Gestational age acceleration is associated with epigenetic biomarkers of prenatal physiologic stress exposure

Abstract

Background Physiological maternal stress response, such as imbalance in the glucocorticoid pathway and immune system seems to be mediated by DNA methylation (DNAm) and might translate intrauterine stress exposures into phenotypic changes in a sex-specific manner. DNAm in specific sites can also predict newborn gestational age and gestational age acceleration (GAA). GAA occurs when the predicted biological age is higher than the chronological age. In adults, poor health outcomes related to this deviance are well documented and raise questions for the interpretation and prediction in early stages of life. Boys seem to be more vulnerable to intrauterine stress exposure than girls; however, the mechanisms of adaptive sex-specific responses are still unclear. We hypothesize that intrauterine stress exposure is associated with GAA and could be different in boys and girls if inflammatory or glucocorticoid pathways exposure is considered. Results Using the Western Region Birth Cohort (ROC—São Paulo, Brazil) (n = 83), we calculated DNAm age and GAA from cord blood samples. Two epigenetic risk scores were calculated as an indirect proxy for low-grade inflammation (i-ePGS) and for glucocorticoid exposure (GES). Multivariate linear regression models were applied to investigate associations of GAA with prenatal exposures. The i-ePGS and GES were included in different models with the same co-variates considering sex interactions. The first multivariate model investigating inflammatory exposure (adj. R2 = 0.31, p = < 0.001) showed that GAA was positively associated with i-ePGS (CI, 0.26–113.87, p = 0.049) and negative pregnancy-related feelings (CI, 0.04–0.48 p = 0.019). No sex interaction was observed. The second model investigating glucocorticoid exposure (adj. R2 = 0.32, p = < 0.001) showed that the higher was the GAA was associated with a lower the lower was the GES in girls (CI, 0.04–2.55, p = 0.044). In both models, maternal self-reported mental disorder was negatively associated with GAA. Conclusion Prenatal epigenetic score of exposure to low-grade inflammatory was a predictor of GAA for both sexes. Glucocorticoid epigenetic score seems to be more important to GAA in girls. This study supports the evidence of sex-specificity in stress response, suggesting the glucocorticoid as a possible pathway adopted by girls to accelerate the maturation in an adverse condition.

Prenatal stress and gestational epigenetic age: No evidence of associations based on a large prospective multi-cohort study

“…Overall, our ndings do not support a link between prenatal stress exposure and gestational epigenetic age (or age acceleration/deceleration) at birth in the general paediatric population. These ndings differ from previously published studies reporting a link between prenatal stress and either gestational epigenetic age deceleration 26,25,19 or acceleration [27] [21] [52]. Several factors may explain these discrepancies.…”

“…In contrast, a study in Brazil in 83 newborns found an association between gestational epigenetic age acceleration and maternal negative feelings related to pregnancy, though this was not associated with any other psychosocial variables. They further found that gestational epigenetic age acceleration could be predicted by epigenetic scores of low-grade in ammation and glucocorticoid exposure [27]. A study in the Democratic Republic of Congo, on 141 newborns, also found that those prenatally exposed to general trauma and war trauma displayed epigenetic age acceleration at birth.…”

Identifying biomarkers and trajectories of executive functions and language development in the first 3 years of life: design, methods and initial findings of the Germina cohort study

“…The fetal hypothalamic-pituitary-adrenal (HPA) axis is especially susceptible to glucocorticoids long-term programming, and these effects can persist throughout life (Moisiadis & Matthews, 2014). A previous study in Brazil found accelerated gestational epigenetic age in infants exposed to glucocorticoids and low-grade inflammation indices (Euclydes et al, 2022).…”

Cumulative stress, PTSD, and emotion dysregulation during pregnancy and epigenetic age acceleration in Hispanic mothers and their newborn infants

“…Since LES only measures recent stressful and traumatic events, whereas STRESS assesses lifetime events and associated PTSD symptoms, we can speculate that cumulative exposure and trauma-specific symptoms might be necessary for reliable epigenetic changes to occur. In addition, PTSD usually co-occurs with immune dysregulation [ 67 ], which might influence gestational epigenetic age acceleration [ 68 ].…”