Gestational benzene exposure leads to sexually dimorphic immunological adaptations along the placenta-brain axis

Maternal immune activation (MIA) during pregnancy is highly associated with adverse offspring outcomes, such as neurodevelopmental delays and infectious susceptibility. In the modern era, air pollutants, such as benzene, have become one of the most prominent MIA triggers. The placenta-brain axis provides a unique window into how gestational programing facilitates neuroimmune development and predicts offspring disease risk. However, the mechanisms of how the placenta modulates MIA and how the fetal neuroimmune system responds to placental signals are poorly understood. To study this, pregnant C57BL/6J mice were exposed to benzene (5 ppm) for 24 hours/day from embryonic day (E) 0.5-12.5. E12.5 litters were sacrificed for bulk RNA-seq, qPCR, and flow cytometry. Placenta transcriptomics showed intrinsic sex differences in regulation of neurodevelopment. After benzene, enrichment analysis showed placenta biological pathways were predominately immunological in males and metabolic in females. qPCR confirmed regulation of interferon-stimulated genes, IFI44 and IRF8, was sexually dimorphic in placenta and fetal brain. MHCII+ placenta macrophages were significantly decreased in males versus females in flow cytometry. Our results suggest benzene-induced MIA causes dysregulation of the developing neuroimmune system in a sex-specific manner. Particularly, the interferon pathway may be a key mechanistic target to understanding sex-specific adaptations and postnatal disease susceptibility.