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。人们的怀疑主要集中在环境雌激素是一种致病因素。其中，双酚A(BPA)由于广泛的人类接触而特别令人感兴趣。围产期啮齿动物暴露在与环境相关的低剂量双酚A中，会在雌激素靶组织中诱导多种营养效应，这种效应在暴露结束很长时间后才表现出来。特别是，对动情周期至关重要的细胞核的性分化改变，以及促性腺激素释放激素(GnRH)神经元激活的改变，可能会对生育力和繁殖力产生影响，而乳腺的形态发生改变可能会损害哺乳。我们预计，在暴露于双酚A的雌性雌激素靶组织中观察到的影响将削弱她们产生可存活的、健康的后代的能力。拟议的研究将建立双酚A作用的因果机制链，包括细胞、组织和组织水平；因此，它们将是综合和分析的。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。这一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，我们提出了一个双重的方法来研究BPA如何改变两个重要的靶组织--发育中的下丘脑(HYP)和乳腺(MG)的组织结构。HYP对于整个生殖成功至关重要，而MG对于新生儿的存活至关重要。此外，HYP还可通过调节垂体促性腺激素、卵巢激素的合成和催乳素的释放来影响MG的发育。目的1：双酚A如何影响围产期暴露的女性的生殖结局？将评估生育力、繁殖力和MG功能，以确定发育低剂量双酚A暴露对生殖的影响。目标2：双酚A暴露如何改变发育中的HYP的组织结构？我们假设双酚A改变了核的结构和连通性，对促性腺激素释放的调节很重要。我们将研究这些核团：i)细胞存活、凋亡和连接模式的变化；ii)类固醇受体、睾酮代谢酶的表达，以及雌激素作用的下游因素，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。目的3：双酚A暴露如何影响MG的基因表达和组织结构？我们假设：i)BPA直接作用于MG原(在MG器官培养中通过QRT-PCR测试)；ii)BPA的作用是由ERα和/或β(使用空ER小鼠进行QRT-PCR测试)介导的；iii)这些初始事件转化为改变的间质-上皮相互作用。为了从双酚A对内分泌系统的影响中分离出双酚A暴露对MG的影响，将双酚A暴露和非暴露动物的MG移植到暴露和未暴露的宿主体内。为了评估BPA暴露是否永久性地改变了间质、上皮或两个隔室，将进行组织重组研究。这一目标将开始揭示双酚A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在靶组织中的作用与其组织后果联系起来的机械性信息。它还将揭示当前环境暴露水平是否在代孕模型中产生显著的健康影响。这些信息对于制定关于内分泌干扰的公共政策是至关重要的。