Mismatched Prenatal and Postnatal Maternal Depressive Symptoms and Child Behaviours: A Sex-Dependent Role for NR3C1 DNA Methylation in the Wirral Child Health and Development Study

Chris Murgatroyd,Nicola Wright,Jonathan Hill,Helen Sharp,John P. Quinn,Andrew Pickles

doi:10.3390/cells8090943

Abstract

Evolutionary hypotheses predict that male fetuses are more vulnerable to poor maternal conditions (Sex-biased Maternal Investment), but female fetuses are at greater risk of glucocorticoid-mediated disorders where there is a mismatch between fetal and postnatal environments (Predictive Adaptive Response). Self-reported prenatal and postnatal depression and maternal report of child anxious-depressed symptoms at 2.5, 3.5 and 5.0 years were obtained from an ‘extensive’ sample of first-time mothers (N = 794). Salivary NR3C1 1-F promoter methylation was assayed at 14 months in an ‘intensive’ subsample (n = 176) and stratified by psychosocial risk. Generalised structural equation models were fitted and estimated by maximum likelihood to allow the inclusion of participants from both intensive and extensive samples. Postnatal depression was associated with NR3C1 methylation and anxious-depressed symptoms in daughters of mothers with low prenatal depression (prenatal-postnatal depression interaction for methylation, p < 0.001; for child symptoms, p = 0.011). In girls, NR3C1 methylation mediated the association between maternal depression and child anxious-depressed symptoms. The effects were greater in girls than boys: the test of sex differences in the effect of the prenatal-postnatal depression interaction on both outcomes gave X2 (2) = 5.95 (p = 0.051). This was the first human study to show that epigenetic and early behavioural outcomes may arise through different mechanisms in males and females.

Highlights

The ‘fetal origins’ hypothesis was first proposed to account for associations between low birth weight and obesity, cardiovascular disease, and type II diabetes in middle and old age [1]
We previously reported that the association between prenatal anxiety and child emotional and behavioural outcomes is only seen in the presence of low maternal stroking, consistent with animal studies of the protective effects of postnatal tactile stimulation [8]
In the first study to examine the interplay between prenatal and postnatal depression in relation to NR3C1 gene methylation, we showed that the association between postnatal maternal depression and NR3C1 1-F promoter methylation in children was stronger where mothers had reported lower depression during pregnancy, in line with the Predictive Adaptive Response’ (PAR) hypothesis [32]

Summary

Introduction

The ‘fetal origins’ hypothesis was first proposed to account for associations between low birth weight and obesity, cardiovascular disease, and type II diabetes in middle and old age [1]. According to this hypothesis, low birth weight reflects evolved adaptive mechanisms that confer advantages later in life where food is scarce but create risk in the presence of high calorie diets, common in. We previously reported that the association between prenatal anxiety and child emotional and behavioural outcomes is only seen in the presence of low maternal stroking, consistent with animal studies of the protective effects of postnatal tactile stimulation [8]. We showed that mismatched prenatal–postnatal maternal anxiety was associated with elevated child irritability at age 7 years, only in the presence of low maternal stroking [10], consistent with a mismatch effect creating vulnerability that is modified by early tactile stimulation

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