Objectives Oxytocin (OXT) is widely used to facilitate labor. However, little is known about the effects of perinatal OXT exposure on the developing brain. We investigated the effects of maternal OXT administration on gene expression in perinatal mouse brains. Methods Pregnant C57BL/6 mice were treated with saline or OXT at term (n=6–7/group). Dams and pups were euthanized on gestational day (GD) 18.5 after delivery by C-section. Another set of dams was treated with saline or OXT (n=6–7/group) and allowed to deliver naturally; pups were euthanized on postnatal day 9 (PND9). Perinatal/neonatal brain gene expression was determined using Illumina BeadChip Arrays and real time quantitative PCR. Differential gene expression analyses were performed. In addition, the effect of OXT on neurite outgrowth was assessed using PC12 cells. Results Distinct and sex-specific gene expression patterns were identified in offspring brains following maternal OXT administration at term. The microarray data showed that female GD18.5 brains exhibited more differential changes in gene expression compared to male GD18.5 brains. Specifically, Cnot4 and Frmd4a were significantly reduced by OXT exposure in male and female GD18.5 brains, whereas Mtap1b, Srsf11, and Syn2 were significantly reduced only in female GD18.5 brains. No significant microarray differences were observed in PND9 brains. By quantitative PCR, OXT exposure reduced Oxtr expression in female and male brains on GD18.5 and PND9, respectively. PC12 cell differentiation assays revealed that OXT induced neurite outgrowth. Conclusions Prenatal OXT exposure induces sex-specific differential regulation of several nervous system-related genes and pathways with important neural functions in perinatal brains.

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OBJECTIVE: The hormone/neuropeptide oxytocin (OXT) facilitates childbirth, and promotes maternal social bonding and lactation. However, little is known about the effects of prenatal OXT exposure on the developing brain. Given the behavioral effects of synthetic OXT, we investigated the effect of maternal OXT administration on gene expression in peri-and neonatal mouse brains. STUDY DESIGN: Pregnant C57BL/6 mice (10 weeks old, gestational day 18) were given saline or OXT (1U/mouse) subcutaneously every 30 minutes for 2 hours. 4 hours later, dams (7 saline, 7 oxytocin) and pups (delivered by C-section) were euthanized. Other dams (6 saline, 7 oxytocin) delivered naturally and pups were euthanized on postnatal day 9 (PND9). DNA and RNA were isolated from pup tails and brains, respectively. Gender was determined by PCR. Brain RNA (12F, 12M, with RIN >9.3) was converted to ds-cDNA and hybridized to MouseWG6v2.0 BeadChip (Illumina), scanned (via Illumina HiScan) and analyzed using Genome Studio v2011.1 (Illumina). Differential expression analysis was done with the moderated t-test in the R limma package. Findings were confirmed by RT-qPCR. Pathway analysis was performed with the R gage package and the mm_GO, mm_metabolic, and mm_pathway annotated gene sets from the R gskb package. GSEA was performed on the clustered pathways. RESULTS: We identified distinct gene expression patterns in perinatal mouse brains following in utero OXT exposure ( Fig 1A). Female perinatal brains exposed to OXT showed significantly more differential expression patterns than male brains, with changes in several genes implicated in neurodevelopment and neuropsychiatric disorders. Although OXT-exposed PND9 brains showed no significant differences vs saline-brains, when both timepoints were analyzed together >1700 genes were differentially expressed ( Fig 1B), including Sfrs11 (pre-mRNA processing), Jak1 (promotes astrogliosis), and Tardbp (implicated in dementia). Sexspecific differences were found in gene expression and in pathways, including DNA repair, DNA replication, myelin sheath, and INCEP. CONCLUSION: Prenatal OXT exposure leads to differential regulation of several nervous system-related genes and pathways in peri-and postnatal brains. Ongoing studies are linking gene expression patterns to neurodevelopment, social behaviors, and disease states.

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