Endocrine Disruption of the Developing Dopamine System

项目总结 内分泌干扰物(EDCs)影响广泛的内分泌和神经生物学 功能。动物模型显示了暴露和不良后果之间的因果关系， 在人类中的流行病学数据支持EDC暴露和 神经行为缺陷。我的建议旨在调查围产期EDC暴露的影响 雌激素敏感的神经中脑多巴胺(DA)环路的发育 注意力和情感奖赏加工行为。在这里，我将检验这一假设 围产期EDC暴露将通过干扰雌激素而导致DAR能行为缺陷 调控细胞、分子和表观遗传过程的信号机制 开发脑DA系统。此外，孕期暴露会影响胎儿和 胎儿性腺内发育的生殖细胞成为导致F2的精子/卵子 一代。因此，我的工作将集中在F1和F2代的两性大鼠上。至 为此，我将利用Aroclor 1221建立的多氯联苯的EDC模型 (A1221)，一种弱雌激素混合物。妊娠期接触A1221扰乱神经生物学 发育，并对神经内分泌功能、大脑中的基因表达、 和行为，以一种性别特有的方式。然而，它对注意力和情感奖励的影响- 处理行为是未知的；这是知识中的一个重要缺口。暴露的影响将 观察两代人：F1(怀孕期间暴露)和F2(暴露为 发育中的生殖细胞)。主要结果将是展示注意力和情感奖励- 处理成年期的行为结果，因为这些行为是雌激素敏感的 与人类的性别偏见心理健康障碍有关。另外，我会量化 大脑多巴胺系统的神经解剖组织的相应变化，以及 雌激素和多巴胺信号转导相关基因的表达。因为至少有一部分 大脑组织的机制是通过激素对DNA甲基化的作用 这些基因在以后的生命中如何发挥作用，这项研究还将确定表观遗传学 改变(DNA甲基化)是基因表达长期改变的一种机制 在关键发育期对EDC暴露的反应。这些目标符合NIEHS的 战略目标是“调查环境对基因组结构和功能的影响”， 包括对生物过程的表观遗传调控，同时将性作为一种生物 变量。此外，该建议扩大了我们对环境影响的理解 与人类认知和行为障碍相关的行为和分子终点。

PROJECT SUMMARY Endocrine-disrupting chemicals (EDCs) affect a wide range of endocrine and neurobiological functions. Animal models show causal relationships between exposure and adverse outcomes, and epidemiological data in humans support correlations between EDC exposure and neurobehavioral deficits. My proposal seeks to investigate the effects of perinatal EDC exposure on the development of estrogen-sensitive neural midbrain dopamine (DA) circuits involved in attentional and affective reward-processing behaviors. Here, I will test the hypothesis that perinatal EDC exposure will lead to deficits in DAergic behaviors via disruption of estrogenic signaling mechanisms that regulate cellular, molecular and epigenetic processes in the developing brain DA system. Furthermore, gestational exposure affects both the fetus and developing germ cells within the fetal gonad that become the sperm/ova leading to the F2 generation. Therefore, my work will focus on rats of both sexes in the F1 and F2 generations. To do this, I will utilize a well-established EDC model of polychlorinated biphenyls using Aroclor 1221 (A1221), a weakly estrogenic mixture. Gestational exposure to A1221 perturbs neurobiological development, and has latent effects on neuroendocrine functions, gene expression in the brain, and behavior, in a sex-specific manner. However, its influence on attentional and affective reward- processing behaviors is unknown; this is an important gap in knowledge. Effects of exposures will be observed across two generations: F1 (exposed during gestation) and F2 (exposed as developing germ cells). A primary outcome will be the display of attentional and affective reward- processing behavioral outcomes during adulthood, as these behaviors are estrogen-sensitive and associated with sex-biased mental health disorders in humans. Additionally, I will quantify corresponding changes in the neuroanatomical organization of the brain’s dopamine system, and expression of genes involved in estrogen and dopamine signaling. Because at least part of the mechanism for brain organization is through actions of hormones on DNA methylation to “program” how these genes function later in life, the research will also determine if epigenetic changes (DNA methylation) are a mechanism for long-term changes in gene expression in response to EDC exposure during critical developmental periods. These goals meet the NIEHS’ strategic goal to “investigate the effects of the environment on genome structure and function”, including epigenetic regulation of biological processes, while including sex as a biological variable. Moreover, the proposal extends our understanding of environmental influences on behavioral and molecular endpoints relevant to cognitive and behavioral disorders in humans.