Sexually dimorphic effects of endocrine disruptors on brain and behavior

摘要 每个人都有内分泌干扰化学物质（EDCs）的身体负担，并且EDCs的水平与 有生殖内分泌和神经行为缺陷作为环境应激源，内分泌干扰物与 其他类型的压力源增加慢性疾病和损害生活质量。这项建议旨在 了解行为压力的相互作用如何塑造个体的发展轨迹 在污染的两个生命阶段。我们专注于社会行为表型， 社会行为的反应规范可以深刻地改变个人与社区的关系， 他/她的生殖成功和心理健康。我们假设在一个被污染的世界里， 改变了个体的基线社会表型，并且进一步的生活压力源覆盖在EDC上， 表型造成更大的偏离行为规范。我们将在几部小说中探讨这个问题。 的方式首先，我们将建立一个模型，在整个生命过程中，持续低水平暴露于常用的内分泌干扰物的混合物中， 评估情绪反应和社会性。其次，我们将研究一个典型的生活挑战（轻度）的影响。 压力）在两个关键的生命阶段：母亲（怀孕期间），在青春期的个人， 或两者第三，我们将比较男性和女性;这使我们能够确定可能与以下方面有关的能力： 在疾病和神经行为功能障碍方面存在明确的性别差异。最后，通过测量 神经分子活动和神经解剖组织的变化，在一个定义的网络互连 边缘系统和前脑核调节社会表型，我们可以获得这些机制的见解 流程.因此，我们的总体假设是，每个生活压力源（终身EDC暴露，轻度 产前压力和青春期的轻度压力）串联起来，改变了 神经发育和社会行为，以及压力源的组合加剧了不良反应。 神经生物学健康的结果。从机制上讲，我们进一步提出，内分泌干扰物和压力调节， 这种表型通过扰乱正常的互补性雌激素和雄激素信号传导， 大脑的社会决策网络。有三个具体目标。目的是我将建立性 终生暴露于低水平的常用内分泌干扰物混合物的二态行为表型， 在关键的生命阶段（妊娠期、青少年期或两者），在其上叠加有轻度压力。Aim II将 确定终身EDC暴露引起变化的潜在神经分子机制， 妊娠期/青春期压力源，重点是雌激素/雄激素敏感电路。目标三将确定 神经解剖学和细胞结构基质的变化所造成的内分泌干扰物和压力，优先考虑 雌激素-雄激素信号通路。拟议的工作有可能产生广泛的影响， 社会和政府政策，慢性病增加造成的健康危机， 分子、细胞和有机体水平的基本生物学原理。

ABSTRACT Every human has a body burden of endocrine-disrupting chemicals (EDCs), and levels of EDCs correlate with reproductive, endocrine, and neurobehavioral deficiencies. As environmental stressors, EDCs interact with other types of stressors to increase chronic disease and impair the quality of life. This proposal seeks to understand how the developmental trajectory of an individual is shaped by the interaction of behavioral stress during two life stages in the context of contamination. We focus on the social behavioral phenotype, as shifts in the reaction norms of social behavior can profoundly change an individual’s relationship to its community, his/her reproductive success, and mental health. We postulate that neurodevelopment in a contaminated world changes an individual’s baseline social phenotype, and that further life stressors overlaid upon the EDC phenotype create greater deflections from the behavioral norm. We will approach this question in several novel ways. First, we will model constant low-level exposure to a mixture of common-use EDCs throughout life, and assess emotional reactivity and sociality. Second, we will examine the effects of a typical life challenge (mild stress) during two critical life periods: to the mother (during pregnancy), to the individual during adolescence, or both. Third, we will compare males and females; this enables us to identify susceptibilities that may relate to well-established gender differences in disease and neurobehavioral dysfunction. Finally, by measuring changes in neuromolecular activity and neuroanatomical organization in a defined network of interconnected limbic and forebrain nuclei regulating the social phenotype, we can gain mechanistic insights into these processes. Thus, our overarching hypothesis is that each life stressor (lifelong EDC exposures, mild prenatal stress, and mild stress during adolescence) concatenates to shift the reaction norms for neurodevelopment and social behavior, and that the combination of stressors exacerbates adverse outcomes for neurobiological health. Mechanistically, we further propose that EDCs and stressors modulate this phenotype through perturbing the normal complementarity of estrogen and androgen signaling in the social decision-making network of the brain. There are 3 Specific Aims. Aim I will establish the sexually dimorphic behavioral phenotype of a lifetime of exposure to low levels of a mixture of common-use EDCs, upon which is superimposed mild stress during critical life stages (gestational, adolescent, or both). Aim II will determine underlying neuromolecular mechanisms for the changes caused by lifelong EDC exposures and gestational/adolescent stressors, focusing on estrogen/androgen-sensitive circuits. Aim III will identify neuroanatomical and cytoarchitectural substrates for the changes caused by EDCs and stressors, prioritizing estrogen-androgen signaling pathways. Proposed work has the potential to have a broad impact, ranging from societal and government policies, the health crisis caused by increasing chronic disease, and understanding fundamental biological principles at the molecular, cellular and organismal levels.