Prenatal stress and immune activation show opposing fetal brain transcriptional effects in mice

A study in Molecular Psychiatry examined whether prenatal stress and maternal immune activation influence fetal development through shared placental pathways. Researchers combined mouse placental single-cell RNA sequencing, matched placental and fetal brain transcriptomics, and maternal cytokine profiling with human placental RNA sequencing. Pregnant mice underwent two hours of restraint daily for seven days; immune challenge used poly(I:C) on gestational day 16.5. Sample sizes were not provided in the supplied text.

Chronic stress suppressed interferon signaling in placental immune cells and reduced oxidative phosphorylation pathway expression in trophoblasts. Stressed dams also showed a blunted type I interferon response to poly(I:C). Fetal brain analyses identified overlapping DNA repair, synaptic, and translational networks regulated in opposite directions: stress favored transcriptional signatures of premature maturation, whereas immune activation favored replication stress. In human placentas, higher perceived stress was associated with chromatin-regulatory, RNA-metabolic, and extracellular-matrix modules resembling the mouse stress signature.

The findings suggest that these prenatal exposures may perturb shared developmental pathways through distinct molecular trajectories. However, transcriptional signatures do not establish later psychiatric outcomes, and opposing molecular effects should not be interpreted as clinical protection from immune activation. The human findings are associative, while restraint and poly(I:C) are experimental models. Mouse sample sizes were not predetermined statistically, and each experiment used one independent cohort. The results do not establish changes to prenatal clinical management.