Etiologies underlying sex differences in Autism Spectrum Disorders

Schaafsma, Sara M.; Pfaff, Donald W.

doi:10.1016/j.yfrne.2014.03.006

Cited by 153 publications

(132 citation statements)

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“…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).…”

mentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

Schaafsma

Gagnidze

Reyes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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104

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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...

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confidence: 99%

mentioning

confidence: 99%

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

Schaafsma

Gagnidze

Reyes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

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“…The high diversity of clinical presentation may also be caused by the influence of interactions between genetic and environmental factors on clinical manifestation or differential environmental exposures experienced by different individuals (19,20). As for the striking sex-bias in autism, early exposure to androgenic hormones and early maternal immune activation are environmental factors, and have been proposed to affect the sex-specific susceptibility to ASD (21). Baron-Cohen's hypothesis that autism results from exposure to high intrauterine testosterone levels is considered in the context of a hormonal hypothesis of sex ratio and the notion of multifactorial inheritance (22).…”

Section: Discussionmentioning

confidence: 99%

22q12.3 microduplication overlapping the LARGE gene as a male-only affected loci responsible for increasing the risk of autism spectrum disorder

2017

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Abstract. The present study describes a three-generation Chinese family with one male who was diagnosed with an autism spectrum disorder (ASD) disease. The male proband presented with features of an autism spectrum disorder. Magnetic resonance imaging demonstrated an abnormal high-intensity zone in the frontal white matter. Whole-genome single nucleotide polymorphism-microarray demonstrated an interstitial 575-kb duplication of chromosome 22p12.3 that involved the LARGE gene among the six family members, which included three healthy female carriers, the affected boy and two male fetuses. Fluorescence in situ hybridization analysis, using special probes, and LARGE gene sequencing were performed, which exhibited a submicroscopic 22q13 duplication that involved the LARGE gene. Combined with a review of the literature, the present findings support the hypothesis that the 22q12.3 microduplication overlapping the LARGE gene may be a male-only affected loci, which is responsible for increasing the ASD risk.

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“…These individuals often have increased autism-like symptoms and are more likely to develop autism (Schaafsma & Pfaff, 2014). In Klinefelter syndrome (47, XXY) males often have language-based learning disabilities (Geschwind, Boone, Miller, & Swerdloff, 2000) and display social withdraw and higher levels of autistic traits (Tartaglia, Cordeiro, Howell, Wilson, & Janusz, 2010;van Rijn & Swaab, 2011).…”

Section: Geneticmentioning

confidence: 99%

“…These sexual dimorphisms can affect how each sex develops a disease, their signs and symptoms of that disease, and their response to therapy (Becker et al, 2005). The effect of endogenous steroids on sexual differentiation of the brain, early life diagnosis of ASD, and higher incidence of ASD in males, has launched investigations aimed at understanding the potential role of steroid hormones in differential susceptibility of the sexes to ASD (Alycia K. Halladay, 2015; M. C. Lai et al, 2013;Schaafsma & Pfaff, 2014;Werling & Geschwind, 2013).…”

Section: Prenatal Steroid Hormonesmentioning

confidence: 99%

Using a mouse model to investigate male bias in autism spectrum disorder incidence.

Gordon¹

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The review (Chapter 1) overviews our current understanding of the sex bias in autism spectrum disorders (ASD), whereby males are 4 times more likely to develop the condition. The longstanding uncertainty surrounding the etiology of autism can be informed by inclusion of both sexes in future research to better understand the mechanism responsible for this sex bias. Both clinical studies and animal models are useful tools to elucidate the underlying cause(s) of sexual dimorphic morphological, physiological, and behavioral differences in the ASD phenotype.Sex differences in social behaviors are common across species, underscoring the importance of assessing baseline sex differences in behavior, especially when sexually dimorphic effects on behavior are expected. I examined pre-pubertal behavior (Chapter 2) in 3 strains of mice (C57BL/6, CFW, and CF1) using a wheel-running assay developed to be relevant to autism-like behaviors. The results indicated no sex differences in wheel running behaviors or social interaction with all mouse strains displaying typical wheel running behavior, i.e. more time running on the wheel when it would turn and increased performance of other activities when it was jammed. iv Studies have found that elevated levels of fetal testosterone (fT) are correlated with later ASD diagnosis. Prenatal valproic acid (VPA) treatment is a common animal model of ASD in rodents, mimicking many of the features of ASD including increased male vulnerability. I used the VPA model (Chapter 3) to evaluate sex-specific responses to prenatal VPA treatment, and to assess if masculinization of females with perinatal testosterone propionate (TP) after prenatal VPA treatment would masculinize their susceptibility for abnormalities in development relevant to ASD. My findings confirmed that VPA exposure results in impaired motor development abilities, and provide novel evidence that the combined effects of VPA, TP, and maleness (triple hit) led to more severe motor development deficiencies in some tasks. I also present evidence that the triple hit resulted in reduced anxiety, but elevated cognitive rigidity and self-grooming compared to control females. The results provide some evidence for increased vulnerability of triple hit males to behavioral deficits relevant to ASD, but more research is needed to better understand this effect.

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Etiologies underlying sex differences in Autism Spectrum Disorders

Cited by 153 publications

References 253 publications

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

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

22q12.3 microduplication overlapping the LARGE gene as a male-only affected loci responsible for increasing the risk of autism spectrum disorder

Using a mouse model to investigate male bias in autism spectrum disorder incidence.

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