Meeting Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is broadly characterized by repetitive behavior, and atypical social behavior and communication. It also commonly presents with anxiety and hyperactivity. ASD occurs 1 in 68 children in the U.S. and is five times more common in males than in females. The reason for this sex bias is unknown. The “extreme male brain theory” hypothesizes that a hyper-androgenic fetal environment aberrantly hyper-masculinizes the developing brain, resulting in an autistic behavioral phenotype. Evidence for this includes correlational findings that sexually dimorphic brain regions that are larger in males are even more enlarged in autistic patients, and increased fetal testosterone concentrations increase risk for ASD. Androgens impact brain development by binding androgen receptor (AR) as testosterone or its metabolite 5α-dihydrotestosterone to elicit AR-dependent responses, or testosterone can be converted to estradiol, which binds to estrogen receptors (ER) to elicit ER-dependent responses. We test whether prenatal overexposure to AR- or ER-specific testosterone metabolites induces ASD-like behavior in the rat, and if effects occur more often in males. We show estradiol consistently induces autistic-like behavior in male but not female rats, similar to the sex bias seen in humans with autism. Our findings provide key insights toward establishing the link between fetal endocrine environment and autism, and support the extreme male brain theory. However, we identify a new paradox possibly related to the non-linear effects caused by endocrine feedback mechanisms that must be considered before we can truly understand ASD in the context of the extreme male brain theory.
