Sex Bias in Maternal Immune Activation-Induced Neurodevelopmental Disorder Begins at the Placenta

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 ASD-related phenotypes in offspring, consisting of deficits in communication and socialization, as well as repetitive behaviors. In this model of maternal immune activation (MIA), elevated production of maternal serum cytokines is known to promote alterations in fetal neurodevelopment. Although male and female littermates are exposed to the same maternal inflammation, we show that behavioral deficits can be elicited preferentially in the male offspring, mirroring the sex bias observed in human ASD. Because the placenta is partially derived from fetal cells and is the first site of fetal exposure to hematogenous maternal inflammation, we hypothesized that sex-specific reactions to MIA may originate at the placenta and that characterization of these sex differences may offer new insights into the orgins of neurodevelopmental disorders. To characterize responses to MIA at the maternal-fetal interface, we conducted bulk RNA sequencing of the placenta from polyI:C- and saline-treated embryos at several time points post-injection. We identified male-biased elevation in the expression of inflammatory signatures involving neutrophils, innate immune signaling, and antigen presentation. Placental transcriptomics analysis also identified male-specific downregulation of cholesterol and fatty acid synthesis as well as a gene signature suggesting failing placental health. Interestingly, we found that MIA induced the differential expression of a large percentage of high-risk autism genes at the placenta. These findings shed new light on how sex and maternal inflammation interface to shape placental responses and may help to reveal new molecular players underpinning sex differences in neurodevelopmental disorders.