‘Mismatched Beginnings’ - Investigating the role of perinatal stress and the epigenetic regulation of the Oxytocin Receptor gene in maternal mental health and offspring outcomes

Smith, Laura Catherine (2025) ‘Mismatched Beginnings’ - Investigating the role of perinatal stress and the epigenetic regulation of the Oxytocin Receptor gene in maternal mental health and offspring outcomes. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

Background: Approximately 20% of women encounter perinatal mental health issues during pregnancy or postpartum, resulting in a staggering annual cost of £1.2 billion to the NHS. Prenatal stress (PreNS) encompasses a wide range of stressors, from daily events to severe experiences like trauma, which can have negative consequences for both mother and offspring. Postnatal depression (PostND) is a persistent and often debilitating mental health condition that can endure for up to five years after childbirth. Alarmingly, suicide ranks as a leading cause of mortality in women during both prenatal and postnatal periods. Oxytocin (OXT), colloquially called the "love hormone," plays a critical role in maternal-infant attachment. The "mismatch hypothesis" suggests that experiencing PreNS, but not postnatal stress, or vice versa, may impact offspring development differently. Research conducted by Murgatroyd et al., in 2015 has demonstrated that a foetus exposed to PreNS displays enhanced resilience to the impact of postnatal stressors. This implies that the prenatal foetus may better prepare itself to handle postnatal stress when exposed to PreNS. Animal models are essential for understanding this phenomenon, accounting for genetics and environment. Aims: This comprehensive study encompasses a multifaceted investigation. Firstly, it aims to establish a rat-based stress model capable of simulating prenatal, postnatal and perinatal stress. The offspring of these rats will undergo extensive behavioural testing to evaluate mood, behaviour and cognition. Additionally, their blood and brain tissue will be collected for in-depth molecular investigations, shedding light on the underlying mechanisms of stress programming and gene pathways within the brain. The dams will also undergo behavioural assessments to gauge the efficacy of stressors. Furthermore, the study seeks to examine the 'mismatch hypothesis,' exploring whether exposure to both prenatal and postnatal stressors have a 'protective' effect that is more favourable than exposure to either stressor individually. Valid molecular techniques will be employed to quantify hormone levels and DNA methylation in the rats. The ‘mismatch hypothesis’ can also be tested in a cohort of human samples from the Wirral Child Health and Development Study (WCHADS). This study enables us to investigate the impact of prenatal and postnatal depression on infant OXTR DNA methylation and subsequently assess the potential 'mismatch' effect. Finally, the study ventures into understanding how perceived discrimination can affect the oxytocinergic system in Latina mothers, adding a unique dimension to the research. Methods: This complex study included a pilot rat study exploring perinatal stress and two human studies, one taking a translational epigenetic approach using mother/infant DNA methylation and SNP data and the other looking at a sample of Latina women and their DNA methylation profiles. A wide range of behavioural tests were utilised for behavioural analysis in the rat study. The rat study also included ELISA for measuring hormonal differences and bisulphite pyrosequencing to measure and compare OXTR DNA methylation. Bisulphite pyrosequencing was employed again in the human studies, and additionally, SNP assays were used to assess the OXTR SNP rs53576. Results: The pilot rat study, which aimed to explore the 'mismatch hypothesis,' was hindered by an incomplete perinatal protocol, and as a result, the 'mismatch hypothesis' remained untested. Despite this setback, intriguing data emerged. It is evident that maternal stress has a notable impact on rat offspring, specifically affecting mood and behaviour. Using ELISAs to assess hormonal levels in the dams and their offspring, it became apparent that while PreNS had the most significant effect on OXT levels, it was the postnatal protocol that prominently increased CORT serum levels, notably observed in male offspring. To understand the reasons behind this gender-specific impact, further research with a complete perinatal protocol would be warranted. In the WCHADS study, it was discovered that prenatal depression is associated with elevated OXTR methylation in male infants. Additionally, postnatally, a negative correlation between stroking and PostND and anxiety was discovered at the 5-week postpartum mark. We also identified a noteworthy connection between the G allele of rs53576 in mothers and higher OXTR methylation, primarily when they had male infants. This allele also showed a link to increased OXTR methylation in female infants. The Latina study presented new evidence highlighting the distinct significance of the oxytocinergic system in PostND within high-risk populations. Conclusions: Although not completed, the pilot rat study was unique in its attempt to elucidate the harmful effects of maternal stress on offspring. While the 'mismatch hypothesis' remains untested, this study provided captivating insights into the impact of prenatal and postnatal stress on rat offspring, emphasising the need for further research with a complete perinatal study. The results from the human studies suggest the potential role of OXTR methylation in the aetiology of maternal depression, underscoring the need to consider gender when comprehending the impact of OXTR genotype on methylation.