Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation

Abstract

BackgroundRecent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior.MethodsExperiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERβ knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing.ResultsEight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERβ expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERβ activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERβ and its target genes by demethylation of DNA and histone on the ERβ promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior.ConclusionsWe conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application.Electronic supplementary materialThe online version of this article (10.1186/s13229-018-0225-5) contains supplementary material, which is available to authorized users.

Abnormal Cerebellar Development Is Involved in Dystonia-Like Behaviors and Motor Dysfunction of Autistic BTBR Mice

“…All data collection and analyses were performed randomly by experimenters blinded to the genotypes. The sample sizes are similar to those of previous publications (Huang et al, 2016(Huang et al, , 2019Xie et al, 2018) and listed in the figure legends. Data are represented as the means ± standard deviation (SD), and statistical analysis included the Chi squared test, non-parametric Mann-Whitney U test (for data that failed normality test), unpaired t-test, two-way ANOVA, and two-way repeated-measures ANOVA with post hoc Bonferroni multiple comparisons test were performed using SPSS 19.0 software (SPSS Inc., United States).…”

Berberine Ameliorates Prenatal Dihydrotestosterone Exposure-Induced Autism-Like Behavior by Suppression of Androgen Receptor

“…We have previously found that prenatal progestin exposure suppresses ERβ expression in the amygdala instead of in other brain areas and subsequently contributes to ASD development in offspring, with male offspring being more susceptible than females. Additionally, ERβ overexpression in the amygdala significantly restores prenatal progestin exposure-induced ALB Xie et al, 2018), and maternal diabetesinduced autistic offspring show significant SOD2 suppression in the amygdala as well (Wang et al, 2019). Our results indicate that gene expression in the amygdala plays an important role in ASD development.…”

“…The DHT treatment was used to mimic PCOS conditions during the in vivo rat experiments (Mannerås et al, 2007;Noroozzadeh et al, 2017;Paixão et al, 2017). Our results show that prenatal DHT exposure induces ALB in offspring with suppressed expression of ERβ and SOD2 in the amygdala Li et al, 2018;Xie et al, 2018). AR knockdown partly diminishes this effect, indicating that DHT induces ALB through the AR signaling pathway.…”

“…Both prenatal and postnatal treatment of BBR protects from prenatal DHT exposure-induced ALB in offspring, indicating that BBR may be a potential candidate for the treatment of PCOS-induced ASD. We have previously found that prenatal progestin exposure and maternal diabetes contribute to ASD development through ERβ suppression, and ERβ overexpression in the brain restores this effect, indicating that ERβ suppression may contribute to ASD development Li et al, 2018;Xie et al, 2018;Wang et al, 2019). On the other hand, many potential prenatal factors may suppress ERβ expression, and DHT is only one of them.…”

“…It has been reported that prenatal androgen levels are associated with ASD, and fetal testosterone predicts sexually-differentiated childhood behavior (Tordjman et al, 1997;Auyeung et al, 2009;Ruta et al, 2011). Furthermore, our recent studies have shown that suppression of estrogen receptor β (ERβ) and its target gene is associated with ASD development, while the expression of estrogen receptor α (ERα) has little correlation Li et al, 2018;Xie et al, 2018), leading us to suppose that prenatal androgen exposure may induce ASD development through ERβ suppression.…”