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

Li, Jianbo; Liang, Yujie; Jiang, Xing; Xu, Jiankun; Sun, Yang; Wang, Zichen; Li, Gang; Niu, Yanbin; Song, Sang-Keun; Zhang, Huawei; Xue, Zhenpeng; Lu, Jianping; Yao, Paul

doi:10.3389/fnins.2021.634781

Cited by 14 publications

(26 citation statements)

References 62 publications

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“…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 .…”

Section: Discussionsupporting

confidence: 82%

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

Niu

Jia³

et al. 2022

Commun Biol

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Retinoic acid-related orphan receptor alpha (RORA) suppression is associated with autism spectrum disorder (ASD) development, although the mechanism remains unclear. In this study, we aim to investigate the potential effect and mechanisms of RORA suppression on autism-like behavior (ALB) through maternal diabetes-mediated mouse model. Our in vitro study in human neural progenitor cells shows that transient hyperglycemia induces persistent RORA suppression through oxidative stress-mediated epigenetic modifications and subsequent dissociation of octamer-binding transcription factor 3/4 from the RORA promoter, subsequently suppressing the expression of aromatase and superoxide dismutase 2. The in vivo mouse study shows that prenatal RORA deficiency in neuron-specific RORA null mice mimics maternal diabetes-mediated ALB; postnatal RORA expression in the amygdala ameliorates, while postnatal RORA knockdown mimics, maternal diabetes-mediated ALB in offspring. In addition, RORA mRNA levels in peripheral blood mononuclear cells decrease to 34.2% in ASD patients (n = 121) compared to the typically developing group (n = 118), and the related Receiver Operating Characteristic curve shows good sensitivity and specificity with a calculated 84.1% of Area Under the Curve for ASD diagnosis. We conclude that maternal diabetes contributes to ALB in offspring through suppression of RORA and aromatase, RORA expression in PBMC could be a potential marker for ASD screening.

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Section: Discussionsupporting

confidence: 82%

“…Thus, RORA mRNA level in PBMC could be a potential autistic marker for screening of ASD. Additionally, only male offspring were selected in this study to avoid possible interference from estrogen in female offspring 22 , 25 , 26 .…”

Section: Discussionmentioning

confidence: 99%

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

Niu

Jia³

et al. 2022

Commun Biol

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“…OXTR is expressed in a variety of human tissues and is highly expressed in limbic regions such as the amygdala ( 12 , 20 ). It has been reported that the OXT/OXTR signaling pathway plays a role in regulation of a variety of social behaviors ( 11 , 16 ) as well as ASD etiology ( 18 , 19 , 59 ) and is involved with anxiety-like behaviors ( 13 , 14 ).…”

Section: Discussionmentioning

confidence: 99%

“…The mouse ERβ expression lentivirus was prepared previously in our lab ( 20 ). The cDNA for mouse RORA was purchased from Open Biosystems and then amplified using the following primers with underlined restriction sites: RORA forward primer: 5’- gtac - gggccc- atg gag tca gct ccg gca gcc -3’ (ApaI) and RORA reverse primer: 5’- gtac - tctaga- tta ccc atc gat ttg cat ggc -3’ (Xba1), and then subcloned into the pLVX-Puro vector (from Clontech).…”

Section: Methodsmentioning

confidence: 99%

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Prenatal Progestin Exposure-Mediated Oxytocin Suppression Contributes to Social Deficits in Mouse Offspring

et al. 2022

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Epidemiological studies have shown that maternal hormone exposure is associated with autism spectrum disorders (ASD). The hormone oxytocin (OXT) is a central nervous neuropeptide that plays an important role in social behaviors as well as ASD etiology, although the detailed mechanism remains largely unknown. In this study, we aim to investigate the potential role and contribution of OXT to prenatal progestin exposure-mediated mouse offspring. Our in vitro study in the hypothalamic neurons that isolated from paraventricular nuclei area of mice showed that transient progestin exposure causes persistent epigenetic changes on the OXT promoter, resulting in dissociation of estrogen receptor β (ERβ) and retinoic acid-related orphan receptor α (RORA) from the OXT promoter with subsequent persistent OXT suppression. Our in vivo study showed that prenatal exposure of medroxyprogesterone acetate (MPA) triggers social deficits in mouse offspring; prenatal OXT deficiency in OXT knockdown mouse partly mimics, while postnatal ERβ expression or postnatal OXT peptide injection partly ameliorates, prenatal MPA exposure-mediated social deficits, which include impaired social interaction and social abilities. On the other hand, OXT had no effect on prenatal MPA exposure-mediated anxiety-like behaviors. We conclude that prenatal MPA exposure-mediated oxytocin suppression contributes to social deficits in mouse offspring.

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Dietary nutrients that potentially mitigate autism spectrum disorder and dietary recommendations for children and pregnant women

Li,

Kong,

Tian

et al. 2024

Food Frontiers

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The increasing incidence of autism spectrum disorder (ASD) worldwide poses serious social and family problems. Various risk factors for ASD are gradually being recognized, and there are also various options for the treatment of ASD. It is worth noting that dietary interventions have been shown to have a positive effect in terms of mitigating and preventing some psychiatric disorders, such as epilepsy, Parkinson's disease, and ASD, and they are gradually receiving attention as a safe adjuvant treatment. In this review, based on the current understanding of the pathogenic factors and intervention strategies for ASD, different dietary patterns that can be selected for children with ASD are discussed in depth. Moreover, a review was conducted on the use of dietary factors, such as natural products from food sources, prebiotics, and probiotics, as effective supplements to existing dietary patterns. As increasing evidence shows that maternal risk factors, such as obesity, diabetes, and hypertension, are associated with an increased risk of ASD in offspring, dietary suggestions are also made for pregnant woman with ASD‐related risk factors to counteract the impact of these risk factors. With compensation from food‐derived natural products, prebiotics, and probiotics, suitable dietary patterns can further enhance the effectiveness of dietary interventions for ASD. In addition, dietary recommendations for pregnant woman may reduce the potential impact of obesity, diabetes, and hypertension and may help to prevent the occurrence of ASD to the maximum extent possible.

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

Cited by 14 publications

References 62 publications

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

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

Prenatal Progestin Exposure-Mediated Oxytocin Suppression Contributes to Social Deficits in Mouse Offspring

Dietary nutrients that potentially mitigate autism spectrum disorder and dietary recommendations for children and pregnant women

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