Animal Model of Autism Induced by Valproic Acid Combined with Maternal Deprivation: Sex-Specific Effects on Inflammation and Oxidative Stress.

ABSTRACT

Autism spectrum disorder (ASD) etiology probably involves a complex interplay of both genetic and environmental risk factors, which includes pre- and perinatal exposure to environmental stressors. Thus, this study evaluated the effects of prenatal exposure to valproic acid (VPA) combined with maternal deprivation (MD) on behavior, oxidative stress parameters, and inflammatory state at a central and systemic level in male and female rats. Pregnant Wistar rats were exposed to VPA during gestation, and the offspring were submitted to MD. Offspring were tested for locomotor and social behavior; rats were euthanized, where the cerebellum, posterior cortex, prefrontal cortex, and peripheric blood were collected for oxidative stress and inflammatory analysis. It was observed that young rats (25-30 days old) exposed only to VPA presented a lower social approach when compared to the control group. VPA + MD rats did not present the same deficit. Female rats exposed to VPA + MD presented oxidative stress in all brain areas analyzed. Male rats in the VPA and VPA + MD groups presented oxidative stress only in the cerebellum. Regarding inflammatory parameters, male rats exposed only to MD exhibited an increase in pro-inflammatory cytokines in the blood and in the cortex total. The same was observed in females exposed only to VPA. Animals exposed to VPA + MD showed no alterations in the cytokines analyzed. In summary, gestational (VPA) and perinatal (MD) insults can affect molecular mechanisms such as oxidative stress and inflammation differently depending on the sex and brain area analyzed. Combined exposition to VPA and MD triggers oxidative stress especially in female brains without evoking an inflammatory response.