Mechanism of developmental toxicity of Bisphenol-A

双酚A的发育毒性机制

• 批准号: 7892741
• 负责人: ANA SOTO
• 金额: $ 33.75万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892741
• 关键词: Adult; Affect; Age-Months; Aging; Animal Mammary Glands; Animals; Apoptosis; Architecture; Aromatase; Astrocytes; Birth; Brain; Cell Nucleus; Cell Survival; Cues; Data; Development; Dose; Ductal; Embryo; Employee Strikes; Endocrine Disruptors; Endocrine disruption; Endocrine system; Endometrium; Environmental Estrogen; Environmental Exposure; Environmental Pollution; Enzymes; Epithelium; Estrogen Receptors; Estrogens; Estrus; Event; Exposure to; Female; Fertility; Funding; Gene Expression; Genes; Genital system; Glutamate Decarboxylase; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Growth; Harvest; Health; Hormonal; Human; Hypothalamic structure; Implant; In Vitro; Kidney; Lactation; Lateral; Link; Mammary gland; Measures; Mediating; Mediator of activation protein; Metabolism; Milk; Modeling; Molecular; Morphogenesis; Mus; Neurons; Organ; Organ Culture Techniques; Organizational Change; Outcome; Ovarian hormone; Ovary; Ovulation; Oxytocin; Pathway interactions; Pattern; Pattern Formation; Perinatal; Perinatal Exposure; Periodicity; Physiological; Pituitary Gonadotropins; Play; Pregnancy; Process; Production; Progesterone Receptors; Prolactin; Property; Prosencephalon; Puberty; Public Policy; Regulation; Reproduction; Rodent; Role; SCID Mice; Secondary to; Sex Characteristics; Side; Steroid Receptors; Structure of nucleus infundibularis hypothalami; Synapses; Syndrome; Testing; Testosterone; Time; Tissue Recombination; Tissues; Toxic effect; Translating; Transplantation; Trees; Uterus; Weight Gain; Work; base; bisphenol A; capsule; exposed human population; fetal; gamma-Aminobutyric Acid; hormone related cancer; hypothalamic pituitary gonadal axis; interest; malformation; mammary gland development; mature animal; morphogens; mutant; neonate; offspring; postnatal; pup; receptor expression; reproductive; reproductive axis; reproductive success; research study; response

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 pleiotropic 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 a and/or ft (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.

生殖道畸形和与生殖器有关的癌症的增加是生殖系统中的重大问题。 工业化世界。怀疑集中在环境雌激素作为一个致病因素。之间 其中，双酚A（BPA）由于广泛的人体暴露而特别令人感兴趣。围产期暴露 啮齿类动物对低环境相关剂量BPA的耐受性诱导了雌激素靶点的多效性效应 组织，在暴露结束后很久才显现出来。特别是，改变了性分化的一个 对动情周期重要的核，以及改变的促性腺激素释放激素（GnRH）神经元 激活可能对生育力和繁殖力产生影响，而乳腺癌的形态发生改变， 腺体可能损害泌乳。我们预计，在暴露于BPA的雌激素靶组织中观察到的效应 雌性会削弱它们生育健康后代的能力。拟议的研究将建立 BPA作用的因果机制链，包括细胞、组织和生物体水平， 因此，它们将是综合性和分析性的。在综合方面，我们将评估 围产期暴露的雌性小鼠的繁殖成功率。这些信息对于阐明 上一个供资周期中描述的分子事件的生理后果。上 在分析方面，我们提出了一种双重方法来研究BPA如何改变两个组织的组织结构， 重要的靶组织，发育中的下丘脑（HYP）和乳腺（MG）。HYP是 MG对总体生殖成功至关重要，并且MG对新生儿的存活至关重要。此外，本发明还提供了一种方法， HYP可通过调节垂体促性腺激素和卵巢激素影响MG的发生发展 合成和催乳素释放。 目的1：BPA如何影响围产期暴露女性的生殖结果？生育力，繁殖力， 和MG功能，以确定发育低剂量的生殖影响 BPA暴露。目的2：BPA暴露如何改变HYP发展中的组织结构？我们 假设BPA改变了调节细胞核的结构和连接性， 促性腺激素释放我们将检查这些细胞核：i）细胞存活，凋亡， ii）类固醇受体、睾酮代谢酶和因子的表达 雌激素作用的下游，如谷氨酸脱羧酶和星形胶质细胞分化。 这些研究的完成将确定GnRH神经元激活改变的潜在机制。目标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原基上充当形态发生剂（在MG器官培养物中通过QRT-PCR测试）; ii）BPA效应由ER α和/或ER β介导（使用无效ER小鼠通过QRT-PCR测试），和 这些初始事件转化为改变的基质-上皮相互作用。为了分析其对人类的影响 由于BPA对内分泌的作用， 系统中，BPA暴露和未暴露动物的MG将被移植到暴露和 未暴露的主机。评估基质、上皮或两者是否永久性 将进行组织重组研究。这一目标将开始揭示 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BPA在靶组织中作用的机制信息， 其有机后果。它还将揭示目前的环境暴露水平是否会产生 在替代模型中的显著健康影响。制定公共政策急需这些信息 关于内分泌紊乱