Maternal oxytocin administration modulates gene expression in the brains of perinatal mice

Abstract

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.

Oxytocin-induced birth causes sex-specific behavioral and brain connectivity changes in developing rat offspring

“…Consistent with the effect of prolonged Oxt exposure on the Oxtr, 32 , 33 , 39 we noted a decrease in Oxtr gene and protein expression in the developing brain. Our observations are largely consistent with sex-specific Oxtr downregulation observed at GD18.5 and P9 after perinatal Oxt administration reported by Hsieh et al., 47 but at odds with those of Hirayama et al. 45 This inconsistency can be partly explained by differences in the mode of administration (intravenous vs. subcutaneous), the duration of Oxt exposure, and whether or not Oxt administration resulted in birth.…”

“…Our work adds significantly to the growing body of animal research suggesting that perinatal exposure to Oxt could be consequential for the offspring. 31 , 45 , 46 , 47 , 48 Our model, however, is distinctive because: (i) Oxt was administered to induce and augment labor making it contextually relevant to modern obstetric practice, (ii) the biological effects of Oxt on cyclical uterine contractility were comprehensively studied and validated previously, 38 (iii) measures of maternal-neonatal wellbeing after Oxt exposure were assayed and confirmed, and (iv) the sophisticated social behavioral repertoire of the offspring from a genetically robust, outbred rat strain was fully leveraged to enable thorough characterization of ASD-specific neurobehavioral changes. By simulating management of human labor with Oxt infusion and ensuring maternal-neonatal wellbeing, results from our work are likely to be translationally relevant than currently existing preclinical models.…”

“… 38 Briefly, saline-primed iPrecio pump implantation was performed on gestational day (GD)16, followed by initiation of birth induction with Oxt on GD21. We focused on the direct effects of Oxt motivated by prior reports suggesting a direct effect on Oxtr in the developing brain, 31 , 47 and based on our data that excluded oxidative stress as a potential mechanism. 38 Experiments were performed in multiple cohorts over a 3-year period ( Table S1 ).…”

Maternal oxytocin treatment at birth increases epigenetic age in male offspring

“…Though the above studies are informative, they do not simulate labor induction because in these studies exposure to oxytocin occurred after birth. One study simulating labor induction found that maternal oxytocin treatment in mice resulted in widespread differential gene expression in embryonic brains, with enrichment for genes involved in protein localization within the cell (Hsieh et al., 2022). This same group, however, found no differential gene expression in the brains of mice born to saline‐ and oxytocin‐treated dams at postnatal day 9 (Hsieh et al., 2022).…”