Environmentally Induced Alterations In Neuron And Glia Development and Aging

发育中的神经系统易受环境因素的影响，一直是儿童健康问题的一个主要关切，随着幼儿年龄段儿童大量接触环境因素以及自闭症和精神分裂症等发育障碍的增加，这一问题也变得更加令人关切。 大脑中各种细胞类型之间的形成和相互作用是关键的定时事件，代表了环境暴露的脆弱性的年龄窗口。 最近的一个问题是在发育过程中感染或刺激或改变免疫系统的影响（Harry和Kraft，2012; Harry和Lein，2011）。 这种反应的一个组成部分是诱导白细胞介素-6，这与母亲感染和改变儿童结局有关。 这种细胞因子具有促炎和抗炎特性，但也作为生长因子发挥作用。 在以前的工作中，我们证明了这种细胞因子的严格调节对于维持对化学损伤的正常神经胶质反应至关重要。 多项研究表明，IL-6是由于发育中的炎症引起的脑损伤的关键决定因素，然而，这些研究利用了全身感染或高水平炎症反应的模型。我们现在已经证明，在没有完全的全身免疫应答的情况下，发育中的小鼠脑直接暴露于IL-6可以改变脑发育，表现为运动性个体发育的早期发作，潜在地改变少突胶质细胞祖细胞的分化并产生社会行为的长期变化（Brunssen等人，2012年）。 这些效应是非常特异性的，并且不会复制由更严重和全身性炎症反应诱导的明显行为改变。这项工作证明了IL-6在大脑发育和神经保护过程中的关键作用，并提供了早期发育暴露于环境暴露和长期改变的免疫介导事件之间的可能联系。 2. N-丁基苯磺酰胺（NBBS）被广泛用作聚缩醛、聚酰胺和聚碳酸酯的增塑剂，并已在地下水和废水处理场的流出物中发现。 文献中有限的研究报告了NBBS对家兔和大鼠的神经毒性。当我们通过经口灌胃（5 ml/kg bwt）每天/每周5天/连续27天将大鼠暴露于NBBS（100、200或300 mg/kg/d）时，未观察到步态、自发活动和直立行为的变化。 在睾丸、精囊、前列腺、附睾和前列腺中未观察到组织学病变。 与以前的报告相反，没有证据表明周围神经病变或海马或小脑神经胶质增生。 在海马体中，胶质细胞酸性蛋白、干扰素γ、CXCR-3、细胞内粘附分子-1和CD 11b的mRNA水平没有改变，而Iba-1水平降低（Rider等人，2012年）。 3. 我们已经开发了一个模型系统来检查不同年龄的海马颗粒下区的祖细胞群，并确定毒物或药物暴露是否会直接改变这些细胞或改变体内环境，从而改变这些祖细胞分化为成熟功能神经元的能力。 我们正在使用这个模型来识别新的信号传导因子，这些因子可以促进成人神经发生并改善大脑修复和认知功能。 对于这些研究，我们继续使用许多方法来检查暴露于环境因子后发育中的神经系统的改变，包括免疫组织化学和共聚焦成像，检查mRNA水平的分子技术，如qRT-PCR，微阵列，RNA酶保护测定，用于分离和富集特定区域的激光捕获显微切割，神经祖细胞培养物，成人来源的神经干/祖细胞，以及神经行为功能的评估。

The susceptibility of the developing nervous system to environmental agents has been a major concern with regard to children's health issues and has become of additional concern with the high level of exposure to children of toddler age and the increase in developmental disorders such as autism and schizophrenia. The formation and interactions between the various cell types in the brain are critically timed events and represent age windows of vulnerability for environmental exposure. One recent issue of concern is the impact of infection or a stimulation or alteration in the immune system during development (Harry and Kraft, 2012; Harry and Lein, 2011). One component of this response is the induction of interleukin-6 which has been linked to maternal infection and altered childhood outcomes. This cytokine has both pro- and anti-inflammatory properties but also plays a role as a growth factor. In previous work we demonstrated that tight regulation of this cytokine is critical for maintaining a normal glial response to chemical injury. Multiple studies have suggested that IL-6 is the critical determining factor for brain damage due to inflammation in development however, these studies utilized models of systemic infection or high levels of an inflammatory response. We have now demonstrated that direct exposure of the developing mouse brain to IL-6, in the absence of a full systemic immune response, can alter brain development with manifestation of an early onset of motoric ontogeny, potentially altering differentiation of oligodendroglia progenitors and produce long term changes in social behavior (Brunssen et al., 2012). These effects are very specific and do not replicate the pronounced behavioral alterations induced with a more severe and generalized inflammatory response. This work demonstrates a critical role for IL-6 in both brain development and in neuroprotective processes and provides a possible link between early developmental exposure to immune mediated events from environmental exposure and long-term alterations. 2.N-Butylbenzenesulfonamide (NBBS) is widely used as a plasticizer in polyacetals, polyamides, and polycarbonates and has been found in ground water and effluent from wastewater treatment sites. Limited studies in the literature report neurotoxicity of NBBS in rabbits and rats. When we exposed rats to NBBS (100, 200, or 300 mg/kg/d) via oral gavage (5 ml/kg bwt) daily/5 days/week for 27 days we did not observe changes in gait, locomotor activity, and rearing behavior. No histological lesions were observed in the testis, seminal vesicles, coagulating gland, epididymis, and prostate. Contrary to previous reports, there was no evidence of peripheral nerve lesions or gliosis in the hippocampus or cerebellum. mRNA levels for glial fibrillary acidic acid protein, interferon gamma, CXCR-3, intracellular adhesion molecule-1, and CD11b were not altered in the hippocampus while Iba-1 levels were decreased (Rider et al., 2012). 3. We have developed a model system to examine the progenitor cell population from the subgranular zone ofthe hippocampus at different ages and to determine if toxicant or drug exposure will alter these cells directly or alter the in vivo environment such that the ability of these progenitor cells to differentiate to mature functioning neurons is altered. We are using this model to identify novel signaling factors that can promote adult neurogenesis and improve brain repair and cognitive functioning. For these studies we continue to use a number of methods to examine alterations in the developing nervous system following exposure to environmental agents including immunohistochemistry and con-focal imaging, molecular techniques to examine mRNA level such as qRT-PCR, microarray, RNase protection assays, laser capture microdissection for isolation and enrichment of specific areas, neuroprogenitor cell cultures, adult derived neural stem/progenitor cells, as well as assessment of neurobehavioral functioning.