Maternal prenatal stress and placental gene expression of NR3C1 and HSD11B2: The effects of maternal ethnicity

Highlights

• Prenatal stress (maternal symptoms of depression, anxiety and life events) was associated with altered placental expression of HPA-axis genes.

• There was a significant interaction with ethnicity.

• There was increased placental NR3C1 and decreased HSD2B11 expression in Caucasians but no change in non-Caucasians.

• Further research is needed to examine the potential effects of ethnicity on the association between prenatal stress & placental gene expression.

Summary

Background

Prenatal stress is associated with altered fetal and infant development. Previous studies have suggested that these effects may be mediated in part via altered functioning of placental enzymes and receptors involved in the HPA-axis, including the glucocorticoid receptor (NR3C1) and HSD11B2, the enzyme which metabolises cortisol. However, previous studies have not examined the potential ethnicity effects on these associations. This study aimed to characterise the association between maternal prenatal stress and placental genes expression and subsequently, any potential effect of maternal ethnicity.

Method

Pregnant women(n = 83) were recruited prior to elective caesarean section and assessed for trait anxiety, depression and life events. Placentas were collected and placental gene expression of NR3C1 and HSD11B2 were analysed. We examined associations between maternal prenatal stress and placental gene expression, and the tested for a possible moderating effect of maternal ethnicity(59.0% Caucasian;41.0% non-Caucasian:12.0% South Asian;6.0% African/African-American;14.4% Other;8.4% Mixed).

Results

Analyses demonstrated a trend in the association between both maternal trait anxiety and depression symptoms with placental gene expression of NR3C1(adj.β = 0.220,p = 0.067;adj.β = 0.212,p = 0.064 respectively). We found a significant interaction with maternal ethnicity(β = 0.249;p = 0.033). In Caucasian women only prenatal trait anxiety and depressive symptoms were associated with an increase in placental NR3C1 expression(adj.β = 0.389,p = 0.010;adj.β = 0.294;p = 0.047 respectively). Prenatal life events were associated with a down regulation of HSD11B2(adj.β = 0.381;p = 0.008), but only in Caucasians.

Conclusion

These results support previous findings of an association between maternal prenatal stress and the expression of placental genes associated with the HPA-axis, but only in Caucasians. These ethnic specific findings are novel and require replication in different populations.

Introduction

There is good evidence that maternal prenatal stress, including anxiety, depression and stressful life events, is associated with an increased risk of altered behavioural, cognitive and emotional development of the child (Glover et al., 2015, O'Connor et al., 2007, O'Connor et al., 2003). These changes in child development are, in turn, indicators of vulnerability for the development of psychopathology later in life (Schlotz and Phillips, 2009), with an increase in psychiatric risk during later childhood and adolescence following exposure to maternal prenatal distress (Capron et al., 2015, O'Donnell et al., 2014, Pawlby et al., 2011, Pearson et al., 2013). However, the underlying biological changes that may mediate the associations between maternal prenatal mood and child outcome are not well understood.

One potential mechanism is an alteration in the metabolism of cortisol by the placenta. Cortisol is known to cross the placenta, to some degree, and the correlation between maternal plasma and amniotic fluid cortisol has been found to be greater in more anxious mothers, suggesting an increased permeability to cortisol associated with raised anxiety (Glover et al., 2009). In animal studies, fetal exposure to raised levels of cortisol has been associated with a wide range of effects in offspring, including a reduction in birth weight, increase in adult blood pressure, and an increase in anxiety behaviours (Seckl and Holmes, 2007). In humans, fetal exposure to increased cortisol has been associated with a decrease in child cognitive function (Bergman et al., 2010).

The placenta has high levels of corticosteroid 11-beta-dehydrogenase 2 (HSD11B2), the enzyme that converts cortisol into inactive cortisone. This enzyme is located within the syncytiotrophoblast during the second and third trimester of human pregnancy (Pepe et al., 1999, Schoof et al., 2001). Studies in rodents have shown that exposure to maternal prenatal stress is associated with a decrease in the gene expression of placental HSD11B2 (Jensen Peña et al., 2012, Mairesse et al., 2007). Some human studies have also shown a down-regulation of HSD11B2 gene expression and reduction of enzymatic activity in the placentae of mothers with higher levels of prenatal anxiety (O'Donnell et al., 2012). This finding has been replicated in an Australian birth cohort, where high anxiety and depressive symptom scores at 28–34 weeks gestation were associated with a reduction in placental HSD11B2 gene expression (Seth et al., 2015). Monk et al. (2016) have found an association between maternal prenatal distress, placental methylation of HSD11B2 and altered fetal behaviour (Monk et al., 2016). However, a study by Reynolds et al. reported no association between maternal depressive symptoms and placental gene expression of HSD11B2 (Reynolds et al., 2015).

Maternal prenatal depression has been associated with an increase in the expression of the glucocorticoid receptor (NR3C1) gene in the placenta in several studies (Conradt et al., 2013, Mina et al., 2015, Reynolds et al., 2015). NR3C1 is a nuclear receptor which functions both a transcription factor and as a transcription factor regulator (Palma-Gudiel et al., 2015). NR3C1 has been shown to be expressed in placental tissue and although its function is unclear, it has been postulated that it may be an upstream regulator of placental HSD11B2 gene expression (Garbrecht and Schmidt, 2013). Thus an increase in placental NR3C1 gene expression may be a mechanism through which the placenta increases its sensitivity to glucocorticoids and fetal glucocorticoid exposure (Seckl and Holmes, 2007).

Thus previous research has shown that a range of different types of prenatal stress, including symptoms of anxiety, depression as well as life events, are associated with increased risk of altered outcome for the child including psychopathology (Glover et al., 2014, Kinsella and Monk, 2009). Prenatal symptoms of both anxiety and depression have also been found to be associated with altered expression of HPA-axis associated genes in the placenta. The majority of this research has been conducted in predominantly Caucasian populations and therefore, it is currently unclear if there are different associations seen in different populations. It is important to study both Caucasian and non-Caucasian populations. The current study was designed to investigate the associations between maternal prenatal depressive symptoms, anxiety symptoms and life events with placental gene expression of NR3C1 and HSD2B11, and includes subjects with different ethnicities.