Common oxytocin polymorphisms interact with maternal verbal aggression in early infancy impacting blood pressure at age 5-6: The ABCD study
Laetitia J. C. A. SmariusThea G. A. StriederTheo DoreleijersTanja G. M. VrijkotteMohammad Hadi ZafarmandSusanne R. de Rooij
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Early life stress has been shown to contribute to alterations in biobehavioral regulation. Genetic make-up, especially related to social sensitivity, might affect the child’s vulnerability to these alterations. This study examined whether maternal verbally aggressive behavior in early infancy interacts with oxytocin polymorphisms in changing resting cardiovascular outcomes at age 5–6. In the Amsterdam-Born-Children-and-their-Development-(ABCD)-study, a large prospective, observational, population-based birth cohort, maternal verbally aggressive behavior was assessed in the 13th postnatal week (range 11–25 weeks, SD 2 weeks) by a questionnaire (maternal self-report). Indicators of resting cardiac autonomic nervous system activity (sympathetic drive by pre-ejection period, parasympathetic drive by respiratory sinus arrhythmia), heart rate, and blood pressure were measured at age 5–6 years. Data on oxytocin receptor gene polymorphisms rs53576, rs2268498 and oxytocin polymorphisms rs2740210, rs4813627, were collected (N = 966 included). If the child was carrier of the rs53576 GG variant, exposure to maternal verbally aggressive behavior (10.6%) was associated with increased systolic blood pressure at age 5–6 (B = 4.9 mmHg,95% CI[2.2;7.7]). If the child was carrier of the rs2268498 TT/TC variant, exposure to maternal verbally aggressive behavior was associated with increased systolic blood pressure at age 5–6 (B = 3.0 mmHg,95%CI[1.0:5.0]). No significant interactions of maternal verbally aggressive behavior with oxytocin gene polymorphisms on heart rate or cardiac autonomic nervous system activity were found. In conclusion, oxytocin receptor gene polymorphisms may partly determine a child’s vulnerability to develop increased systolic blood pressure after being exposed to maternal verbally aggressive behavior in early infancy.Keywords:
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Oxytocin receptor
Oxytocin and the oxytocin receptor have two important roles in labour. Evidence in all mammalian species suggests that neurohypophysical oxytocin plays a role in the expulsive phase and, although there are less supporting data, a role for oxytocin in the initiation of labour is likely. The initiation of labour may be mediated in women and rhesus monkeys by paracrine rather than endocrine mechanisms. Although initial characterisation of the oxytocin knockout mouse suggested that oxytocin is not important in this species, subsequent investigations have demonstrated that oxytocin is important for the precise timing of the onset of labour. Studies in knockout mice also confirm important interrelationships between oxytocin and prostaglandins. Oxytocin stimulates prostaglandin release in many species, mainly in the decidua/uterine epithelium. The effects of oxytocin are mediated by tissue-specific oxytocin receptor expression, which leads directly to contraction in the myometrium and prostaglandin formation in the decidua. There is a dramatic increase in oxytocin receptor expression in these tissues in late pregnancy and pharmacological inhibition delays delivery, which suggests that, in contrast to oxytocin, the oxytocin receptor is essential for normal labour.
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Oxytocin is used widely for the induction and augmentation of labour, but there is little information about the dynamics of oxytocin receptors in human myometrium during parturition, and the possible effect of oxytocin infusion. This information is important because G protein-coupled receptors, such as the oxytocin receptor, undergo desensitization after prolonged or repeated stimulation. The concentration of myometrial oxytocin receptors and the steady state of its mRNA were measured in patients undergoing Caesarean sections before or during spontaneous or induced labour. The concentration of receptors before labour was 477 (175-641) fmol mg(-1) protein (median, quartile range), and decreased to 140 (72-206; P < 0.05) and 118 (69-75; P < 0.01) fmol mg(-1) protein during prolonged oxytocin-augmented and oxytocin-induced labour, respectively. The corresponding oxytocin receptor mRNA concentrations decreased by 60- and 300-fold, respectively. The decrease in receptor binding and mRNA in women receiving oxytocin infusion indicates that homologous receptor desensitization occurs in vivo.
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Abstract Background Clinical efficacy of chronic intranasal administration of oxytocin is increasingly explored in autism spectrum disorder (ASD), but to date, little is known regarding its biological effects and in particular how chronic administration regimes impact endogenous oxytocinergic function. Methods To fill this gap, this double-blind, randomized, placebo-controlled study explored chronic oxytocin administration effects on endogenous salivary oxytocin levels and oxytocin receptor gene ( OXTR ) epigenetics (DNA methylation) in 8-to-12-year-old children with ASD (n = 79, 16 females). Biological sampling was performed at baseline (pre-treatment), immediately (24 hours) after the four-week oxytocin administration period (12 IU, twice daily) and at a follow-up session, four weeks after the last nasal spray administration. Results Compared to placebo, children receiving the oxytocin nasal spray displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at the four-week follow up session. Regarding epigenetics, oxytocin-induced reductions in OXTR methylation were observed, reflecting a facilitation of oxytocin receptor expression in the oxytocin, compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reduced OXTR DNA methylation and improved feelings of secure attachment. Conclusion Four weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with ASD, as evidenced by increased salivary oxytocin levels and reduced OXTR DNA methylation (indicating increased receptor expression).
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Oxytocin and vasopressin mediate various physiological functions that are important for osmoregulation, reproduction, cardiovascular function, social behavior, memory, and learning through four G protein-coupled receptors that are also implicated in high-profile disorders. Targeting these receptors is challenging because of the difficulty in obtaining ligands that retain selectivity across rodents and humans for translational studies. We identified a selective and more stable oxytocin receptor (OTR) agonist by subtly modifying the pharmacophore framework of human oxytocin and vasopressin. [Se-Se]-oxytocin-OH displayed similar potency to oxytocin but improved selectivity for OTR, an effect that was retained in mice. Centrally infused [Se-Se]-oxytocin-OH potently reversed social fear in mice, confirming that this action was mediated by OTR and not by V1a or V1b vasopressin receptors. In addition, [Se-Se]-oxytocin-OH produced a more regular contraction pattern than did oxytocin in a preclinical labor induction and augmentation model using myometrial strips from cesarean sections. [Se-Se]-oxytocin-OH had no activity in human cardiomyocytes, indicating a potentially improved safety profile and therapeutic window compared to those of clinically used oxytocin. In conclusion, [Se-Se]-oxytocin-OH is a novel probe for validating OTR as a therapeutic target in various biological systems and is a promising new lead for therapeutic development. Our medicinal chemistry approach may also be applicable to other peptidergic signaling systems with similar selectivity issues.
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Oxytocin and the oxytocin receptor have two important roles in labour. Evidence in all mammalian species suggests that neurohypophysical oxytocin plays a role in the expulsive phase and, although there are less supporting data, a role for oxytocin in the initiation of labour is likely. The initiation of labour may be mediated in women and rhesus monkeys by paracrine rather than endocrine mechanisms. Although initial characterisation of the oxytocin knockout mouse suggested that oxytocin is not important in this species, subsequent investigations have demonstrated that oxytocin is important for the precise timing of the onset of labour. Studies in knockout mice also confirm important interrelationships between oxytocin and prostaglandins. Oxytocin stimulates prostaglandin release in many species, mainly in the decidua/uterine epithelium. The effects of oxytocin are mediated by tissue‐specific oxytocin receptor expression, which leads directly to contraction in the myometrium and prostaglandin formation in the decidua. There is a dramatic increase in oxytocin receptor expression in these tissues in late pregnancy and pharmacological inhibition delays delivery, which suggests that, in contrast to oxytocin, the oxytocin receptor is essential for normal labour.
Oxytocin receptor
Myometrium
Knockout mouse
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Citations (272)
Oxytocin receptor
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