Effect of prepubertal administration of 17β-estradiol on autism-related behaviors in male mice prenatally exposed to valproic acid

Autism spectrum disorder (ASD) is more frequently diagnosed in males than females, suggesting the existence of biological mechanisms conferring resilience in females. Among known environmental risk factors, prenatal exposure to valproic acid (VPA) is strongly associated with the development of ASD-related behaviors, both in humans and animal models. Our group has shown that VPA-exposed male mice display social deficits and stereotyped behaviors, whereas females do not, indicating potential protective effects mediated by gonadal hormones. Additionally, results from our group indicate that diverse environmental factors and stimuli during the pre-pubertal period can modulate the effect of prenatally administered VPA on adult sociability. Here, we administered 17β-estradiol (E2) between postnatal days (PD) 21 and 35, to evaluate whether gonadal hormones in this sensitive period can reverse ASD-like behavioral alterations in VPA-exposed males. Using a validated murine model and a previously tested oral E2 administration protocol, we assessed adult sociability, repetitive and stereotyped behaviors, anxiety-, and depression-related behaviors. We found that VPA mice not exposed to E2 did not exhibit the expected impairments in sociability. This unexpected result may be attributable to the manipulation inherent to the prepubertal treatment procedure, further supporting the possibility that handling during this critical period can rescue social impairments in VPA-exposed animals.