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

Abstract

Many epidemiology studies have shown that maternal polycystic ovary syndrome (PCOS) results in a greater risk of autism spectrum disorders (ASD) development, although the detailed mechanism remains unclear. In this study, we aimed to investigate the potential mechanism and provide a possible treatment for PCOS-mediated ASD through three experiments: Experiment 1: real-time PCR and western blots were employed to measure gene expression in human neurons, and the luciferase reporter assay and chromatin immunoprecipitation (ChIP) was used to map the responsive elements on related gene promoters. Experiment 2: pregnant dams were prenatally exposed to dihydrotestosterone (DHT), androgen receptor (AR) knockdown (shAR) in the amygdala, or berberine (BBR), and the subsequent male offspring were used for autism-like behavior (ALB) assay followed by biomedical analysis, including gene expression, oxidative stress, and mitochondrial function. Experiment 3: the male offspring from prenatal DHT exposed dams were postnatally treated by either shAR or BBR, and the offspring were used for ALB assay followed by biomedical analysis. Our findings showed that DHT treatment suppresses the expression of estrogen receptor β (ERβ) and superoxide dismutase 2 (SOD2) through AR-mediated hypermethylation on the ERβ promoter, and BBR treatment suppresses AR expression through hypermethylation on the AR promoter. Prenatal DHT treatment induces ERβ suppression, oxidative stress and mitochondria dysfunction in the amygdala with subsequent ALB behavior in male offspring, and AR knockdown partly diminishes this effect. Furthermore, both prenatal and postnatal treatment of BBR partly restores prenatal DHT exposure-mediated ALB. In conclusion, DHT suppresses ERβ expression through the AR signaling pathway by hypermethylation on the ERβ promoter, and BBR restores this effect through AR suppression. Prenatal DHT exposure induces ALB in offspring through AR-mediated Abbreviations: ALB, autism-like behavior; AR, androgen receptor; ASD, autism spectrum disorders; BBR, berberine; ChIP, chromatin immunoprecipitation; DHT, dihydrotestosterone; ERβ, estrogen receptor β; O .-2 , superoxide anions; PCOS, polycystic ovary syndrome; ROS, reactive oxygen species; SOD2, superoxide dismutase 2. Frontiers in Cellular Neuroscience | www.frontiersin.org 1 April 2020 | Volume 14 | Article 87 Xiang et al. Berberine Ameliorates Androgen-Induced AutismERβ suppression, and both prenatal and postnatal treatment of BBR ameliorates this effect. We conclude that BBR ameliorates prenatal DHT exposure-induced ALB through AR suppression, this study may help elucidate the potential mechanism and identify a potential treatment through using BBR for PCOS-mediated ASD.

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

“…Many factors, including genetics/epigenetics, sex and environmental factors have been reported to be associated with ASD development ( Rossignol and Frye, 2012 ; Bralten et al, 2018 ). We have previously reported that prenatal hormone exposure ( Zou et al, 2017 ; Li et al, 2018 ; Xie et al, 2018 ; Xiang et al, 2020 ) and maternal diabetes ( Xiang et al, 2018 ; Wang et al, 2019 ) contribute to ASD development, although the detailed mechanism for the etiology of ASD remains largely unknown and various other factors may still need to be investigated.…”

Polycystic Ovary Syndrome and Risk of Five Common Psychiatric Disorders Among European Women: A Two-Sample Mendelian Randomization Study

“…These confounders include high testosterone level, obesity (high body mass index), insulin resistance, and inflammation. Prenatal exposure to dihydrotestosterone can induce anxiety- and autism-like behaviors in rats (Domonkos et al, 2018 ; Xiang et al, 2020 ). Testosterone is elevated in the cerebrospinal fluid of schizophrenia patients (Misiak et al, 2018 ), and the androgen receptor is up-regulated in patients with bipolar disorder (Owens et al, 2019 ).…”

Neurobehavioral alternations of the female offspring born to polycystic ovary syndrome model rats administered by Chinese herbal medicine

“…The literature shows that Chinese medicine has a positive effect on PCOS, which can target reproductive and metabolic defects, regulate abnormal hormone levels, and reduce related mental stress [ 5 – 7 ]. Chinese medicine has been found to improve the autism-like behavior of offspring caused by prenatal DHT exposure by inhibiting androgen receptors [ 31 ] and reduce growth retardation and behavioral changes caused by "fetal damage" in pregnant rats [ 32 ].…”

“…Many studies have found that PCOS affects the neural development of progeny, such as autism spectrum disorder [ 28 ], attention deficit hyperactivity disorder [ 29 ], anxiety and emotional borderline symptoms [ 30 ]. Although TCM has a positive effect on the neural development of offspring [ 31 , 32 ], there are few studies on the effect of TCM, particularly the TCM formula, on the nervous system of PCOS offspring.…”