证明，新生大鼠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，包括前列腺癌的发生。最近，我们还发现，生命早期暴露于环境相关水平的双酚A，一种在塑料和环氧树脂中发现的普遍环境雌激素，增加了成年前列腺癌对激素致癌的易感性。我们的工作假设是，在发育过程中，自然的、合成的或环境中相应剂量的雌激素暴露可能是老年男性前列腺癌的易感因素，并为这种成人疾病提供了发育起源。我们已经确定DNA甲基化的表观遗传变化是这次发育重新编程事件的分子基础。降解cAMP的磷酸二酯酶4D4(PDE4D4)基因在新生儿雌激素/双酚A暴露后发生永久性低甲基化，导致PDE4D4基因表达增加，这可能与肿瘤的发生有关。这种洞察力为早期干预提供了一个独特的机会，目的是逆转该腺体的雌激素重编程。饮食中甲基供体的可获得性会直接影响基因甲基化。目前的提案将调查一种干预策略，通过母体饮食补充叶酸，旨在消除对前列腺癌的不良雌激素效应。提出了两个具体的目标：目的1：确定母亲在发育早期补充甲基供体是否可以逆转由雌激素引起的新生儿前列腺癌前病变。目的：确定母体膳食叶酸能否逆转雌激素诱导的PDE4D4低甲基化，并使其表达增加与致癌相关。我们预测，这些孕期和哺乳期的母婴喂养研究将有效地预防、逆转或延缓由于早期暴露于升高的雌二醇或环境相关剂量的双酚A而导致的成人前列腺癌前病变的发生。如果是这样的话，这将为目前担心意外接触环境雌激素化合物的孕妇和哺乳新生儿提供有效和简单的干预措施。首席调查者：普林斯，盖尔·S项目叙述越来越多的证据表明，许多成人疾病可能源于胎儿，这可能适用于前列腺癌，因为胎儿接触雌激素并随着年龄的增长而增加前列腺癌的风险。有证据表明，雌激素重编程具有表观遗传学基础，涉及DNA甲基化模式的改变。孕妇在孕期和哺乳期补充甲基供体，如叶酸和维生素B12，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变化。这些发现将支持孕妇使用膳食补充剂，以抵消人类对普遍存在的具有致癌潜力的环境内分泌干扰物(例如双酚A)的暴露。

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.