Abstract
Animal and human studies suggest that prenatal exposure to stress is associated with adverse health outcomes such as type 2 diabetes. Epigenetic modification, such as DNA methylation, is considered one possible underlying mechanism. The 1998 Quebec ice storm provides a unique opportunity to study an independent prenatal stressor on child outcomes. C-peptide is the best measure of endogenous insulin secretion and is widely used in the clinical management of patients with diabetes. The objectives of this study are to determine 1) the extent to which prenatal exposure to disaster-related stress (maternal objective hardship and maternal cognitive appraisal) influences children’s C-peptide secretion, and 2) whether DNA methylation of diabetes-related genes mediates the effects of prenatal stress on C-peptide secretion. Children’s (n = 30) C-peptide secretion in response to an oral glucose tolerance test were assessed in blood at 13½ years. DNA methylation levels of selected type 1 and 2 diabetes-related genes were chosen based upon the genes associated with prenatal maternal objective hardship and/or cognitive appraisal levels. Bootstrapping analyses were performed to determine the mediation effect of DNA methylation. We found that children whose mothers experienced higher objective hardship exhibited higher C-peptide secretion. Cognitive appraisal was not directly associated with C-peptide secretion. DNA methylation of diabetes-related genes had a positive mediation effect of objective hardship on C-peptide secretion: higher objective hardship predicted higher C-peptide secretion through DNA methylation. Negative mediation effects of cognitive appraisal were observed: negative cognitive appraisal predicted higher C-peptide secretion through DNA methylation. However, only one gene, LTA, remained a significant mediator of cognitive appraisal on C-peptide secretion after the conservative Bonferroni multiple corrections. Our findings suggest that DNA methylation could act as an intervening variable between prenatal stress and metabolic outcomes, highlighting the importance of epigenetic mechanisms in response to environmental factors.
Highlights
The prevalence of metabolic diseases has recently escalated among children and adolescents, holding lifelong implications for health [1]
Retrospective case-control studies [15, 18] suggest that there is increased risk of insulin resistance among young adults whose mothers experienced stressful life events during pregnancy: a prenatal maternal stress (PNMS) group of young adults who reported that their mothers had had stressful life events during pregnancy showed elevated fasting insulin, elevated insulin after an oral glucose tolerance test, higher C-peptide levels, and decreased low density lipoprotein (LDL) levels compared to a non-stressed comparison group, even after controlling for body mass index (BMI) and other potential confounding variables [18]
Mediation effect of DNA methylation on C-peptide secretion one factor contributing to dysfunctions related to metabolic outcomes such as insulin resistance and type 1 or type 2 diabetes mellitus among offspring. These data highlight the important role of DNA methylation of diabetes-related genes on mediating the relationship between specific aspects of prenatal maternal stress and metabolic outcomes in offspring
Summary
The prevalence of metabolic diseases has recently escalated among children and adolescents, holding lifelong implications for health [1]. Retrospective case-control studies [15, 18] suggest that there is increased risk of insulin resistance among young adults whose mothers experienced stressful life events during pregnancy: a PNMS group of young adults who reported that their mothers had had stressful life events during pregnancy showed elevated fasting insulin, elevated insulin after an oral glucose tolerance test, higher C-peptide levels, and decreased low density lipoprotein (LDL) levels compared to a non-stressed comparison group, even after controlling for body mass index (BMI) and other potential confounding variables [18]. Mothers in retrospective studies may be biased in their reporting of life events based on their impressions of their children’s health outcomes. These limitations could be partly overcome by a human model analyzing a stressor that is independent of the parents’ potential influence, and whose severity is randomly distributed
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