Associations of prenatal depressive symptoms with DNA methylation of HPA axis-related genes and diurnal cortisol profiles in primary school-aged children

Abstract

Epigenetic DNA modifications in genes related to the hypothalamic-pituitary-adrenal (HPA) axis are discussed as a mechanism underlying the association between prenatal depression and altered child HPA activity. In a longitudinal study, DNA methylation changes related to prenatal depressive symptoms were investigated in 167 children aged 6 to 9 years. At six candidate genes, 126 cytosine-guanine dinucleotides were considered without correcting for multiple testing due to the exploratory nature of the study. Further associations with the basal child HPA activity were examined. Children exposed to prenatal depressive symptoms exhibited lower bedtime cortisol (p = .003, ηp2 = 0.07) and a steeper diurnal slope (p = .023, ηp2 = 0.06). For total cortisol release, prenatal exposure was related to lower cortisol release in boys, and higher release in girls. Furthermore, prenatal depressive symptoms were associated with altered methylation in the glucocorticoid receptor gene (NR3C1), the mineralocorticoid receptor gene (NR3C2), and the serotonin receptor gene (SLC6A4), with some sex-specific effects (p = .012-.040, ηp2 = 0.03-0.04). In boys, prenatal depressive symptoms predicted bedtime cortisol mediated by NR3C2 methylation, indirect effect = -0.07, 95% confidence interval [-0.16, -0.02]. Results indicate relations of prenatal depressive symptoms to both child basal HPA activity and DNA methylation, partially fitting a mediation model, with exposed boys and girls being affected differently.

Epigenetic Mechanisms in the Neurodevelopmental Theory of Depression

“…Early childhood experiences associated with severe stressors (considered a risk factor for depression in adult life) are linked with modifications in gene expression [14,15]. Changes in the scope of gene expression affect genes involved in response to stress (hypothalamic-pituitaryadrenal axis, HPA), related to autonomic nervous system hyperactivity and cortical and subcortical processes of neuroplasticity and neurodegeneration [3], including among other genes encoding the glucocorticoid receptor, FK506binding protein 5 (FKBP5) [16], arginine vasopressin and oestrogen receptor alpha, 5-hydroxytryptamine transporter gene (SLC6A4) [17], and brain-derived neurotrophic factors [18][19][20].…”

“…In a study conducted by Stonawski et al [19] (167 children aged 6-9 years), the diagnosis of depression during pregnancy was associated with reduced methylation in the gene encoding the glucocorticoid receptor (NR3C1), the gene encoding the mineralocorticoid receptor (NR3C2), and in the gene for the serotonin receptor (SLC6A4). In this study, genes related to the operation of the HPA axis were selected.…”

Neuroendocrine and immune pathways from pre- and perinatal stress to substance abuse

“…Prenatal stress exposure may also impact offspring's neuroendocrine functioning beyond infancy. A study of school-aged children exposed prenatally to maternal depressive symptoms exhibited altered methylation of the NR3C1 gene and lower cortisol release for boys and higher cortisol release in girls ( Stonawski et al, 2018 ). Prenatal intimate partner violence exposure was also linked to increased cortisol reactivity to stress for 11 month-13 month old infants ( Levendosky et al, 2016 ).…”

Environmentally Induced Epigenetic Plasticity in Development: Epigenetic Toxicity and Epigenetic Adaptation

“…However, this overactivation, which does not allow the HPA axis to fully return to normal can lead to a state of an exhausted HPA axis [96,97]. Such exhausting may manifest itself in terms of persistent hypermethylation of NR3C1 but decreased cortisol concentration in long-term, which results in a restriction of stress adaptation responses and increases the vulnerability to chronic complex disorders, in both the mental and physical realms, later in life [98]. This interpretation is supported by a cross-sectional study which showed that hypermethylation of NR3C1 was associated with a flattened cortisol recovery slope (a delayed recovery time) in adolescents [99].…”