环境危险因素暴露所致的遗传毒性损伤是孤独症重要发病机制之一。HIPK2是调控多种遗传毒性损伤相关转录因子表达的关键性激酶。本课题组前期动物实验发现大鼠孕期砷暴露可诱导子代孤独症样行为（autism-like behavior，ALB）、额叶皮层神经元HIPK2低甲基化；随后的临床实验检测孤独症患儿血清发现HIPK2及其下游调控的转录因子p53表达明显增加，但HIPK2相关通路的异常在孤独症中的作用和机制尚不清楚。因此，本项目提出孕期砷暴露可通过降低HIPK2甲基化异常活化p53致子代额叶皮层神经元发育障碍，从而诱导ALB的假说。为此，我们将利用已构建的大鼠孕期和额叶皮层神经元原代培养砷染毒模型，采用放射性核素标记、流式细胞检测、神经电生理、RNA干扰调节通路等手段，研究孕期砷暴露下HIPK2-p53信号通路调控异常所致ALB的具体作用机制。预期结果将为孤独症的防治提供新的策略和靶点。

Genotoxicity caused by the exposure of environmental risk factors is one of the important pathogenesis of autism. HIPK2 is a key kinase that regulates the expression of a variety of genotoxic injuries-related transcription factors. Our previous animal study found that arsenic exposure during pregnancy induces autism-like behavior (ALB) of offspring, and the hypomethylation of HIPK2 in frontal cortex. Subsequent the clinical trials revealed that obviously increased expression of serum HIPK2 and its downstream regulatory transcription factors p53 was observed in children with autism, however, the role and mechanism of abnormal HIPK2-related signaling pathways in autism is still not clear. Therefore, we hypothesized that arsenic exposure during pregnancy could result in neuronal dysplasia of prefrontal cortex by HIPK2 hypomethylation and abnormal activation of p53, may contribute to the ALB in rat offspring. To this end, we will take advantage of the established model of arsenic exposure during pregnancy and in vitro arsenic exposure of frontal cortex neuron, using radionuclide labeling, flow cytometry, electrophysiological and RNA interference regulatory pathways to study the specific mechanism of ALB caused by abnormal regulation of HIPK2-p53 signaling pathway in arsenic exposure during pregnancy. The expected results will provide new strategies and targets for the prevention and treatment of autism.