Sex Bias In Maternal Immune Activation-Induced Neurodevelopmental Disease Begins At The Maternal-Fetal Interface

Abstract Systemic maternal inflammation during pregnancy is increasingly thought to be a risk factor for development of autism spectrum disorder (ASD), which is diagnosed at a rate 4-fold higher in males than in females. Administration of the viral mimic polyI:C to pregnant mice at mid-gestation leads to an ASD-like phenotype in the offspring, consisting of deficits in socialization and communication as well as repetitive behaviors. In this model of maternal immune activation (MIA), elevated production of maternal serum cytokines, specifically IL-6 and IL-17, contributes to alterations in fetal neurodevelopment. Although male and female littermates are exposed to the same maternal inflammation, we show that behavioral deficits manifest only in the male offspring, mirroring the sex bias observed in human ASD. Because the placenta is derived from fetal cells and is the first site of fetal exposure to hematogenous maternal inflammation, we hypothesized that sex-specific reactions to MIA that have deleterious impacts on fetal neurodevelopment originate there. Our preliminary findings show that MIA leads to sexually dimorphic alterations in placental pathology. To further characterize responses to MIA at the maternal-fetal interface over the course of gestation, we conducted bulk RNA-sequencing of the placenta/decidua from polyI:C- and saline-treated embryos at several time points post-injection. Sex of the embryos was determined by PCR genotyping for comparison of male and female placental transcriptomes. We find previously undescribed signatures related to myeloid cells in placentas from MIA males, as well as sex-based differences under homeostasis. This data set will shed light on the immune mechanisms that impact fetal brain health.