Neuroimmune dysregulation with developmental exposure to trichloroethylene

描述（由申请人提供）：三氯乙烯（TCE）是一种主要的工业化学品，已成为一种常见的环境污染物。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性三氯乙烯暴露有关的健康影响。在我们发表的研究中，MRL+/+小鼠在妊娠期和早期生活中持续暴露于TCE可诱导幼鼠出生后（PND）的CD4+ T细胞促炎细胞因子42。这些全身免疫效应与不良的神经和行为效应相关，包括小脑氧化还原状态的改变和与神经炎症和神经发育基因表达改变相称的攻击行为的增加。这些改变已经在包括自闭症和帕金森氏病在内的几种神经系统疾病中被发现，这一事实强调了这些发现的潜在临床意义。系统性免疫失调伴随着这些疾病，可能在环境毒物、神经免疫稳态丧失和不良神经系统预后之间提供了机制联系。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性TCE暴露相关的免疫、神经和相关行为改变所需的特定易感窗口。本研究将验证这样一种假设，即发育过程中暴露于TCE会诱导全身促炎反应，从而失调外周免疫和神经免疫程序，从而促进不良的神经行为结果。MRL+/+小鼠将在三个不同的发育窗口暴露于0、0.01和0.1 mg/ml TCE，包括1)产前暴露[妊娠日（GD） 0- gd18], 2)产后暴露（PND0-PND42）， 3)持续暴露（GD0-PND42）。在以下目的中，雄性后代将在PND42时牺牲，以确定受TCE暴露影响的特定发育窗口期。目的1将研究对照组和tce暴露的PND42雄性后代以及妊娠中期（GD7）和哺乳期中期（PND10）的母鼠的外周免疫反应。目的2将通过确定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雄性后代的神经免疫反应。神经病理学评估将描述tce诱导的神经炎症变化是源于外周免疫细胞浸润还是源于大脑。目的3将对每个治疗组的PND 42雄性后代进行全面的神经行为评估。使用这个模型来更好地理解一种常见的环境毒物如何调节神经和免疫发育程序，可以为许多与环境相关的神经系统疾病的有效筛选、治疗和预防策略的发展做出重大贡献。

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.