ABSTRACT

Autism spectrum disorders (ASD) are neurodevelopmental disorders, and their incidence is increasing worldwide. Increased exposure to environmental metal lead (Pb) has been proposed as a risk factor associated with ASD. In the present study, BTBR T+ tf/J (BTBR) mice with ASD-like behavioral characteristics and control FVB mice were exposed gestationally and/or neonatally to Pb, and compared with highly social FVB mice to investigate neuroimmunological abnormalities. IgG1 and IgG2a levels in fetal brains from BTBR dams exposed to Pb (BTBR-Pb) were significantly higher than those of BTBR-controls (BTBR-C). However, this change did not occur in FVB mice exposed to Pb. The IgG1:IgG2a ratio was higher in both fetal and postnatal brains of BTBR mice compared to FVB animals regardless of Pb exposure. The IL-4:IFN-γ ratio was elevated in BTBR-Pb relative to BTBR-C mice, but this ratio was not markedly affected following Pb exposure in FVB animals. These findings suggest the potential for a Pb-driven predominant T_H2-like reactivity profile in brain microenvironment present in BTBR mice. Brain-derived neurotrophic factor was decreased in fetal and postnatal BTBR-Pb brains relative to BTBR-C brains but not in FVB-Pb relative to FVB-C mice. Taken together, data demonstrate that Pb exposure might contribute to developmental brain abnormalities associated with ASD, particularly in individuals with genetic susceptibility to ASD.

摘要

自闭症谱系障碍 (ASD) 是神经发育障碍，其发病率在全球范围内不断增加。增加暴露于环境金属铅 (Pb) 已被认为是与 ASD 相关的风险因素。在本研究中，BTBR T+  tf具有 ASD 样行为特征的 /J (BTBR) 小鼠和对照 FVB 小鼠在妊娠期和/或新生儿期暴露于铅，并与高度社交的 FVB 小鼠进行比较以研究神经免疫异常。来自暴露于 Pb 的 BTBR 母猪（BTBR-Pb）的胎儿大脑中的 IgG1 和 IgG2a 水平显着高于 BTBR 对照组（BTBR-C）。然而，这种变化在暴露于 Pb 的 FVB 小鼠中没有发生。与 FVB 动物相比，BTBR 小鼠的胎儿和出生后大脑中的 IgG1:IgG2a 比率更高，无论是否接触铅。与 BTBR-C 小鼠相比，BTBR-Pb 中的 IL-4:IFN-γ 比率升高，但在 FVB 动物中接触 Pb 后，该比率并未受到显着影响。这些发现表明 Pb 驱动的主要 T _H的潜力BTBR 小鼠大脑微环境中的 2 样反应性特征。相对于 BTBR-C 大脑，胎儿和出生后 BTBR-Pb 大脑中的脑源性神经营养因子降低，但相对于 FVB-C 小鼠，FVB-Pb 中的脑源性神经营养因子降低。总之，数据表明铅暴露可能导致与 ASD 相关的大脑发育异常，特别是在具有 ASD 遗传易感性的个体中。