ReviewEtiologies underlying sex differences in Autism Spectrum Disorders

- We review genetic, hormonal, and environmental mechanisms underling ASD's male bias.
- The genome influences the susceptibility to ASD.
- ASD studies should include both genetic and environmental factors.
- MIA is likely to be an important environmental factor in ASD's male bias.
- Environmental stressors are possibly more detrimental in males due to high prenatal T.

The male predominance of Autism Spectrum Disorders (ASD) is one of the best-known, and at the same time, one of the least understood characteristics of these disorders. In this paper we review genetic, epigenetic, hormonal, and environmental mechanisms underlying this male preponderance. Sex-specific effects of Y-linked genes (including SRY expression leading to testicular development), balanced and skewed X-inactivation, genes that escape X-inactivation, parent-of-origin allelic imprinting, and the hypothetical heterochromatin sink are reviewed. These mechanisms likely contribute to etiology, instead of being simply causative to ASD. Environments, both internal and external, also play important roles in ASD's etiology. Early exposure to androgenic hormones and early maternal immune activation comprise environmental factors affecting sex-specific susceptibility to ASD. The gene-environment interactions underlying ASD, suggested here, implicate early prenatal stress as being especially detrimental to boys with a vulnerable genotype.