Sex-specific gene–environment interactions underlying ASD-like behaviors

Abstract

The male bias in the incidence of autism spectrum disorders (ASDs) is one of the most notable characteristics of this group of neurodevelopmental disorders. The etiology of this sex bias is far from known, but pivotal for understanding the etiology of ASDs in general. Here we investigate whether a "three-hit" (genetic load × environmental factor × sex) theory of autism may help explain the male predominance. We found that LPS-induced maternal immune activation caused male-specific deficits in certain social responses in the contactin-associated protein-like 2 (Cntnap2) mouse model for ASD. The three "hits" had cumulative effects on ultrasonic vocalizations at postnatal day 3. Hits synergistically affected social recognition in adulthood: only mice exposed to all three hits showed deficits in this aspect of social behavior. In brains of the same mice we found a significant three-way interaction on corticotropin-releasing hormone receptor-1 (Crhr1) gene expression, in the left hippocampus specifically, which co-occurred with epigenetic alterations in histone H3 N-terminal lysine 4 trimethylation (H3K4me3) over the Crhr1 promoter. Although it is highly likely that multiple (synergistic) interactions may be at work, change in the expression of genes in the hypothalamic-pituitary-adrenal/ stress system (e.g., Crhr1) is one of them. The data provide proof-of-principle that genetic and environmental factors interact to cause sex-specific effects that may help explain the male bias in ASD incidence.maternal immune activation | prenatal stress | sex differences | Cntnap2 | autism A utism spectrum disorders (ASDs) comprise a heterogeneous group of neurodevelopmental disorders. The core symptoms of ASD are deficits in social communication and social interactions (Diagnostic and Statistical Manual of Mental Disorders V) and one of the most noticeable biological constants in this group of disorders is the sex difference: ∼80% of the children diagnosed with an ASD are boys (1). Many genes have been implicated in the etiologies underlying ASD in humans and ASD-like behavior in animal models. Some of these genes are located on the sex chromosomes and many of these genes may be able to affect other sex-chromosomal genes or may otherwise indirectly lead to sex-specific effects (reviewed in ref.2). However, it seems unlikely that these genes can account for the full sex bias in incidence and it is becoming increasingly clear that environmental factors play a very important role as well (3), and that these factors can interact with one another (2, 4). Moreover, prenatal testosterone (an indirect genetic factor) affects human behavior (5, 6) and may increase the risk to develop an ASD (7).Although today it is commonly proposed that many neurodevelopmental disorders result from interactions between "nature" and "nurture," studies investigating the gene-environment interaction in the development of ASD are scarce.In this study we tested whether an interaction between an ASD-related genetic mutation and an environmental factor may be a...

Genetic evidence of gender difference in autism spectrum disorder supports the female-protective effect

“…This result further implies that DNMs can only explain a small part of the gender difference in ASD, and the detailed mechanisms are clearly more complex. Therefore, future work investigating the gender difference in ASD is needed to integrate distinct aspects that are typically considered in isolation, such as inherited variants 71 , epigenetic factors 72 , structural variants 73 , environmental factors 74,75 , and mRNA levels 2 . Moreover, we identified novel candidate genes that might reveal specific functions related to the gender difference in ASD, which can offer guidance for further research to provide new insight into clinical diagnoses and treatments.…”

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

“…The animal behavior test of offspring was carried out at 7-8 weeks of age. ALB was evaluated using ultrasonic vocalizations (Silverman et al, 2010;Schaafsma et al, 2017), social recognition tests (Moy et al, 2004;Schaafsma et al, 2017) and a three-chambered social test (Moy et al, 2004;Silverman et al, 2010;Schaafsma et al, 2017;Choi et al, 2019;Wang et al, 2019).…”

Immunity and ultrasonic vocalization in rodents

“…Finally, an interesting study investigated possible interactions between three of the main variables that have been involved in ASD in humans: MIA, genetic load, and sex differences, in what the authors call a “three‐hit theory of autism.” It has been reported that the large majority of children diagnosed with ASD are boys, and that certain genetic mutations, such as homozygous mutations in contactin‐associated protein‐like 2 (CNTNAP2), lead to an ASD‐like disorder in about 75% of the cases . Thus, Schaafsma and colleagues used heterozygous Cntnap2 matings to evaluate isolation‐induced 60‐kHz USVs in 3‐day‐old, male and female knockout (KO) and wild‐type offspring.…”