Maternal Diabetes Induces Immune Dysfunction in Autistic Offspring Through Oxidative Stress in Hematopoietic Stem Cells.

Jianping Lu,Jianping Lu,Paul Yao,Paul Yao,Xiaoling Guo,Zichen Wang,Zichen Wang,Ling Li,Min Wang,Kelly Liu,Yujie Liang,Yujie Liang,Meifang Xiao,Jianchang Xu,Gang Zeng,Liyan Liu

doi:10.3389/fpsyt.2020.576367

Abstract

Autism spectrum disorders (ASD) have been found to be associated with immune dysfunction and elevated cytokines, although the detailed mechanism remains unknown. In this study, we aim to investigate the potential mechanisms through a maternal diabetes-induced autistic mouse model. We found that maternal diabetes-induced autistic offspring have epigenetic changes on the superoxide dismutase 2 (SOD2) promoter with subsequent SOD2 suppression in both hematopoietic stem cells (HSC) and peripheral blood mononuclear cells (PBMC). Bone marrow transplantation of normal HSC to maternal diabetes-induced autistic offspring transferred epigenetic modifications to PBMC and significantly reversed SOD2 suppression and oxidative stress and elevated inflammatory cytokine levels. Further, in vivo human study showed that SOD2 mRNA expression from PBMC in the ASD group was reduced to ~12% compared to typically developing group, and the SOD2 mRNA level-based ROC (Receiver Operating Characteristic) curve shows a very high sensitivity and specificity for ASD patients. We conclude that maternal diabetes induces immune dysfunction in autistic offspring through SOD2 suppression and oxidative stress in HSC. SOD2 mRNA expression in PBMC may be a good biomarker for ASD diagnosis.

Highlights

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by impairment of verbal communication and social skills in addition to restricted and repetitive behaviors
We conclude that maternal diabetes induces immune dysfunction in autistic offspring through oxidative stress in hematopoietic stem cells (HSC) and that superoxide dismutase 2 (SOD2) mRNA levels in peripheral blood mononuclear cells (PBMC) may be a good biomarker for the diagnosis of ASD patients
We evaluated mRNA expression in HSC, and the results showed that estrogen receptor b (ERb) and SOD2 mRNA levels in the streptozotocin. typically developing (TD) (STZ) group decreased to 65% and 26%, respectively, compared to the CTL group, while ERa mRNA levels showed no significant changes

Summary

Introduction

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by impairment of verbal communication and social skills in addition to restricted and repetitive behaviors. Maternal Diabetes Induces Immune Dysfunction factors, sex, and immune system [4], have been reported to contribute to ASD development, while the detailed mechanism remains largely unclear [3, 5,6,7]. We have recently reported that prenatal progestin exposure [6, 8, 9] and maternal diabetes [10,11,12] contribute to ASD development through suppressed expression of estrogen receptor b (ERb) and superoxide dismutase 2 (SOD2) in neurons [12]. Our preliminary data showed that SOD2 expression in peripheral blood mononuclear cells (PBMC) was significantly decreased in the ASD group compared to the typically developing (TD) group. Since PBMC are typically derived from hematopoietic stem cells (HSC), we hypothesize that SOD2 suppression in PBMC is due to gene suppression of HSC during embryonic development [13, 14]

Objectives

Methods

Results

Discussion

Conclusion