Mechanism of developmental toxicity of Bisphenol-A

双酚A的发育毒性机制

• 批准号: 7291668
• 负责人: ANA SOTO
• 金额: $ 37.71万
• 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/7291668
• 关键词: Adult; Affect; Age; Age-Months; 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 Receptor alpha; 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; Rate; 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; day; exposed human population; fetal; gamma-Aminobutyric Acid; hormone related cancer; hypothalamic pituitary gonadal axis; interest; malformation; mature animal; morphogens; mutant; neonate; postnatal; pup; receptor expression; reproductive; reproductive axis; reproductive success; research study; response

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）：生殖道畸形和激素相关癌症的增加是工业化世界的重大问题。人们怀疑环境雌激素是致病因素之一。其中，双酚 A (BPA) 由于人类广泛接触而受到特别关注。啮齿类动物在围产期接触环境相关剂量的低剂量 BPA 后，会在雌激素靶组织中产生多效作用，这种作用在接触结束后很长时间才会显现出来。特别是，对动情周期重要的细胞核性别分化的改变和促性腺激素释放激素（GnRH）神经元激活的改变可能会对生育力和生育能力产生影响，而乳腺形态发生的改变可能会损害泌乳。我们预计，在接触 BPA 的雌性雌性激素靶组织中观察到的影响将损害其生育可存活和健康后代的能力。拟议的研究将建立 BPA 作用的因果机制链，涵盖细胞、组织和组织水平；因此，它们既是综合性的又是分析性的。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——发育中的下丘脑 (HYP) 和乳腺 (MG) 的组织组织。 HYP 对于整体生殖成功至关重要，而 MG 对于新生儿的存活至关重要。此外，HYP还可以通过调节垂体促性腺激素和卵巢激素的合成以及催乳素的释放来影响MG的发展。目标 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。目标 2：BPA 暴露如何改变发育中 HYP 的组织组织？我们假设 BPA 改变了对促性腺激素释放调节很重要的细胞核的结构和连接性。我们将检查这些细胞核的： 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（例如谷氨酸脱羧酶和星形胶质细胞分化）的表达。完成这些研究将确定 GnRH 神经元激活改变的机制。目标 3：BPA 暴露如何影响 MG 中的基因表达和组织组织？我们假设： i) BPA 作为直接作用于 MG 原基的形态发生素（将在 MG 器官培养中通过 QRT-PCR 进行测试）； ii) BPA 效应由 ER α 和/或 β 介导（使用无效 ER 小鼠通过 QRT-PCR 进行测试），以及 iii) 这些初始事件转化为改变的基质-上皮相互作用。为了剖析 BPA 暴露对 MG 原基的影响以及由于 BPA 对内分泌系统的作用而产生的全身影响，暴露和未暴露 BPA 的动物的 MG 将被移植到暴露和未暴露的宿主中。为了评估间质、上皮或两个区室是否因 BPA 暴露而永久改变，将进行组织重组研究。该目标将开始揭示 BPA 扰乱雌激素靶器官组织和结构的机制。该项目的实现将提供将 BPA 在靶组织中的作用与其机体后果联系起来的机制信息。它还将揭示当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。制定有关内分泌干扰的公共政策迫切需要这些信息。