Sexually dimorphic effects of endocrine disruptors on brain & behavior

内分泌干​​扰物对大脑的性别二态性影响

• 批准号: 8663703
• 负责人: David P Crews
• 金额: $ 35.65万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-09 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663703
• 关键词: Address; Adult; Amygdaloid structure; Area; Behavior; Behavior Control; Behavioral; Biological; Biological Models; Body Burden; Brain; Brain region; Cardiovascular Diseases; Cells; Chemical Exposure; Collaborations; Development; Disease; Endocrine; Endocrine Disruptors; Endocrine disruption; Endocrine system; Environment; Environmental Pollution; Epigenetic Process; Estrogen Receptors; Estrogens; Exposure to; Female; Fetus; Food; Gene Expression; Genes; Goals; Guide prevention; Health; Health Policy; Hippocampus (Brain); Hormone Receptor; Hormones; Human; Hypothalamic structure; Immunohistochemistry; Individual; Infertility; Knowledge; Life; Mediating; Medical; Modeling; Modification; Molecular; Nervous system structure; Neurobiology; Outcome; Perinatal Exposure; Pesticides; Phenotype; Physiological; Physiological Processes; Plastics; Polychlorinated Biphenyls; Pregnancy; Preventive Intervention; Process; Proteins; Psychologist; Public Health; Public Policy; Rattus; Regulation; Reproductive Behavior; Research; Soil; Sprague-Dawley Rats; Techniques; Testing; Time; Tissues; Water; brain behavior; critical period; early life exposure; exposed human population; functional outcomes; male; neurodevelopment; neuromechanism; offspring; prenatal; programs; promoter; relating to nervous system; research study; sex; sexual dimorphism; success

DESCRIPTION (provided by applicant): Endocrine-disrupting chemicals (EDCs) are compounds in the environment that perturb endocrine systems. EDCs are ubiquitous in the modern world, and detectable in virtually all humans and wildlife. Many effects of EDCs are mediated by hormone receptors such as estrogen receptors (ERs) that are widely distributed in the brain, and thereby EDCs perturb neurobiological functions. The hypothalamus, hippocampus and amygdala are brain regions with high expression of ERs, and are proven targets for endocrine disruption. However, the cellular, molecular and physiological processes for these effects, and the functional behavioral implications for exposures of these brain regions to EDCs, are not well explored. Furthermore, the brain has a number of structural and functional sexual dimorphisms that develop early in life, a process that is sculpted by actions of estrogens on ERs, and disrupted by EDCs. Therefore, it is the overarching goal of this research to determine the molecular and cellular mechanisms by which exposure of developing fetuses to ecologically-relevant levels of EDCs perturb the sexual differentiation of specific brain areas, and the consequences on behaviors regulated by these regions. The proposed studies will fill a gap in knowledge by testing effects of perinatal exposure to a class of endocrine-disrupting chemicals, specifically polychlorinated biphenyls (PCBs), on sexually dimorphic neurobiological processes. PCBs are a ubiquitous and persistent environmental contaminant, and while banned for decades, they are still prevalent in soil and groundwater, leach into food and water, and are detectable in tissues of virtually all humans. The proposed studies will use a well-established rat model already in use in the PIs' labs to test effects of exposure to PCBs during a critical hormone-sensitive developmental window of late gestation, a critical period for brain sexual differentiation during which the developing nervous system is exquisitely sensitive to both endogenous and exogenous hormones, particularly estrogens. The experiments will quantify expression of a network of estrogen-regulated genes (Aim 1); elucidate some potential epigenetic mechanisms for regulation of identified targets (Aim 2); determine the manifestation of gene expression changes through protein immunohistochemistry (Aim 3); and ascertain the final outcome as a behavioral phenotype (Aim 4). These experiments have broad implications for humans as exposure to PCBs is universal, persistent, and has wide-ranging effects on health and disease. Therefore, understanding the latent effects of PCBs on neural development, and their underlying mechanisms, can inform public policy, medical interventions, and prevention. In addition, results on PCBs, used as a "model" EDC for decades, can help us better understand effects of other estrogenic EDCs still in common use such as those in plastics, pesticides, and beyond.

描述（由申请人提供）：内分泌干扰化学物质（EDC）是扰动内分泌系统环境中的化合物。 EDC在现代世界中无处不在，几乎可以在所有人类和野生动植物中检测到。 EDC的许多作用是由广泛分布在大脑中的激素受体（例如雌激素受体（ER））介导的，因此EDC扰动了神经生物学功能。下丘脑，海马和杏仁核是具有高度表达的大脑区域，并且被证明是内分泌干扰的靶标。然而，对这些作用的细胞，分子和生理过程以及对这些大脑向EDC暴露的功能行为含义并未得到很好的探索。此外，大脑具有许多结构和功能性二态性，这些性二态性在生命的早期发展，这一过程是由雌激素对ERS的作用雕刻而来的，并被EDC造成的破坏。因此，这项研究的总体目的是确定分子和细胞机制，通过这种机制，胎儿向生态相关水平的EDC暴露于特定大脑区域的性别分化以及这些地区对行为的后果。拟议的研究将通过测试围产期暴露于一类内分泌干扰化学物质（特别是多氯联苯（PCB））对性二态性神经生物学过程的影响来填补知识的空白。 PCB无处不在且持续的环境污染物，在被禁止使用数十年时，它们在土壤和地下水中仍然很普遍，浸入食物和水中，并且在几乎所有人类的组织中都可以检测到。拟议的研究将使用已在PIS实验室中使用的公认的大鼠模型来测试妊娠后期激素敏感的发育窗口中暴露于PCB的影响，这是脑性分化的关键时期，在此期间，发育中的神经系统对内源性和外源激素非常敏感，尤其是雌激素，尤其是雌激素。实验将量化雌激素调节基因网络的表达（AIM 1）；阐明一些潜在的表观遗传机制，以调节已识别靶标的调节（AIM 2）；确定基因表达的表现通过蛋白质免疫组织化学变化（AIM 3）；并确定最终结果是行为表型（AIM 4）。这些实验对人类具有广泛的影响，因为接触PCB是普遍的，持久的，并且对健康和疾病具有广泛的影响。因此，了解PCB对神经发展及其潜在机制的潜在影响可以为公共政策，医疗干预和预防提供信息。此外，数十年来，PCB上用作“模型” EDC的结果可以帮助我们更好地理解其他常用使用的雌激素EDC的效果，例如塑料，农药及以后的雌激素EDC。