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

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.

Maternal diabetes-mediated RORA suppression in mice contributes to autism-like offspring through inhibition of aromatase

“…This study has potential limitations for its clinical application due to limited cohort, while a power with n = 118 should be qualified to make a conclusion for RORA as an ASD biomarker, another much bigger clinical investigation is currently in our progress to establish a more accurate Pass/Fail Cut/Off value for ASD diagnosis. In addition, our results suggest that in the presence of prenatal exposure of risk factors (e.g., maternal diabetes) 22 , 25 , RORA expression is not only suppressed in neurons but is also suppressed in PBMC; this can be explained by the hypothesis that maternal diabetes-induced RORA suppression in hematopoietic stem cells during embryonic development can be inherited in PBMC as reported previously 39 . Furthermore, we have previously reported that prenatal hormone exposure, such as progestin and androgen 6 – 8 , 27 , is associated with ASD development 40 .…”

Hematopoietic stem cell transplantation ameliorates maternal diabetes–mediated gastrointestinal symptoms and autism‐like behavior in mouse offspring

“…We have previously found that maternal diabetes–mediated oxidative stress triggers epigenetic changes and gene suppression in both HSCs and PBMCs. PBMCs can inherit the similar properties from HSCs during differentiation after HSCT operation, and these properties may include epigenetic changes and subsequent gene suppression 25 . In this study, we showed that GFP lentivirus–infected HSCs from donor mice were found in PBMCs from recipient mice with ∼16.3% GFP + after HSCT; this further shows that HSCs can differentiate into PBMCs after HSCT, even though the number of transduced cells is relatively low.…”

“…We have previously reported that maternal diabetes induces epigenetic changes and gene suppression in neurons that, subsequently, contribute to autism‐like behaviors (ALBs) in offspring 4–6 . Furthermore, maternal diabetes–mediated epigenetic modifications in HSCs can be inherited by peripheral blood mononuclear cells (PBMCs) during differentiation, 24 subsequently inducing immune dysfunction in autism‐like offspring 25,26 . While HSC‐based therapeutic treatment has been shown to ameliorate ASD symptoms, 27,28 the underlying mechanism remains unclear and the strategy needs improvement 29 …”

“…It has been early reported that transient hyperglycemia can induce persistent epigenetic changes and alter gene expression during subsequent normoglycemia 30 . We have recently found that maternal diabetes induces persistent gene suppression of superoxide dismutase 2 (SOD2) 5 and oxytocin receptor 4 in brain regions, and these changes contribute to ALB in rodent offspring 25 . Furthermore, in those studies, which used a maternal diabetes model of streptozotocin injection–induced type I diabetes, the subsequent mouse offspring showed ALBs in almost every individual, which included suppressed ultrasonic vocalization (USV), as well as impaired social recognition and interaction 4,6,25 …”

Maternal Diabetes-Induced Suppression of Oxytocin Receptor Contributes to Social Deficits in Offspring

“…We found that hyperglycemia suppresses the expression of both OXT and OXTR, and OXTR expression remains low, while OXT expression returns to normal during subsequent normoglycemia. This effect can be completely reversed by SOD2 expression, indicating that hyperglycemia-induced OXTR suppression is due to hyperglycemia-induced consistent oxidative stress, which has been termed “hyperglycemia memory” ( El-Osta et al, 2008 ; Lu et al, 2020 ). Further investigation showed that hyperglycemia-induced OXTR suppression is due to oxidative stress-mediated consistent histone methylation on the OXTR promoter, indicating that these types of epigenetic changes can be inherited in offspring as a result of maternal diabetes.…”