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）：生殖道和与激素有关的癌症的畸形增加是工业化世界的重大问题。怀疑集中在环境雌激素作为一种因果药物中。其中，由于人类的广泛暴露，双酚A（BPA）特别感兴趣。将啮齿动物暴露于低剂量的BPA下，在暴露后很长时间结束的雌激素靶组织中会诱导雌激素靶组织中的多生型作用。特别是，对发情循环重要的核的性分化改变，并改变了促性腺激素释放激素（GNRH）神经元激活可能会对生育和繁殖力产生影响，而改变了乳腺的形态形成可能会损害乳腺的形态。我们预计，在BPA暴露女性的雌激素靶组织中观察到的影响会损害其产生可行和健康后代的能力。拟议的研究将建立一个因果关系链，用于BPA作用，包括细胞，组织和有机体的组织水平；因此，它们将既是综合又分析。在综合方面，我们将评估围产期暴露的雌性小鼠的生殖成功。该信息对于阐明上一个资金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如何改变两个重要目标组织的组织组织，即发育中的下丘脑（HYP）和乳腺（MG）。催眠对于总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，催眠可以通过调节垂体促性腺激素和卵巢激素合成和催乳素释放来影响MG发育。目标1：BPA如何影响围产期暴露的女性的生殖结果？将评估生育能力，繁殖力和MG功能，以定义发育低剂量BPA暴露的生殖影响。 AIM 2：BPA暴露如何改变发展中的HYP中的组织组织？我们假设BPA改变了对调节促性腺激素释放重要的核的结构和连通性。我们将检查以下这些核：i）细胞存活，凋亡和连通性的模式的变化； ii）表达类固醇受体，睾丸激素代谢的酶以及雌激素作用的因子，例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直接在MG Anlagen上充当形态学（在MG器官培养中QRT-PCR测试）； ii）BPA效应是由ERα和/或β（使用null ER小鼠测试的）和/或β介导的，iii）这些初始事件转化为改变的基质 - 上皮相互作用。为了剖析因BPA对内分泌系统的作用而导致BPA暴露于全身效应的BPA导致的影响，BPA暴露和暴露的动物的MG将被移植到暴露的和未暴露的宿主中。为了评估基质，是否会通过BPA暴露永久改变上皮或两个隔室，将进行组织重组研究。该目标将开始揭示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与目标组织中BPA作用及其有机物后果联系起来的机械信息。它还将揭示当前环境暴露水平是否在替代模型中产生重大健康影响。这些信息是至关重要的，以制定内分泌干扰的公共政策。