Maternal distress associates with placental genes regulating fetal glucocorticoid exposure and IGF2: Role of obesity and sex

Abstract

Maternal emotional distress symptoms, including life satisfaction, anxiety and depressed mood, are worse in Severely Obese (SO) than lean pregnancy and may alter placental genes regulating fetal glucocorticoid exposure and placental growth. We hypothesised that the associations between increased maternal distress symptoms and changes in placental gene expression including IGF2 and genes regulating fetal glucocorticoid exposure are more pronounced in SO pregnancy. We also considered whether there were sex-specific effects. Placental mRNA levels of 11β-HSDs, NR3C1-α, NR3C2, ABC transporters, mTOR and the IGF2 family were measured in term placental samples from 43 lean (BMI≤25kg/m(2)) and 50 SO (BMI≥40kg/m(2)) women, in whom distress symptoms were prospectively evaluated during pregnancy. The mRNA levels of genes with a similar role in regulating fetal glucocorticoid exposure were strongly inter-correlated. Increased maternal distress symptoms associated with increased NR3C2 and IGF2 isoform 1(IGF2-1) in both lean and SO group (p≤0.05). Increased distress was associated with higher ABCB1 and ABCG2 mRNA levels in SO but lower ABCB1 and higher 11β-HSD1 mRNA levels in lean (p≤0.05) suggesting a protective adaptive response in SO placentas. Increased maternal distress associated with reduced mRNA levels of ABCB1, ABCG2, 11β-HSD2, NR3C1-α and IGF2-1 in placentas of female but not male offspring. The observed sex differences in placental responses suggest greater vulnerability of female fetuses to maternal distress with potentially greater fetal glucocorticoid exposure and excess IGF2. Further studies are needed to replicate these findings and to test whether this translates to potentially greater negative outcomes of maternal distress in female offspring in early childhood.

Sex Differences in Vulnerability to Prenatal Stress: a Review of the Recent Literature

“…Similarly, Vangeel et al ( N  = 45) found an interaction such that prenatal anxiety was positively associated with cord blood DNA methylation in the GABA-B receptor subunit 1 gene ( GABBR1 ) in infant boys but not girls [53]. Mina et al found sex-specific associations suggesting that infant girls might be particularly susceptible to the effects of prenatal maternal distress on placental mRNA levels of genes regulating fetal glucocorticoid exposure and placental growth [68]. Finally, data from the Barwon Infant Study ( N = 481) showed no evidence of sex dependence in associations between PNMS and cord blood NR3C1 glucocorticoid receptor gene methylation [25].…”

Sexual dimorphism in the effect of maternal obesity on antioxidant defense mechanisms in the human placenta

“…Several studies have shown sexual dimorphism of gene expression in the human placenta [40–42] and in response to adverse environments e.g. maternal distress [43]. In murine models obesity alters placental morphology, cell proliferation and inflammation [44] and maternal diet alters placental gene expression [45] and epigenetic systems [46] in a sexually dimorphic manner.…”

A maternal high-fat, high-sucrose diet has sex-specific effects on fetal glucocorticoids with little consequence for offspring metabolism and voluntary locomotor activity in mice

“…However, while a low protein diet decreased 11β-HSD2 activity near the end of pregnancy, it had the opposite effect earlier in pregnancy [17]. Similarly, maternal stress generally reduces placental 11β-HSD2 activity [5,18,19], although some studies have found the opposite pattern [5]. The effects of maternal overnutrition and/or obesity on placental 11β-HSD2 activity have received less study [20], although a high-fat diet decreases placental 11β-HSD2 expression and enzymatic activity in mice [21,22].…”