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

Abstract

Autism spectrum disorder (ASD) arises from genetic and environmental risk factors. One environmental factor, maternal immune activation (MIA)-in which pathogenic infection during pregnancy increases ASD risk in offspring-disproportionately affects males. However, the basis for this male-specific vulnerability and the mechanisms by which inflammatory signals cross the maternal-fetal interface to affect the male embryo remain largely unknown. Using the poly(I:C) mouse model of neurodevelopmental disorders, we characterize fetal, placental, and amniotic changes occurring within 24 hours of MIA. We find that 30% of embryos exhibit large-scale teratogenic abnormalities-ranging from decreased fetal weight to altered sensory organ development-while 70% develop normally. These abnormalities occur exclusively in a subset of males, never in females. Single-nucleus transcriptomics revealed robust induction of proinflammatory gene programs in the placentas of affected males across a broad range of cell types, and most prominently in spongiotrophoblasts-fetally derived cells that partly form the maternal-fetal border. These cells simultaneously down-regulate extracellular matrix and hormone biosynthesis pathways, coinciding with a breakdown in placental structural integrity and the accumulation of immune cells and cytokines in the amniotic fluid. One such cytokine, interleukin-6, is required for MIA-evoked developmental abnormalities to emerge. Our data indicate that MIA drives a rapid shift from an immunosuppressive to a proinflammatory maternal-fetal interface in a vulnerable subset of male embryos, producing acute, sex-restricted developmental deficits. We propose that male embryos may express unique proteins capable of triggering this inflammatory response, which-combined with MIA-induced loss of maternal immunosuppression-selectively derails male embryonic development.