Prenatal environmental toxicants induce neuroinflammation causing autistic behaviors

尽管针对脑抗原的抗体（Abs）与ASD的发展有关， 尽管这些抗体的特异性开始被鉴定，但还没有直接定量这些抗体的特异性。 与ASD相关的行为异常机制。之间的通信 不同大脑区域的神经元需要神经元建立具有扩展的 臂连接位于不同距离的神经元。干扰正确的连接会影响 许多行为以及正常的身体功能。这项研究将利用患有ASD的小鼠的大脑- 相似行为（BTBR株）和那些行为正常的人，除非暴露于改变的母胎影响 HgCl 2和/或柴油机排气颗粒（DEP）的有毒物质暴露。产前汞和DEP的影响 据报道，诱导ASD样行为类似于BTBR小鼠的行为，BTBR小鼠具有抗脑抗体， 神经炎症大脑中的这些免疫活动被认为会干扰正常发育。 神经元连接假设是环境毒物诱导胎儿先天性 免疫细胞（小胶质细胞）活性和母体抗体，以启动有害的神经炎症反应， 大脑发育由此产生的炎症和免疫干扰神经元结构/功能改变 突触神经元连接和功能导致后代的ASD样行为。小胶质细胞是 已知会影响神经元回路的发育，因此，可以改变神经元回路的有毒物质 免疫细胞表型，可以直接影响从卵黄囊祖细胞发育的小胶质细胞的类型， 在脑中的分布，以及它们在免疫复合物（Ab和脑抗原）存在下的功能。 来自小鼠研究的常见特异性将用于探索新生儿血液中的Ab特异性， 目前已知患有ASD的儿童。在拟定的研究中，将在以下器官型共培养物中测定Ab： 来自不同脑区域的胎儿或新生儿组织，以量化“神经元连接”的调节。大脑 区域将来自正常的未处理小鼠或来自Hg和Hg的胎儿或新生儿的脑区域， 暴露于DEP的母鼠±具有实验小鼠和人类新生儿共同特异性的Ab。通过 混合小鼠大脑区域的来源，我们将调查是否损害更多与发芽或 目标区域。该研究对ASD研究领域具有短期和长期的影响。最 直接影响是鉴定“ASD的抗体生物特征”，其可以诊断ASD表型， 出生另一个短期影响将是界定抗体的特性和作用方式， 识别ASD相关机制的小胶质细胞，从长远来看，这可能有助于确定干预措施 可能是最合适的识别对正常神经元连接有害的机制 和功能可以帮助开发治疗干预措施。该研究还将验证 建立一个实验模型系统，以筛选额外的环境毒物。

Although antibodies (Abs) to brain antigens have been implicated in the development of ASD, and the specificities of these Abs are beginning to be identified, there has been no direct quantification of the mechanisms responsible for the behavioral aberrancies associated with ASD. Communication between neurons in different brain regions requires the neurons to establish information delivery circuits with extended arms connecting the neurons located at different distances. Interference with proper connections can affect numerous behaviors as well as normal body functions. This study will utilize brains from mice that have ASD- like behaviors (BTBR strain) and those with normal behavior unless exposed to altered fetomaternal influences from toxicant exposures with HgCl2 and/or diesel exhaust particles (DEP). Prenatal Hg and DEP effects have been reported to induce ASD-like behaviors similar to those of BTBR mice, which have anti-brain Abs and neuroinflammation. These immune activities in the brain are posited to interfere with development of proper neuronal connections. The hypothesis is that environmental toxicants induce a combination of fetal innate immune cell (microglial) activities and maternal Abs to initiate a detrimental neuroinflammatory response in the developing brain. The resultant inflammation and immune interferences with neuronal structures/functions alter synaptic neuronal connections and functions resulting in the ASD-like behaviors of offspring. Microglia are known to influence the development of neuronal circuits, so it is not surprising that toxicants, which can alter immune cell phenotypes, could directly affect the type of microglia developed from yolk sac progenitors, their distribution in the brain, and their functions in the presence of immune complexes (Abs and brain antigens). The common specificities from mouse studies will be used to explore the Ab specificities in newborn blood of children now known to have ASD. In the proposed study, Abs will be assayed in organotypic co-cultures of fetal or neonatal tissue from different brain regions to quantify modulation of “neuronal connectivity”. The brain regions will come from normal untreated mice or from brain regions of the fetuses or neonates from Hg and DEP exposed dams ± the Abs with common specificities of experimental mice and human newborns. By mixing the source of the mouse brain region, we will investigate if the detriment is more with the sprouting or targeted region. The study has short-term and long-term impact on the field of ASD research. The most immediate impact is identification of an “Ab Biosignature of ASD” that could diagnose the ASD phenotype at birth. Another short-term impact would be delineation of the specificities and mode of action of the Abs and microglia that identify ASD-related mechanisms, which in the long-term could aid in determining interventions that might be most appropriate. Identification of the mechanisms detrimental to normal neuronal connectivity and function could assist in the development of therapeutic interventions. The study also will validate the establishment of an experimental model system to screen additional environmental toxicants.