Prenatal environmental toxicants induce neuroinflammation causing autistic behaviors

尽管抗脑抗原抗体(Abs)与ASD的发展有关，而且 这些抗体的特异性已经开始被识别，还没有直接的量化 ASD相关行为异常的机制。相互之间的通信 不同脑区的神经元需要神经元建立与延长的信息传递回路 连接位于不同距离的神经元的手臂。干扰正确的连接可能会影响 许多行为以及正常的身体功能。这项研究将利用患有自闭症的小鼠的大脑。 类似的行为(BTBR品系)和那些行为正常的人，除非暴露在改变的母胎影响中 接触有毒物质HgCl2和/或柴油废气颗粒物(DEP)。产前汞和DEP的影响 据报道，可以诱导类似于BTBR小鼠的ASD行为，BTBR小鼠具有抗脑抗体和 神经炎。大脑中的这些免疫活动被认为是干扰正常发育的 神经元连接。这个假设是环境毒物诱导了胎儿先天的结合 免疫细胞(小胶质细胞)活性和母体抗体启动有害的神经炎性反应 发育中的大脑。由此产生的炎症和免疫干扰对神经元结构/功能的影响 突触神经元的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展，所以也就不足为奇了 免疫细胞表型，可以直接影响从卵黄囊前体细胞发育的小胶质细胞的类型，其 在大脑中的分布，以及它们在免疫复合体(抗体和脑抗原)存在时的功能。 来自小鼠研究的共同特异性将被用来探索新生儿血液中抗体的特异性 现在已知的儿童患有自闭症。在这项拟议的研究中，抗体将在器官型共培养的 来自不同脑区的胎儿或新生儿组织，以量化“神经元连接”的调制。大脑 这些区域将来自正常的未经治疗的小鼠，或来自汞和汞的胎儿或新生儿的大脑区域 DEP暴露的抗体具有实验小鼠和人类新生儿的共同特异性。通过 混合小鼠大脑区域的来源，我们将调查是发芽还是发芽对大脑的损害更大 目标区域。本研究对ASD研究领域具有短期和长期的影响。最多的 立竿见影的效果是鉴定出一种可以诊断ASD表型的ASD抗体生物特征。 出生。另一个短期影响将是描述反兴奋剂机构的特殊性和行动模式，以及 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 这可能是最合适的。识别损害正常神经元连接的机制 和功能可以帮助治疗干预措施的发展。这项研究还将验证 建立筛选额外环境毒物的实验模型系统。

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.