从人群队列到细胞机制:孕期雌三醇暴露通过干扰Notch信号通路和神经细胞增殖诱导子代自闭症谱系障碍OA

Objective To investigate the effect of prenatal estriol(E3)exposure on autism spectrum disorders(ASD)and the role of the Notch signaling pathway in the process.Methods Untargeted metabolomics was performed on plasma samples from 44 mothers of ASD children and 44 matched controls in the Guangxi Zhuang birth cohort.Then E3 was identified as main differential metabolite during pregnancy.SH-SY5Y cells were subjected and divided into a control group and study groups(10,30,50 and 100 µmol/L E3),and proteomics was performed to screen the main pathway involved in the process.CCK-8 assay was employed to detect cell proliferation.Western blotting and RT-qPCR were performed to verify the obtained pathway.Results Metabolomics analysis for plasma metabolite levels in pregnant women showed that the E3 level in the case group was significantly down-regulated than that of the control group(P<0.01).KEGG enrichment analysis indicated that the Notch signaling pathway was a significantly enriched pathway(P<0.01).CCK-8 assay suggested that the concentration of 100 µmol/L was identified as the most significant dose for E3 in the proliferation inhibition of SH-SY5Y cells(P<0.01).Both qPCR and Western blotting indicated that 100 µmol/L E3 treatment resulted in obvious down-regulation in Jagged1(P<0.01),Notch1(P<0.01),and Hes1(P<0.05)at mRNA and protein levels in SH-SY5Y cells.Conclusion Prenatal E3 exposure may be associated with ASD,and its mechanism may be through inhibiting the Notch signaling pathway,and thereby inhibiting neural cell proliferation.