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: 8330794
• 负责人: David P Crews
• 金额: $ 35.86万
• 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/8330794
• 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）：内分泌干扰化学品（EDCs）是环境中干扰内分泌系统的化合物。内分泌干扰物在现代世界中无处不在，几乎在所有人类和野生动物中都可以检测到。内分泌干扰物的许多作用是由激素受体介导的，如广泛分布在大脑中的雌激素受体（ER），从而干扰神经生物学功能。下丘脑、海马和杏仁核是ER高表达的脑区，并且被证明是内分泌干扰的靶点。然而，这些影响的细胞，分子和生理过程，以及这些大脑区域暴露于内分泌干扰物的功能行为影响，还没有得到很好的研究。此外，大脑具有许多在生命早期发展的结构和功能性两性异形，这是一个由雌激素对ER的作用塑造的过程，并被EDCs破坏。因此，本研究的首要目标是确定发育中的胎儿暴露于生态相关水平的内分泌干扰物干扰特定脑区域的性分化的分子和细胞机制，以及对这些区域调节的行为的后果。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品，特别是多氯联苯（PCB）对性二态神经生物学过程的影响，填补知识空白。多氯联苯是一种普遍存在的持久性环境污染物，虽然几十年来一直被禁止，但它们仍然普遍存在于土壤和地下水中，渗入食物和水中，并且几乎在所有人类的组织中都可以检测到。拟议的研究将使用一个已经在PI实验室使用的成熟的大鼠模型，以测试在怀孕后期的关键发育窗口期间暴露于多氯联苯的影响，这是大脑性别分化的关键时期，在此期间，发育中的神经系统对内源性和外源性激素，特别是雌激素非常敏感。这些实验将量化雌激素调节基因网络的表达（目的1）;阐明一些潜在的表观遗传机制，以调节已确定的目标（目的2）;通过蛋白质免疫组化确定基因表达变化的表现形式（目的3）;并确定最终结果为行为表型（目的4）。这些实验对人类具有广泛的影响，因为接触多氯联苯是普遍的、持久的，并且对健康和疾病具有广泛的影响。因此，了解多氯联苯对神经发育的潜在影响及其潜在机制，可以为公共政策，医疗干预和预防提供信息。此外，数十年来一直用作EDC“模型”的多氯联苯的结果可以帮助我们更好地了解仍在常用的其他雌激素性EDC的影响，例如塑料，农药等。