Mechanism of developmental toxicity of Bisphenol-A

双酚A的发育毒性机制

• 批准号: 7211253
• 负责人: ANA SOTO
• 金额: $ 38.83万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211253
• 关键词: chemical structure function; developmental genetics; developmental neurobiology; embryo /fetus; environmental exposure; estrogens; female; female reproductive system; gene environment interaction; gene induction /repression; homeobox genes; hormone receptor; hormone regulation /control mechanism; hypothalamic pituitary axis; immunocytochemistry; in situ hybridization; laboratory mouse; mammalian embryology; mammary gland; morphometry; perinatal; phenols; pituitary hormones; radioimmunoassay; reproductive development; toxicology; women' s health

DESCRIPTION (provided by applicant): Increased malformations of the genital tract and hormone-related cancers are significant problems in the industrialized world. Suspicions have focused on environmental estrogens as one causal agent. Among them, bisphenol A (BPA) is of particular interest due to widespread human exposure. Perinatal exposure of rodents to low, environmentally-relevant doses of BPA induces pleiotrophic effects in estrogen target tissues that manifest long after exposure has ended. In particular, altered sexual differentiation of a nucleus important for estrous cyclicity, and altered gonadotropin-releasing hormone (GnRH) neuronal activation may have repercussions on fertility and fecundity, while altered morphogenesis of the mammary gland may impair lactation. We expect that effects observed in estrogen target tissues of BPA exposed females will impair their ability to produce viable' and healthy offspring. The proposed studies will establish a causal mechanistic chain for BPA action encompassing cellular, tissue and organismal levels of organization; hence, they will be both integrative and analytical. On the integrative side, we will evaluate the reproductive success of perinatally exposed female mice. This information is essential to elucidate the physiological consequences of the molecular events described in the previous funding cycle. On the analytical side, we propose a dual approach to study how BPA alters the tissue organization of two important target tissues, the developing hypothalamus (HYP) and the mammary gland (MG). The HYP is critical to overall reproductive success, and the MG is critical to the survival of the neonates. In addition, the HYP can influence MG development by modulating pituitary gonadotropins and ovarian hormone synthesis and prolactin release. Aim 1: How does BPA affect the reproductive outcome of perinatally exposed females? Fertility, fecundity, and MG function will be assessed in order to define the reproductive impact of developmental low dose BPA exposure. Aim 2: How does BPA exposure alter tissue organization in the developing HYP? We hypothesize that BPA alters the architecture and connectivity of nuclei important for the regulation of gonadotropin release. We will examine these nuclei for: i) changes in patterns of cell survival, apoptosis, and connectivity; ii) expression of steroid receptors, enzymes of testosterone metabolism, and factors downstream of estrogen action such as glutamic acid decarboxylase and astrocyte differentiation. Completion of these studies will identify mechanisms underlying altered GnRH neuronal activation. Aim 3: How does BPA exposure affect gene expression and tissue organization in the MG? We hypothesize that: i) BPA acts as a morphogen directly on the MG anlagen (to be tested by QRT-PCR in MG organ culture); ii) BPA effects are mediated by ER alpha and/or beta (to be tested by QRT-PCR using null ER mice), and iii) these initial events translate into altered stroma-epithelium interactions. To dissect the effects resulting from BPA exposure of the MG anlagen from systemic effects due to the action of BPA on the endocrine system, the MG of BPA exposed and unexposed animals will be transplanted into exposed and unexposed hosts. To assess whether the stroma, the epithelium or both compartments are permanently altered by BPA exposure, tissue recombination studies will be performed. This Aim will begin to reveal the mechanisms by which BPA disturbs the organization and architecture of an estrogen target organ. The realization of this project will provide mechanistic information linking BPA action in target tissues and its organismal consequences. It will also reveal whether current levels of environmental exposure produce significant health effects in a surrogate model. This information is critically needed to develop public policy on endocrine disruption.

描述（由申请人提供）：生殖道畸形和生殖器相关癌症的增加是工业化世界的重要问题。怀疑集中在环境雌激素作为一个致病因素。其中，双酚A（BPA）由于广泛的人体暴露而特别令人感兴趣。啮齿类动物围产期暴露于低环境相关剂量的BPA会诱导雌激素靶组织中的多效性效应，这些效应在暴露结束后很长时间才表现出来。特别是，改变性分化的细胞核重要的发情周期，改变促性腺激素释放激素（GnRH）神经元激活可能会影响生育力和繁殖力，而改变乳腺的形态可能会损害泌乳。我们预计，在暴露于BPA的女性的雌激素靶组织中观察到的影响将损害她们产生存活和健康后代的能力。拟议的研究将建立一个因果机制链双酚A行动，包括细胞，组织和有机体水平的组织，因此，他们将是综合性和分析。在综合方面，我们将评价围产期暴露雌性小鼠的生殖成功率。这些信息对于阐明上一个资助周期中描述的分子事件的生理后果至关重要。在分析方面，我们提出了一种双重方法来研究BPA如何改变两个重要靶组织的组织结构，即发育中的下丘脑（HYP）和乳腺（MG）。HYP对总体生殖成功至关重要，MG对新生儿的存活至关重要。此外，HYP可通过调节垂体促性腺激素和卵巢激素的合成和催乳素的释放来影响MG的发展。目的1：BPA如何影响围产期暴露女性的生殖结果？将评估生育力、生殖力和MG功能，以确定发育低剂量BPA暴露对生殖的影响。目的2：BPA暴露如何改变HYP发展中的组织结构？我们假设BPA改变了对促性腺激素释放调节重要的细胞核的结构和连接。我们将检查这些细胞核：i）细胞存活、凋亡和连接模式的变化; ii）类固醇受体、睾酮代谢酶和雌激素作用下游因子（如谷氨酸脱羧酶和星形胶质细胞分化）的表达。这些研究的完成将确定GnRH神经元激活改变的潜在机制。目的3：BPA暴露如何影响MG的基因表达和组织结构？我们假设：i）BPA直接在MG原基上作为形态发生剂（在MG器官培养物中通过QRT-PCR测试）; ii）BPA作用由ER α和/或β介导（使用无效ER小鼠通过QRT-PCR测试），和iii）这些初始事件转化为改变的基质-上皮相互作用。为了从BPA对内分泌系统的作用引起的全身效应中剖析BPA暴露对MG原基的影响，将BPA暴露和未暴露动物的MG移植到暴露和未暴露的宿主中。为了评估BPA暴露是否永久改变了基质、上皮或两个区室，将进行组织重组研究。这个目标将开始揭示BPA干扰雌激素靶器官的组织和结构的机制。该项目的实现将提供将BPA在靶组织中的作用及其生物后果联系起来的机制信息。它还将揭示目前的环境暴露水平是否会在替代模型中产生重大的健康影响。这一信息对于制定关于内分泌干扰的公共政策至关重要。