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Sex-specific gene–environment interactions underlying ASD-like behaviors
Contributed by Donald W. Pfaff, December 2, 2016 (sent for review August 20, 2016; reviewed by S. Marc Breedlove, Elena Choleris, Curt A. Sandman, and Larry J. Young)

Significance
Autism spectrum disorders (ASDs) comprise a heterogeneous set of neurodevelopmental disorders. Although hundreds of genes have now been identified to be associated with ASD, genetic factors cannot fully explain ASD’s incidence. The early environment is now known to be pivotal in ASD’s etiology too. In the face of this complexity, one aspect of ASD has stood out constantly as a causative biological factor: the sex difference. Approximately 80% of the children diagnosed are boys. This current set of experiments tests, in an animal model, the “three-hit theory of autism,” which states that interactions among (i) being male, (ii) suffering early (especially, prenatal/immunological) stress, and (iii) having certain genetic mutations will predispose to an ASD diagnosis.
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.
Footnotes
↵1Present address: Brain Center Rudolf Magnus, Department of Translational Neuroscience, Universitair Medisch Centrum Utrecht, 3584 CX Utrecht, The Netherlands.
- ↵2To whom correspondence may be addressed. Email: S.M.Schaafsma{at}umcutrecht.nl or pfaff{at}rockefeller.edu.
Author contributions: S.M.S., K.G., and D.W.P. designed research; S.M.S., A.R., N.N., K.M., and K.F. performed research; S.M.S. analyzed data; and S.M.S. and D.W.P. wrote the paper.
Reviewers: S.M.B., Michigan State University; E.C., University of Guelph; C.A.S., University of California, Irvine; and L.J.Y., Yerkes National Primate Center.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1619312114/-/DCSupplemental.
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