Male Gender Bias in Autism and Pediatric Autoimmunity

Becker, Kevin G.

doi:10.1002/aur.1227

Cited by 17 publications

(12 citation statements)

References 102 publications

(117 reference statements)

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“…These results highlight the heterogeneity of symptoms found in ASD and indicate that males are differentially vulnerable to various environmental insults occurring during pregnancy. The basis for this male bias is unknown with theories including the “extreme male brain”, hormonal differences, and genetic influences (for a review see 60 .…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent behavioral deficits and neuropathology in a maternal immune activation model of autism

et al. 2019

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Infections during gestation and the consequent maternal immune activation (MIA) increase the risk of developing neuropsychiatric disorders in infants and throughout life, including autism spectrum disorders (ASD). ASD is a neurodevelopmental disorder that affects three times more males than females and is mainly characterized by deficits in social communication and restricted interests. Consistent findings also indicate that ASD patients suffer from movement disorders, although these symptoms are not yet considered as diagnosis criteria. Here we used the double-stranded RNA analog polyinosinic:polycytidylic acid (poly I:C) MIA animal model of ASD in mice and explored its effects in males and females on social and motor behavior. We then investigated brain areas implicated in controlling and coordinating movements, namely the nigro-striatal pathway, motor cortex and cerebellum. We show that male mice are more affected by this treatment than females as they show reduced social interactions as well as motor development and coordination deficits. Reduced numbers of Purkinje cells in the cerebellum was found more widespread and within distinct lobules in males than in females. Moreover, a reduced number of neurons was found in the motor cortex of males only. These results suggest that females are better protected against developmental insults leading to ASD symptoms in mice. They also point to brain areas that may be targeted to better manage social and motor consequences of ASD.

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Section: Discussionmentioning

confidence: 99%

Sex-dependent behavioral deficits and neuropathology in a maternal immune activation model of autism

et al. 2019

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“…Also, it has been reported that the sex hormone regulates the expression of FOXP1 (Takayama et al, 2014;Fröhlich et al, 2017), SHANK (Berkel et al, 2018), and RORA (Sarachana et al, 2011), which is essential for ASD, further confirming the potential role of the AR signaling pathway on ASD development. This can partly explain why the androgen can be related to male/female bias to ASD (Becker, 2012;Schaafsma and Pfaff, 2014;Mogi et al, 2015). This is the first time that the potential mechanism for PCOS-mediated ASD development has been discovered through AR-mediated ERβ suppression, providing a potential target for PCOS-mediated ASD through AR suppression Lee et al, 2017;Cherskov et al, 2018;Shay et al, 2018).…”

Section: Prenatal Dht Exposure-mediated Autism-like Behaviormentioning

confidence: 92%

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

Xiang

Wei

et al. 2020

Front. Cell. Neurosci.

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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.

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“…Autoimmune diseases, such as systemic lupus erythematosus, Sjogren's syndrome, and rheumatoid arthritis, occur more frequently in women than in men [ 2 ]. However, certain types of autoimmune diseases, such as Goodpasture syndrome in which antibodies attack the basement membrane in lung and kidney cells, occur more commonly in men than in women [ 3 ]. In addition, there is growing evidence that sex hormones may be attributed to the sex-related differences in humoral and cellular responses as well as in infections and vaccinations [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Male-specific association of the FCGR2A His167Arg polymorphism with Kawasaki disease

et al. 2017

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Kawasaki disease (KD) is an acute systemic vasculitis that can potentially cause coronary artery aneurysms in some children. KD occurs approximately 1.5 times more frequently in males than in females. To identify sex-specific genetic variants that are involved in KD pathogenesis in children, we performed a sex-stratified genome-wide association study (GWAS), using the Illumina HumanOmni1-Quad BeadChip data (249 cases and 1,000 controls) and a replication study for the 34 sex-specific candidate SNPs in an independent sample set (671 cases and 3,553 controls). Male-specific associations were detected in three common variants: rs1801274 in FCGR2A [odds ratio (OR) = 1.40, P = 9.31 × 10−5], rs12516652 in SEMA6A (OR = 1.87, P = 3.12 × 10−4), and rs5771303 near IL17REL (OR = 1.57, P = 2.53 × 10−5). The male-specific association of FCGR2A, but not SEMA6A and IL17REL, was also replicated in a Japanese population (OR = 1.74, P = 1.04 × 10−4 in males vs. OR = 1.22, P = 0.191 in females). In a meta-analysis with 1,461 cases and 5,302 controls, a very strong association of KD with the nonsynonymous SNP rs1801274 (p.His167Arg, previously assigned as p.His131Arg) in FCGR2A was confirmed in males (OR = 1.48, P = 1.43 × 10−7), but not in the females (OR = 1.17, P = 0.055). The present study demonstrates that p.His167Arg, a KD-associated FCGR2A variant, acts as a susceptibility gene in males only. Overall, the gender differences associated with FCGR2A in KD provide a new insight into KD susceptibility.

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Male Gender Bias in Autism and Pediatric Autoimmunity

Cited by 17 publications

References 102 publications

Sex-dependent behavioral deficits and neuropathology in a maternal immune activation model of autism

Sex-dependent behavioral deficits and neuropathology in a maternal immune activation model of autism

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

Male-specific association of the FCGR2A His167Arg polymorphism with Kawasaki disease

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