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: 8205524
• 负责人: David P Crews
• 金额: $ 37.56万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205524
• 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. PUBLIC HEALTH RELEVANCE: Exposures of humans to PCBs and other estrogenic EDCs are universal, and these compounds have wide- ranging effects on health and disease. Therefore, understanding the latent effects of PCBs on neural development, and their underlying mechanisms, can inform medical interventions and prevention, and guide public health policy. The rat model is highly conserved with humans, and it enables us to test the cause-and- effect relationship between prenatal PCBs, the development of adult disease, and the neural mechanisms underlying these biomedical processes.

描述（由申请人提供）：内分泌干扰化学品（EDC）是环境中扰乱内分泌系统的化合物。 EDC 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。 EDC 的许多作用是由激素受体介导的，例如广泛分布在大脑中的雌激素受体 (ER)，因此 EDC 会扰乱神经生物学功能。下丘脑、海马体和杏仁核是 ER 高表达的大脑区域，并且已被证明是内分泌干扰的目标。然而，这些效应的细胞、分子和生理过程，以及这些大脑区域暴露于 EDC 的功能行为影响，尚未得到很好的探索。此外，大脑具有许多在生命早期形成的结构和功能性二态性，这一过程是由雌激素对 ER 的作用塑造的，并被 EDC 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 EDC 扰乱特定大脑区域的性别分化的分子和细胞机制，以及对这些区域调节的行为的影响。拟议的研究将通过测试围产期接触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空白。多氯联苯是一种普遍存在且持久的环境污染物，尽管已被禁用数十年，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 PI 实验室中已使用的完善的大鼠模型来测试在妊娠晚期的关键激素敏感发育窗口期间接触 PCB 的影响，该窗口是大脑性别分化的关键时期，在此期间神经细胞正在发育。系统对内源性和外源性激素，特别是雌激素都非常敏感。实验将量化雌激素调节基因网络的表达（目标 1）；阐明一些潜在的表观遗传机制来调节已确定的目标（目标 2）；通过蛋白质免疫组织化学确定基因表达变化的表现（目标 3）；并确定最终结果作为行为表型（目标 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，并对健康和疾病产生广泛的影响。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，几十年来一直被用作“模型”EDC 的 PCB 的结果可以帮助我们更好地了解仍然常用的其他雌激素 EDC 的影响，例如塑料、农药等中的雌激素 EDC。 公共卫生相关性：人类普遍接触 PCB 和其他雌激素 EDC，这些化合物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，可以为医疗干预和预防提供信息，并指导公共卫生政策。大鼠模型与人类高度保守，它使我们能够测试产前 PCB、成人疾病的发展以及这些生物医学过程背后的神经机制之间的因果关系。