From population cohort to cellular mechanisms: prenatal estriol exposure induces autism spectrum disorder in offspring via disrupting the Notch signaling pathway and neuronal proliferation

RAN Guanghui; SONG Anhua; WEI Lijuan; LIU Lili; LI Zhongyi; LAN Liqi; HUANG Xinlei; ZENG Xiaoyun; WANG Lijun

doi:10.16016/j.2097-0927.202511044

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From population cohort to cellular mechanisms: prenatal estriol exposure induces autism spectrum disorder in offspring via disrupting the Notch signaling pathway and neuronal proliferation

Neuroscience | 更新时间：2026-02-04

- From population cohort to cellular mechanisms: prenatal estriol exposure induces autism spectrum disorder in offspring via disrupting the Notch signaling pathway and neuronal proliferation
- Journal of Army Medical University Vol. 48, Issue 2, Pages: 138-146(2026)
- 作者机构：
  
  1.广西医科大学公共卫生学院，广西南宁
  2.桂林医科大学公共卫生学院，广西桂林
- 作者简介：
  
  ZENG Xiaoyun, E-mail：zengxiaoyun@gxmu.edu.cn
  WANG Lijun, E-mail：wanglj1003@163.com
- 基金信息：
  
  the Project of Science and Technology Program of Guangxi Province(2024GXNSFDA999004;GuikeAD23026297);the Project of Young Scientific and Technological Talent Program of Guangxi Program(GXYESS2025001)
- DOI：10.16016/j.2097-0927.202511044
  CLC： R347.913;R363.21;R749.94
- Received：09 November 2025，
  
  Revised：2025-12-23，
  
  Accepted：24 December 2025，
  
  Published：30 January 2026
- 稿件说明：
移动端阅览
冉光辉，宋安华，韦丽娟，等.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［J］.陆军军医大学学报，2026，48（02）：138-146.DOI：10.16016/j.2097-0927.202511044.

RAN G H，SONG A H，WEI L J，et al.From population cohort to cellular mechanisms： prenatal estriol exposure induces autism spectrum disorder in offspring via disrupting the Notch signaling pathway and neuronal proliferation［J］.J Army Med Univ，2026，48（02）：138-146.DOI：10.16016/j.2097-0927.202511044.
冉光辉，宋安华，韦丽娟，等.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［J］.陆军军医大学学报，2026，48（02）：138-146.DOI：10.16016/j.2097-0927.202511044. DOI：

RAN G H，SONG A H，WEI L J，et al.From population cohort to cellular mechanisms： prenatal estriol exposure induces autism spectrum disorder in offspring via disrupting the Notch signaling pathway and neuronal proliferation［J］.J Army Med Univ，2026，48（02）：138-146.DOI：10.16016/j.2097-0927.202511044. DOI：

摘要

目的

探讨孕期雌三醇（estriol，E3）暴露对自闭症谱系障碍（autism spectrum disorders，ASD）的影响及其Notch信号通路机制。

方法

选取广西壮族人群出生队列中44例ASD患儿母亲及44例匹配对照母亲的血浆样本，进行代谢组学检测。通过代谢组学分析筛选孕期主要差异代谢物E3，采用E3（100 μmol/L）处理SH-SY5Y细胞，实验分组为2组：对照组（control组）和实验组（E3组），结合蛋白组学技术，筛选出Notch信号通路，利用CCK-8法检测细胞增殖情况，并通过Western blot和RT-qPCR共同验证Notch信号通路相关分子。

结果

代谢组学检测孕妇血浆代谢物水平，结果显示，与对照组相比，病例组E3水平下调（

0.01）；蛋白组学KEGG富集分析结果显示，Notch信号通路为显著富集通路（

0.01）；CCK-8结果显示，各浓度E3处理SH-SY5Y细胞后，在100 μmol/L浓度时抑制细胞增殖最显著（

0.01）；RT-qPCR结果显示，100 μmol/L浓度的E3处理SH-SY5Y细胞，

Jagged1

（

0.01）、

Notch1

（

0.01）和

Hes1

（

0.05）基因表达水平下降；Western blot结果显示，100 μmol/L浓度的E3处理SH-SY5Y细胞，Jagged1（

0.01）、Notch1（

0.01）和Hes1（

0.05）蛋白表达水平下降。

结论

孕期E3暴露可能与ASD之间存在关联，其机制可能是通过抑制Notch信号通路，进而抑制神经细胞增殖。

Abstract

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

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 (

0.01). KEGG enrichment analysis indicated that the Notch signaling pathway was a significantly enriched pathway (

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 (

0.01). Both qPCR and Western blotting indicated that 100 μmol/L E3 treatment resulted in obvious down-regulation in Jagged1 (

0.01)

Notch1 (

0.01)

and Hes1 (

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.

关键词

Keywords

references

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