Pan Tianying, Jiang Chuan, Cheng Juan, Xie Jiang, Liu Xinghui, Xu Wenming, He Guolin
Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, China.
Reproductive Endocrinology and Regulation Laboratory, West China Second University Hospital, Sichuan University, Chengdu, China.
Front Neurosci. 2021 Dec 23;15:774439. doi: 10.3389/fnins.2021.774439. eCollection 2021.
Autism spectrum disorders (ASD) represent a complex group of neurodevelopmental disorders that are characterized by impaired social behavior and communication as well as repetitive behavior and restricted interests. Prenatal exposure to high levels of testosterone and preeclampsia are thought to be risk factors of ASD. We had previously reported that overexpression of the mitochondrial cholesterol side-chain cleavage enzyme (CYP11A1) could lead to both preeclampsia-like symptoms and increased testosterone levels in pregnant rats. In this study, we investigated the association between high CYP11A1 levels in pregnant rats and autism-like behavior in their offspring. Timed-pregnant Sprague-Dawley (SD) rats were injected with gene-carrying adenoviruses on gestational day 8.5, and their offspring were then compared with those from timed-pregnant control SD rats. Compared with their control counterparts, the offspring of the -ovexpressing dams displayed more symptoms of anxiety and spent less time in social interactions and more time in self-grooming and rearing, all indicators of autism-like behavior. Sequencing of the transcriptome in primary microglia from the offspring of -overexpressing dams revealed that immune pathways were highly activated, and the gamma-aminobutyric acid type A (GABAA) receptor genes were among the top differentially expressed genes. Using primary microglia cultures generated from neonatal rats, tumor necrosis factor-alpha expression was found to be elevated in the cells transfected with -carrying adenoviruses. Additionally, the offspring of -overexpressing dams displayed dysregulated GABAA receptor expression. Taken together, these results suggest that abnormal gene expression in pregnant rats could lead to microglial immune activation and dysregulated GABAA receptor expression in their offspring and thereby anxiety and autism-related behavior. Our study suggests that the pathways regulated by CYP11A1 could be promising preventative and therapeutic targets for ASD.
自闭症谱系障碍（ASD）是一组复杂的神经发育障碍，其特征是社交行为和沟通受损，以及重复行为和兴趣受限。产前暴露于高水平的睾酮和先兆子痫被认为是ASD的危险因素。我们之前曾报道，线粒体胆固醇侧链裂解酶（CYP11A1）的过表达可导致孕鼠出现先兆子痫样症状并使睾酮水平升高。在本研究中，我们调查了孕鼠中高CYP11A1水平与其后代自闭症样行为之间的关联。在妊娠第8.5天给定时怀孕的斯普拉格-道利（SD）大鼠注射携带基因的腺病毒，然后将其后代与定时怀孕的对照SD大鼠的后代进行比较。与对照后代相比，过表达母鼠的后代表现出更多焦虑症状，在社交互动中花费的时间更少，而在自我梳理和抚育上花费的时间更多，这些都是自闭症样行为的指标。对过表达母鼠后代的原代小胶质细胞转录组进行测序发现，免疫途径高度激活，γ-氨基丁酸A型（GABAA）受体基因是差异表达最显著的基因之一。使用新生大鼠产生的原代小胶质细胞培养物，发现用携带腺病毒转染的细胞中肿瘤坏死因子-α表达升高。此外，过表达母鼠的后代表现出GABAA受体表达失调。综上所述，这些结果表明孕鼠中异常的基因表达可导致其后代小胶质细胞免疫激活和GABAA受体表达失调，从而引发焦虑和自闭症相关行为。我们的研究表明，由CYP11A1调节的途径可能是ASD有前景的预防和治疗靶点。
