Neuroimmune dysregulation with developmental exposure to trichloroethylene

说明(申请人提供)：三氯乙烯(TCE)是一种主要的工业化学品，已成为常见的环境污染物。人体研究表明，儿童和孕妇容易受到低水平三氯乙烯的影响。因此，迫切需要了解与发育期三氯乙烯暴露相关的健康影响。在我们发表的研究中，在MRL+/+小鼠的整个孕期和早期持续暴露于TCE会在出生后42天诱导幼年小鼠的CD4+T细胞致炎细胞因子。这些全身性免疫效应伴随着不良的神经学和行为效应，包括小脑氧化还原状态的改变和与神经炎性和神经发育基因表达变化相称的攻击行为的增加。这些变化已经在包括自闭症和帕金森氏症在内的几种神经疾病中被发现，这一事实突显了这些发现的潜在临床意义。全身性免疫失调伴随着其中几种疾病，并可能在环境毒物、神经免疫稳态丧失和不良神经后果之间提供机制联系。我们的主要目标是填补目前的知识空白，使我们能够进一步确定与发育中的三氯乙烯暴露相关的免疫学、神经学和相关行为改变所需的特定易感窗口(S)。这项提议将检验这一假设，即发育过程中暴露于TCE会诱导全身性促炎反应，从而扰乱外周免疫和神经免疫程序，从而促进不良神经行为结果。MRL+/+小鼠将在三个不同的发育窗口暴露于0、0.01和0.1 mg/mlTCE，包括1)产前暴露[妊娠期0-GD18]，2)出生后暴露(PND0-PND42)，以及3)持续暴露(GD0-PND42)。雄性后代将在PND42中被牺牲，以确定TCE暴露影响的特定发育窗口(S)，以实现以下目标。目的1研究妊娠中期(GD7)和哺乳期中期(PND10)母鼠的外周免疫反应。目的2通过研究TCE对特定脑区神经炎症和氧化应激生物标志物的影响，研究暴露于TCE的PND42雄性子代的神经免疫反应。神经病理学评估将描述三氯乙烯引起的神经炎性改变是源于外周免疫细胞的渗透还是起源于脑内。目的3将对来自每个治疗组的42名男性PND后代进行全面的神经行为评估。使用这个模型来更好地了解一种常见的环境毒物如何调节神经和免疫发育程序，从而为许多环境相关的神经疾病开发有效的筛查、治疗和预防策略做出重大贡献。 公共卫生相关性：在关键发育窗口受环境影响而引起的免疫紊乱可能对儿童健康产生深远影响，并可能增加神经发育障碍的易感性。这项提议将定义三氯乙烯诱导的免疫、神经和神经行为功能障碍的发育窗口。

DESCRIPTION (provided by applicant): Trichloroethylene (TCE) is a major industrial chemical that has become a common environmental pollutant. Human studies have shown that children and pregnant women are vulnerable to low level TCE exposure. Thus, there is an urgent need to understand the health effects associated with developmental TCE exposure. In our published studies, continuous exposure to TCE throughout gestation and early life in MRL+/+ mice induced CD4+ T cell proinflammatory cytokines in juvenile mice at postnatal day (PND) 42. These systemic immune effects were associated adverse neurologic and behavioral effects including altered cerebellar redox status and increased aggressive behavior commensurate with alterations in the expression of neuroinflammatory and neurodevelopmental genes. The potential clinical significance of these findings is underscored by the fact that these alterations have been identified in several neurologic disorders including autism and Parkinson's Disease. Systemic immune degregulation accompanies several of these disorders and may provide a mechanistic link between environmental toxicants, loss of neuroimmune homeostasis, and adverse neurologic outcome. Our primary goal is to fill current knowledge gaps that will enable us to further define the specific susceptibility window(s) required for immunologic, neurologic, and associated behavioral alterations linked with developmental TCE exposure. This proposal will test the hypothesis that developmental exposure to TCE induces a systemic proinflammatory response that dysregulates peripheral immune and neuroimmune programming to promote adverse neurobehavioral outcome. MRL+/+ mice will be exposed to 0, 0.01 and 0.1 mg/ml TCE during three distinct developmental windows including 1) prenatal exposure [gestational day (GD) 0-GD18], 2) postnatal exposure (PND0-PND42), and 3) continuous exposure (GD0-PND42). Male offspring will be sacrificed at PND42 to define the specific developmental window (s) affected by TCE exposure in the following Aims. Aim 1 will investigate the peripheral immune response in control and TCE-exposed PND42 male offspring and in dams at mid gestation (GD7) and mid lactation (PND10). Aim 2 will investigate the neuroimmune response in PND42 male offspring exposed to TCE by determining the impact of TCE on biomarkers of neuroinflammation and oxidative stress in defined brain regions. Neuropathology assessment will delineate whether TCE-induced neuroinflammatory changes stem from peripheral immune cell infiltration or originate within the brain. Aim 3 will provide a comprehensive neurobehavioral evaluation in PND 42 male offspring from each treatment group. Using this model to better understand how a common environmental toxicant modulates the neural and immune developmental program could contribute significantly to the development of effective screening, therapeutic, and preventative strategies for many environmentally-related neurologic disorders. PUBLIC HEALTH RELEVANCE: Immune disturbances mediated by environmental influences at critical developmental windows may have far reaching consequences for childhood health and may enhance susceptibility to neurodevelopmental disorders. This proposal will define the developmental window responsible for trichloroethylene-induced immunologic, neurologic, and neurobehavioral dysfunction.