Lactational transfer of synthetic oxytocin suppresses neurodevelopmental risk gene networks in male rat prefrontal cortex

Autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs) affect males at a significantly higher rate than females, yet the environmental factors contributing to this sex-differentiated vulnerability remain largely unknown. Current understanding points to complex genetic and environmental interactions. Synthetic oxytocin (OT) is a universally administered obstetric medication for postpartum hemorrhage (PPH) prophylaxis, making its potential impact on offspring development a critical area of investigation given oxytocin's known role in social behavior and neurodevelopment.

Researchers utilized a clinically translatable postpartum rat model to investigate the effects of maternally administered synthetic oxytocin. They administered synthetic oxytocin (PPH-OT) for postpartum hemorrhage prophylaxis to dams. Lactational transfer was confirmed using stable isotope-labeled OT and LC-MS/MS. Maternal behavior and neonatal cortical OT receptor expression were monitored. Offspring underwent behavioral assessments, including ultrasonic vocalizations during dyadic interaction and social approach tests. Sex-stratified RNA-sequencing was performed on the medial prefrontal cortex (mPFC) and hypothalamus to identify differentially expressed genes.

Lactational transfer of synthetic oxytocin was confirmed, with no observed alterations in maternal behavior or neonatal cortical OT receptor expression. In offspring, PPH-OT exposure altered ultrasonic vocalizations during dyadic interaction and caused a male-specific reduction in social approach, while other behavioral domains remained unaffected. RNA-sequencing of the mPFC revealed significant transcriptional dimorphism: males showed 1,732 differentially expressed genes (DEGs) compared to 693 in females. A sex-by-treatment interaction contrast identified 1,229 formally sex-differentiated genes. Importantly, male mPFC downregulated genes were significantly enriched for high-confidence NDD risk genes across three independent databases:

SFARI score-1 (highest confidence autism genes; OR = 4.56, p = 0.015), DBD autism (OR = 10.34, p = 7.3×10⁻¹²), and SysNDD autosomal dominant (OR = 9.78, p = 8.4×10⁻⁷). This enrichment included core regulators of cortical circuit assembly such as Grin2a, Grin2b, Reln, Tbr1, Mef2c, and Tcf4, a pattern largely restricted to males. Hypothalamic transcriptional changes were pronounced but lacked enrichment for NDD risk genes, establishing mPFC specificity.