Maternal-fetal immune conflict contributes to male-specific impairments in a mouse model of neurodevelopmental disorders.

Autism spectrum disorder (ASD) arises through a combination of genetic and environmental risk factors. One environmental risk factor is maternal immune activation (MIA), wherein pathogenic infections in pregnant individuals increase the risk of ASD in the offspring, an effect seen most prevalently in males. However, the reasons that males exhibit this heightened sensitivity to MIA, and the mechanisms through which inflammatory signals traverse the maternal-fetal interface to impact the developing male embryo, remain largely mysterious. Here, we harness the poly(I:C) mouse model of neurodevelopmental disorders to uncover changes in fetal health and in the structure and composition of the maternal-fetal interface that occur within twenty-four hours of MIA. We find that 30% of embryos exhibit large-scale teratogenic abnormalities-ranging from decreased fetal weight to a lack of external sensory organ development-while 70% of embryos develop normally. Strikingly, these abnormalities only occur in a subset of males, and never in females. Single-nucleus transcriptomics revealed the robust induction of pro-inflammatory gene programs across the placentas of males exhibiting deficits following MIA, including in immune, vascular, and decidual cells. These transcriptomic changes were particularly prominent in spongiotrophoblasts, fetally derived cells that in part comprise the border between the maternal and fetal compartments of the placenta. While upregulating inflammatory pathways following MIA, spongiotrophoblasts simultaneously downregulate extracellular matrix and hormone biosynthesis pathways, concurrent with a breakdown in the structural integrity of the placenta and the accumulation of immune cells and cytokines in the embryo's amniotic fluid. One of these cytokines, IL-6, is necessary for the emergence of MIA-evoked developmental abnormalities. Our data suggest that MIA induces a rapid transition from an immunosuppressive toward a pro-inflammatory maternal-fetal interface in a subset of male embryos, leading to acute developmental deficits that are restricted to this vulnerable cohort. These data suggest that male embryos may harbor unique proteins capable of eliciting an inflammatory response at the maternal-fetal interface that, when coupled with a loss of immunosuppression due to maternal infection, derails embryonic development selectively in males.