Maternal distress associates with placental genes regulating fetal glucocorticoid exposure and IGF2: Role of obesity and sex
Introduction
Obesity and emotional distress symptoms such as anxiety and depression (A&D) are prevalent during pregnancy (Gavin et al., 2005, Heslehurst et al., 2010). Both independently associate with increased obstetric complications, adverse birth outcomes (Alder et al., 2007) postpartum depression (Molyneaux et al., 2014), and also poor infant health (Lawlor et al., 2012), cognitive and behavioural development (Van Lieshout et al., 2011).
One of the key pathways linking maternal obesity and A&D with adverse pregnancy outcomes is altered maternal hypothalamic–pituitary–adrenal (HPA) axis activity (Lopresti and Drummond, 2013). Increased glucocorticoid exposure during pregnancy in association with maternal A&D has been associated with cognitive and behavioural problems (Mina and Reynolds, 2014). It is also strongly linked to low birth weight, leading to increased metabolic and cardiovascular risk in later life (Reynolds, 2013). We previously demonstrated that maternal very severe obesity (SO, WHO obese class III, BMI ≥ 40 kg/m2) is independently associated with antenatal A&D symptoms (Mina et al., 2015), emphasising the importance of co-investigating both conditions to further understand their adverse impact on fetal outcome and future infant health.
Changes in the maternal HPA axis during gestation promote increased glucocorticoids (Mastorakos and Ilias, 2003), which are important for fetal lung maturation. The placenta modulates fetal glucocorticoid exposure, but is also developmentally plastic and is therefore responsive to insults. The fetus is protected from excess maternal cortisol by placental 11beta-hydroxysteroid dehydrogenase (11β-HSD) 2 (Chapman et al., 2013), and down regulation of 11β-HSD2 has been associated with increased maternal anxiety (O’Donnell et al., 2012) but not depression (Ponder et al., 2011, O’Donnell et al., 2012, Reynolds et al., 2015). No studies have linked maternal A&D to placental 11β-HSD1 (Reynolds et al., 2015), which catalyses the regeneration of active glucocorticoids. We recently showed that maternal depressive symptoms associate with increased mRNA levels of placental glucocorticoid receptor (NR3C1) and mineralocorticoid receptor (NR3C2) (Reynolds et al., 2015). This, and the observation of links between maternal A&D and altered methylation of placental NR3C1 (Conradt et al., 2013), implies altered placental sensitivity to glucocorticoids in association with maternal A&D. A further level of control of fetal glucocorticoid exposure is through retrograde transfer of glucocorticoids from placenta to mother via the placental ATP- Binding Cassette (ABC) transporter family (apical ABCB1 and ABCG2, basal ABCC1). Whether mRNA levels of these transporters are associated with maternal A&D has not been investigated.
In animal models maternal prenatal stress also increases expression of placental Insulin-like Growth Factor (IGF) 2 (Pankevich et al., 2009), a key factor regulating placental and fetal growth and development (Burton and Fowden, 2012). Placental IGF2 expression is also vulnerable to maternal obesity, though varies with gestation. For example, increased mRNA levels of igf2 at day 16 of pregnancy were observed in placentas from the fetuses of dams fed with high-fat diet during pregnancy as compared to dams with standard diet, although this effect was no longer observed at day 19 of pregnancy (Sferruzzi-Perri et al., 2013). Preliminary data suggests that igf2 mRNA levels are modulated by prevailing glucocorticoid levels (Vaughan et al., 2012) and may be sex-specific with up-regulation of placental igf2 transcription by glucocorticoids in placentas of male, but not in female mice offspring (Cuffe et al., 2012). Mammalian Target of Rapamycin (mTOR), an intracellular nutrient stress sensor in the placenta (Roos et al., 2009) has been linked to the downstream signalling of both glucocorticoids (Jellyman et al., 2012) and IGF2 (Dai et al., 2011). A small study reporting a lower placental DEP domain-containing mTOR-interacting protein (DEPTOR) in mothers with higher perceived life stress and reduced DEPTOR following increased cortisol in vitro (Mparmpakas et al., 2012) suggests further investigation of these genes is warranted.
In this study, we aimed to evaluate the effects of both maternal obesity and A&D symptoms on placental mRNA levels of genes regulating fetal glucocorticoid exposure and the IGF2 family. We hypothesised that increased maternal emotional distress symptoms would be associated with changes in placental gene expression leading to a reduced placental barrier to excess maternal glucocorticoid levels and increased IGF2 mRNA levels. We speculated that this would be more pronounced in maternal obesity due to the greater levels of distress symptoms compared to lean (Mina et al., 2015). We considered whether there were sex- specific changes in placental gene expression in association with maternal distress. To test this hypothesis we used placental samples collected at term from SO women and lean controls participating in a longitudinal case-control study of obesity in pregnancy and in whom maternal A&D symptoms and serum cortisol levels were assessed prospectively during pregnancy (Mina et al., 2015).
Section snippets
Participants
This study included women with singleton pregnancies participating in a prospective case-control study comparing lean (BMI ≤ 25 kg/m2) and SO (BMI ≥ 40 kg/m2) women in Edinburgh, Scotland, UK. As previously described, SO women were recruited from a specialist antenatal metabolic clinic for women with BMI > 40 kg/m2) whilst lean women were recruited from community antenatal clinics (Mina et al., 2015). Maternal body composition, maternal and pregnancy factors were characterised (Mina et al., 2015). All
The demographics of participants
Table 1 presents the demographics of participants (lean n = 43, SO n = 50) and the details of delivery mode and birth outcomes. SO group had higher maternal emotional distress symptoms and lower serum cortisol levels as compared to the lean women, consistent with the cohort's findings (Mina et al., 2015). There were significantly higher numbers of caesarean deliveries in SO group as compared to lean. In this randomly selected sample there was a significant difference in the sex composition with
Discussion
Our findings demonstrate that maternal emotional distress associates with changes in mRNA levels of several placental genes involved in the regulation of fetal glucocorticoid exposure and placental growth. Contrary to our hypothesis we found that the pattern of changes in mRNA levels in placentas from SO women (who had greater A&D symptoms than lean), were largely similar to those in placentas from lean women. However, in exploratory analyses we observed sex-specific responses, with placentas
Role of funding source
We are grateful to the generous funding from Tommy's the Baby Charity. THM is funded by Principal Development Scholarship, Charles Darwin Scholarship and Global Research Scholarship, University of Edinburgh, Scotland. We acknowledge the support of the British Heart Foundation.
Conflict of interest statement
All authors declare no conflict of interest.
Acknowledgements
We thank the participants, Sister Yvonne Greig, Sister Norma Forson and the antenatal metaboliccare team. We thank past and current team of the Edinburgh Reproductive Tissue Bio-bank. We acknowledge Patrick Lo Cheuk Ngai's assistance in missing data imputation.
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2020, NeuroscienceCitation Excerpt :These effects are less apparent in animal models of reduced OS, especially in female subjects, suggesting that diet-induced metabolic dysfunction, neuroendocrine response and sex/gender all play a role in these regulations (see later in this review) (Bellisario et al., 2014). Worth noticing, these data also confirm clinical evidence showing that the presence of high levels of GCs during gestation can affect the expression of GCs-sensitive genes in the central nervous system, as well as in the periphery, with important effects on HPA axis function and regulation (Mina et al., 2015; Mina et al., 2017). These effects are reminiscent of a solid literature in animal models indicating that prenatal maternal stress affects HPA axis activity and stress regulation through changes in GCs receptors in limbic regions of the brain (Welberg and Seckl, 2001; McGowan et al., 2008; Brunton and Russell, 2010).