Sexually dimorphic effects of endocrine disruptors on brain & behavior

描述(申请人提供)：内分泌干扰物(EDCs)是环境中扰乱内分泌系统的化合物。内分泌细胞在现代世界中无处不在，几乎在所有人类和野生动物中都能检测到。内分泌细胞的许多作用是由激素受体(如雌激素受体)介导的，这些激素受体广泛分布于大脑中，从而扰乱神经生物学功能。下丘脑、海马体和杏仁核是ER高表达的脑区，也是内分泌干扰的靶点。然而，这些效应的细胞、分子和生理过程，以及这些脑区暴露于内皮细胞的功能行为暗示，还没有得到很好的探索。此外，大脑有许多在生命早期发展起来的结构和功能的性二态，这一过程是由雌激素对内质网的作用塑造的，并被内分泌细胞破坏。因此，这项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EDCs扰乱特定大脑区域的性别分化的分子和细胞机制，以及这些区域调控的行为的后果。拟议的研究将通过测试围产期接触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来填补知识空白。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，几乎在所有人的组织中都能检测到。这项拟议的研究将使用PIS实验室中已经使用的成熟的大鼠模型来测试在妊娠晚期对激素敏感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和外源激素，特别是雌激素都非常敏感。这些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学机制来调节已识别的目标(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、持久的，并对健康和疾病有广泛的影响。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，几十年来一直被用作EDC“模型”的多氯联苯的结果，可以帮助我们更好地了解其他仍在常用的雌激素内分泌化合物的影响，如塑料、杀虫剂等中的那些。

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.