Prenatal and pubertal two hit PCB exposure on social behavior & neural correlates

描述（由申请人提供）：内分泌干扰物（EDCs）是一种广泛存在的环境污染物，可影响广泛的内分泌和神经生物学功能，包括青春期的开始、生殖功能和情感行为的表现。实验室动物模型为EDC的作用提供了直接证据，人类流行病学数据支持EDC暴露与生殖和神经行为缺陷之间的相关性。虽然暴露于EDC可能发生在整个生命周期，本提案旨在研究EDC暴露在两个特定的关键时期的影响：妊娠晚期和青春期。妊娠是主要的生命阶段，在此期间，性腺类固醇激素的作用组织大脑，导致大脑和行为的性二态结构和功能变化。同样，青春期性腺类固醇激素释放的增加作用于这些途径，以继续这些组织过程，以及激活生命早期组织的那些途径。这项新的提议将使用“两次打击”模型确定这些EDC暴露期对行为和分子终点的相互作用，检验早期暴露可能放大青春期暴露效应的假设。 在这里，我将利用一个完善的EDC模型的多氯联苯，使用Aroclor 1221（A1221），轻度氯化的混合物。先前的研究表明，妊娠期暴露于A1221会扰乱神经生物学发育，并对神经内分泌功能、大脑基因表达和行为产生潜在影响。对于我的两次打击模型，大鼠将在妊娠期和青春期早期暴露于A1221或载体。这导致四个组（产前第一次击中，青少年第二次击中）：A1221-A1221; Veh-Veh; A1221-Veh; Veh-A1221。主要结果将是在青春期和成年期显示社交和焦虑相关行为结果，因为这些行为对性别敏感，并与人类的性别偏见心理健康障碍相关。此外，我将量化相应的基因表达的变化，选择神经肽在大脑区域以前显示为重要的显示这些行为。最后，由于大脑组织的机制至少有一部分是通过激素对DNA甲基化的作用来“编程”这些基因在以后的生活中如何发挥作用，因此该研究还将确定分子表观遗传学变化是否是关键发育时期EDC暴露引起基因表达长期变化的机制。 这些目标符合NIEHS的战略目标，即“调查环境对基因组结构和功能的影响”，包括生物过程的表观遗传调控，以及“确定对环境暴露影响敏感的关键窗口”。“此外，该提案扩展了我们对与人类生殖和精神健康障碍相关的行为和分子终点的环境影响的理解。

DESCRIPTION (provided by applicant): Endocrine-disrupting chemicals (EDCs) are widespread environmental contaminants that affect a wide range of endocrine and neurobiological functions, including onset of puberty, reproductive function, and display of affective behaviors. Laboratory animal models provide direct evidence for such EDC actions, and epidemiological data in humans support correlations between EDC exposures and reproductive and neurobehavioral deficits. While exposure to EDCs likely occurs throughout the lifetime, this proposal seeks to investigate the effects of EDC exposure during two specific critical periods of development: late gestation and puberty. Gestation is the major life stage during which actions of gonadal steroid hormones organize the brain to cause sexually dimorphic structural and functional changes in the brain and behavior. Likewise, pubertal increases in release of gonadal steroid hormones act upon these pathways both to continue these organizational processes, as well as to activate those pathways organized earlier in life. This novel proposal will identify interactions between these EDC exposures periods on behavioral and molecular endpoints using a "two-hit" model, testing the hypothesis that earlier exposure may amplify effects of pubertal exposure. Here, I will utilize a well-established EDC model of polychlorinated biphenyls, using Aroclor 1221 (A1221), a lightly chlorinated mixture. Previous work has shown that gestational exposure to A1221 perturbs neurobiological development, and has latent effects on neuroendocrine functions, gene expression in the brain, and behavior. For my two-hit model, rats will receive exposures to A1221 or vehicle during gestation and early adolescence. This results in four groups (first hit prenatal, second hit adolescent): A1221-A1221; Veh-Veh; A1221-Veh; Veh-A1221. A primary outcome will be the display of social and anxiety-related behaviors outcomes during both adolescence and adulthood, as these behaviors are hormone-sensitive and associated with sex-biased mental health disorders in humans. Additionally, I will quantify corresponding changes in gene expression of selected neuropeptides in brain regions previously shown as important in the display of these behaviors. Finally, 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 molecular epigenetic changes 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, and to "identify critical windows of susceptibility to the effects of environmental exposures." Moreover, the proposal extends our understanding of environmental influences on behavioral and molecular endpoints relevant to reproductive and mental health disorders in humans.