The Role of Sex-differentiated Variations in Stress Hormones, Antioxidants, and Neuroimmune Responses in Relation to Social Interaction Impairment in a Rodent Model of Autism

Males are more likely to develop autism as a neurodevelopmental disorder than females, but the mechanisms underlying male susceptibility are not fully understood. In this paper, we used a well-characterized propionic acid (PPA) rodent model of autism to study sex differences in stress hormones, antioxidants' status, and the neuroimmune response that may contribute to the preponderance of autism in males. Sprague Dawley rats of both sexes were divided into a saline-treated group as controls and PPA-treated groups, receiving 250 mg/kg of PPA per day for three days. Animals' social behavior was examined using the three-chamber social test. Hormones (ACTH, corticosterone, melatonin, and oxytocin), oxidative stress biomarkers (glutathione, glutathione-S-transferase, and ascorbic acid), and cytokines (IL-6, IL-1α, IL-10, and IFNγ) were measured in the brain tissue of all the animals. The results showed a sex dimorphic social response to PPA treatment, where males were more susceptible to the PPA treatment and exhibited a significant reduction in social behavior with no effects observed in females. Also, sex differences were observed in the levels of hormones, antioxidants, and cytokines. Female rats showed significantly higher corticosterone and lower oxytocin, antioxidants, and cytokine levels than males. The PPA treatment later modulated these baseline differences. Our study indicates that the behavioral manifestation of autism in PPA-treated males and not females could be linked to neural biochemical differences between the sexes at baseline, which might play a protective role in females. Our results can contribute to early intervention strategies and treatments used to control autism, an increasingly prevalent disorder.