Maternal depressive symptoms during pregnancy, placental expression of genes regulating glucocorticoid and serotonin function and infant regulatory behaviors

Abstract

Background.Glucocorticoids and serotonin may mediate the link between maternal environment, fetal brain development and ‘programming’ of offspring behaviors. The placenta regulates fetal exposure to maternal hormonal signals in animal studies, but few data address this in humans. We measured prospectively maternal depressive symptoms during pregnancy and mRNAs encoding key gene products determining glucocorticoid and serotonin function in term human placenta and explored associations with infant regulatory behaviors.Method.Bi-weekly self-ratings of the Center for Epidemiologic Studies Depression Scale from 12th to 13th gestational week onwards and term placental mRNAs of 11beta-hydroxysteroid dehydrogenase type 2 (HSD2B11), type 1 (HSD1B11), glucocorticoid (NR3C1), mineralocorticoid receptors (NR3C2) and serotonin transporter (SLC6A4) were obtained from 54 healthy mothers aged 32.2 ± 5.3 years with singleton pregnancies and without pregnancy complications. Infant regulatory behaviors (crying, feeding, spitting, elimination, sleeping and predictability) were mother-rated at 15.6 ± 4.2 days.Results.Higher placental mRNA levels of HSD2B11 [0.41 standard deviation (s.d.) unit increase per s.d. unit increase; 95% confidence interval (CI) 0.13–0.69, p = 0.005], HSD1B11 (0.30, 0.03–0.57, p = 0.03), NR3C1 (0.44, 0.19–0.68, p = 0.001) and SLC6A4 (0.26, 0.00–0.53, p = 0.05) were associated with more regulatory behavioral challenges of the infant. Higher placental NR3C1 mRNA partly mediated the association between maternal depressive symptoms during pregnancy and infant regulatory behaviors (p < 0.05).Conclusions.Higher placental expression of genes regulating feto-placental glucocorticoid and serotonin exposure is characteristic of infants with more regulatory behavioral challenges. Maternal depression acts, at least partly, via altering glucocorticoid action in the placenta to impact on offspring regulatory behaviors.

Developmental changes in serotonin signaling: Implications for early brain function, behavior and adaptation

“…More recently, evidence is accumulating suggesting that other systems may be similarly ‘programmable’, i.e., that neonatal experiences can have a long-lasting effect on brain development and thus offspring behavior later in life. In line with this, a recent study in 54 healthy human mothers revealed an association between glucocorticoid-related placental mRNA levels and infant regulatory behaviors, but, more importantly, they also found that higher placental mRNA levels of SLC6A4 were associated with more regulatory behavioral challenges of the infants (Raikkonen et al, 2015). …”

Prenatal Depression and Infant Temperament: The Moderating Role of Placental Gene Expression

“…Our findings indicate several inconsistences in the literature. Prenatal depression has been associated with increased NR3C1 and NR3C2 expression in the placenta (Räikkönen et al., ; Reynolds et al., ), but greater NR3C1 methylation (i.e., lower expression) in cord blood (Conradt et al., ; Oberlander et al., ). No previous research has found a significant correlation between maternal depression and placental HSD 11 B 2 expression (O'Donnell et al., ; Ponder et al., ; Räikkönen et al., ; Reynolds et al., ), although lower expression has been associated with increased prenatal anxiety (O'Donnell et al., ).…”

“…However, one previous work by Räikkönen et al. () found an inverse association where greater placental HSD 11 B 2 expression was correlated with infant dysregulated behavior, as measured by crying, feeding, spitting, bowel movement, sleeping, and predictability.…”

“…Increased placental NR3C1 methylation has been associated with decreased gene expression (Bromer, Marsit, Armstrong, Padbury, & Lester, ), poorer attention, greater cortisol stress reactivity, higher arousal, and decreased self‐regulation in infants (Bromer et al., ; Conradt et al., ; Paquette et al., ). In contrast, some studies found that increased placental NR3C1 expression, or decreased NR3C1 methylation, was associated with adverse infant neurobehavioral outcomes, such as lower quality of movement, more lethargy, poorer attention, and decreased self‐regulation (Räikkönen et al., ; Stroud et al., ). Finally, no association between placental MR ( NR3C2 ) and infant neurobehavioral development has been noted.…”

Distress During Pregnancy: Epigenetic Regulation of Placenta Glucocorticoid-Related Genes and Fetal Neurobehavior

“…Higher anxiety was found to be associated with a downregulation of placental mRNA for the gene encoding 11β–hydroxysteroid dehydrogenase type 2 ( HSD11B2 ) (11β-HSD-2 is a barrier enzyme that inactivates glucocorticoids [7]), and higher anxiety and modestly increased DNA methylation of placental HSD11B2 were together associated with lower muscle tone in newborns (10). Maternal depression and greater placental DNA methylation of NR3C1 , the gene encoding the glucocorticoid receptor, predicted poorer self-regulation, lower muscle tone, and more lethargy in neonates (10, 11), although other reports showed maternal adversity (depression, low socioeconomic status) to be associated with increased placental levels of NR3C1 mRNA (12, 13). Placental DNA methylation of FKBP5 (FK506 binding protein, a molecular chaperone of glucocorticoid receptor regulation) was associated with an increased likelihood of high arousal in newborns (14).…”