Guillaume Elgbeili

DNA methylation signatures triggered by prenatal maternal stress exposure to a natural disaster: Project Ice Storm.

Background Prenatal maternal stress (PNMS) predicts a wide variety of behavioral and physical outcomes in the offspring. Although epigenetic processes may be responsible for PNMS effects, human research is hampered by the lack of experimental methods that parallel controlled animal studies. Disasters, however, provide natural experiments that can provide models of prenatal stress. Methods Five months after the 1998 Quebec ice storm we recruited women who had been pregnant during the disaster and assessed their degrees of objective hardship and subjective distress. Thirteen years later, we investigated DNA methylation profiling in T cells obtained from 36 of the children, and compared selected results with those from saliva samples obtained from the same children at age 8. Results Prenatal maternal objective hardship was correlated with DNA methylation levels in 1675 CGs affiliated with 957 genes predominantly related to immune function; maternal subjective distress was uncorrelated. DNA methylation changes in SCG5 and LTA, both highly correlated with maternal objective stress, were comparable in T cells, peripheral blood mononuclear cells (PBMCs) and saliva cells. Conclusions These data provide first evidence in humans supporting the conclusion that PNMS results in a lasting, broad, and functionally organized DNA methylation signature in several tissues in offspring. By using a natural disaster model, we can infer that the epigenetic effects found in Project Ice Storm are due to objective levels of hardship experienced by the pregnant woman rather than to her level of sustained distress.

Prenatal maternal stress predicts stress reactivity at 2½ years of age: The Iowa Flood Study

Prenatal maternal stress (PNMS) predicts psychosocial development in offspring. It has been hypothesized that during PNMS, glucocorticoids pass the placenta, reaching the foetus, leading to a long-term reprogramming and dysregulation of the foetal hypothalamic-pituitary-adrenal (HPA) axis. However, results are inconsistent across PNMS studies. One problem may be the confounding of objective degrees of hardship due to the stressor and subjective degrees of distress in the mother. The present study investigated the association between objective and subjective PNMS due to a natural disaster, the June 2008 Iowa floods, and stress reactivity in the offspring at 2½ years of age. Women who were pregnant during the floods were recruited, on average, within three months of the floods and their stress levels assessed. Mothers and their toddlers (n = 94 dyads) participated in a brief mother-toddler separation to induce physiological stress responses in the offspring. Salivary cortisol samples were collected four times during the procedure. We computed absolute change in cortisol (baseline to 20-minute post-stressor; baseline to 45-minute post-stressor) and Area Under the Curve with respect to increase and ground (AUCi; AUCg). Objective and subjective PNMS were positively correlated with AUCi, as was timing in gestation: the later in pregnancy the exposure occurred, the greater the cortisol increase. Controlling for objective hardship and other covariates, sex-by-subjective PNMS interactions showed a significant and positive association between subjective PNMS and Absolute Increase (45 min) and AUCi in females only, with little effect in males. These results suggest that PNMS leads to long-term alterations in the functioning of the HPA axis, evident as early as 30-months of age.

DNA methylation mediates the impact of exposure to prenatal maternal stress on BMI and central adiposity in children at age 13½ years: Project Ice Storm

Prenatal maternal stress (PNMS) in animals and humans predicts obesity and metabolic dysfunction in the offspring. Epigenetic modification of gene function is considered one possible mechanism by which PNMS results in poor outcomes in offspring. Our goal was to determine the role of maternal objective exposure and subjective distress on child BMI and central adiposity at 13½ years of age, and to test the hypothesis that DNA methylation mediates the effect of PNMS on growth. Mothers were pregnant during the January 1998 Quebec ice storm. We assessed their objective exposure and subjective distress in June 1998. At age 13½ their children were weighed and measured (n = 66); a subsample provided blood samples for epigenetic studies (n = 31). Objective and subjective PNMS correlated with central adiposity (waist-to-height ratio); only objective PNMS predicted body mass index (BMI). Bootstrapping analyses showed that the methylation level of genes from established Type-1 and -2 diabetes mellitus pathways showed significant mediation of the effect of objective PNMS on both central adiposity and BMI. However, the negative mediating effects indicate that, although greater objective PNMS predicts greater BMI and adiposity, this effect is dampened by the effects of objective PNMS on DNA methylation, suggesting a protective role of the selected genes from Type-1 and -2 diabetes mellitus pathways. We provide data supporting that DNA methylation is a potential mechanism involved in the long-term adaptation and programming of the genome in response to early adverse environmental factors.

Disaster-related prenatal maternal stress explains increasing amounts of variance in body composition through childhood and adolescence: Project Ice Storm

BACKGROUND The increasing prevalence of childhood obesity worldwide has become a public health issue. While many factors are involved in the development of obesity, stress during pregnancy has been linked to adiposity. However, research involving stressors that are independent of pregnant womens socioeconomic and psychological characteristics is rare. The present study made use of a natural disaster (1998 Quebec ice storm) to determine which aspect of the womens disaster experience (objective hardship, subjective stress, and/or cognitive appraisal) were associated with body mass index levels and/or waist to height ratio across childhood and adolescence. METHODS Measure of objective hardship, subjective stress, and cognitive appraisal were obtained following the 1998 Quebec ice storm. We measured height, weight, and waist circumference in children at ages 5½, 8½, 11½, 13½, and 15½. RESULTS Our results show that higher prenatal maternal stress was associated with higher body mass index levels and central adiposity in children of ages 5½, 8½, 13½, and 15½. The effects of prenatal maternal stress on anthropometric measurements tend to increase as the children grew older. DISCUSSION The findings of this study highlight the long-lasting effect of prenatal stress on body composition, and are compatible with the current theory of fetal programming. Hopefully, our increased knowledge of the effects of prenatal stress on the fetus will lead to improved awareness and the creation of early intervention programs, ultimately improving womens and childrens health in the future.

DNA methylation mediates the effect of exposure to prenatal maternal stress on cytokine production in children at age 13½ years: Project Ice Storm

BackgroundPrenatal maternal stress (PNMS) is an important programming factor of postnatal immunity. We tested here the hypothesis that DNA methylation of genes in the NF-κB signaling pathway in T cells mediates the effect of objective PNMS on Th1 and Th2 cytokine production in blood from 13½ year olds who were exposed in utero to the 1998 Quebec ice storm.ResultsBootstrapping analyses were performed with 47 CpGs across a selection of 20 genes for Th1-type cytokines (IFN-γ and IL-2) and Th2-type cytokines (IL-4 and IL-13). Six CpGs in six different NF-κB signaling genes (PIK3CD, PIK3R2, NFKBIA, TRAF5, TNFRSF1B, and LTBR) remained as significant negative mediators of objective PNMS on IFN-γ secretion after correcting for multiple comparisons. However, no mediation effects on IL-2, IL-4 and IL-13 survived Bonferroni correction.ConclusionsThe present study provides preliminary evidence supporting the mediating role of DNA methylation in the association between objective aspects of PNMS and child immune states, favoring a Th2 shift.

Prenatal Stress due to a Natural Disaster Predicts Adiposity in Childhood: The Iowa Flood Study

Prenatal stress can affect lifelong physical growth, including increased obesity risk. However, human studies remain limited. Natural disasters provide models of independent stressors unrelated to confounding maternal characteristics. We assessed degree of objective hardship and subjective distress in women pregnant during severe flooding. At ages 2.5 and 4 years we assessed body mass index (BMI), subscapular plus triceps skinfolds (SS + TR, an index of total adiposity), and SS : TR ratio (an index of central adiposity) in their children (n = 106). Hierarchical regressions controlled first for several potential confounds. Controlling for these, flood exposure during early gestation predicted greater BMI increase from age 2.5 to 4, as well as total adiposity at 2.5. Greater maternal hardship and distress due to the floods, as well as other nonflood life events during pregnancy, independently predicted greater increase in total adiposity between 2.5 and 4 years. These results support the hypothesis that prenatal stress increases adiposity beginning in childhood and suggest that early gestation is a sensitive period. Results further highlight the additive effects of maternal objective and subjective stress, life events, and depression, emphasizing the importance of continued studies on multiple, detailed measures of maternal mental health and experience in pregnancy and child growth.

Pregnant women's cognitive appraisal of a natural disaster affects their children's BMI and central adiposity via DNA methylation: Project Ice Storm

We determined the extent to which DNA methylation mediates the effects of maternal cognitive appraisal of a natural disaster during pregnancy on offspring growth at age 13. Negative maternal cognitive appraisal predicted both lower BMI and central adiposity via DNA methylation of diabetes-related genes, suggesting a protective role of epigenetics.

A Potential Psychological Mechanism Linking Disaster-Related Prenatal Maternal Stress with Child Cognitive and Motor Development at 16 Months: The QF2011 Queensland Flood Study.

Fetal exposure to prenatal maternal stress can have lifelong consequences, with different types of maternal stress associated with different areas of child development. Fewer studies have focused on motor skills, even though they are strongly predictive of later development across a range of domains. Research on mechanisms of transmission has identified biological cascades of stress reactions, yet links between psychological stress reactions are rarely studied. This study investigates the relationship between different aspects of disaster-related prenatal maternal stress and child cognitive and motor development, and proposes a cascade of stress reactions as a potential mechanism of transmission. Mothers in the Queensland Flood Study (QF2011) exposed to a major flood during pregnancy completed questionnaires assessing flood exposure, symptoms of peritraumatic distress, dissociation, and posttraumatic stress (PTSD), and cognitive appraisal of the overall flood consequences. At 16 months post-partum, children’s (N = 145) cognitive and motor development was assessed using the Bayley-III. Flood exposure predicted child cognitive development and maternal PTSD symptoms and negative cognitive appraisal were significantly negatively related to child motor development, with all relationships moderated by timing of exposure. Together, a cascade of stress reactions linked maternal flood exposure to poorer fine motor development. These findings suggest that the way stress reactions operate together is as important as the way they operate in isolation, and identifies a potential psychological mechanism of transmission for the effects of prenatal stress. Results have implications for conceptualizing prenatal stress research and optimizing child development in the wake of natural disasters.

Natural disaster-related prenatal maternal stress is associated with alterations in placental glucocorticoid system: the QF2011 Queensland Flood Study

We investigated the effects of a natural disaster (a sudden flood) as a source of prenatal maternal stress (PNMS) on the placental glucocorticoid system and glucose transporters. Whether the gestational age at the time of the flood moderated these effects was also evaluated. Placental samples were collected from participants in the 2011 Queensland Flood Study (QF2011) who were pregnant in the first or second trimester at the onset of the flood. Detailed questionnaire results for objective hardship and composite subjective distress were obtained to assess stress levels. Subjective distress was significantly associated with a reduction in placental NR3C1-β mRNA levels for males only (β = -0.491, p = 0.005). In female placentas, objective hardship was marginally linked with lower SLC2A1 mRNA levels while subjective distress was a marginally significant predictor of higher placental SLC2A4 mRNA levels. Gestational age at the time of the flood was a significant moderator of the effect of subjective distress on placental mRNA levels for NR3C1-α (p = 0.046) and HSD11B1 (p = 0.049) in male placentas: if the flood occurred in mid-pregnancy, lower subjective distress predicted higher HSD11B1 while higher subjective distress predicted lower NR3C1-α placental mRNA level. While results did not show any PNMS effects on placental HSD11B2 mRNA and protein levels, and activity, we showed a reduction in placental NR3C1-β mRNA level in male placentas. Our results show evidence of distinct placental glucocorticoid and glucose systems adaptations to PNMS as a function of fetal sex and gestational timing of exposure, with high subjective PNMS in mid-pregnancy associated with lower levels of expression of glucocorticoid-promoting gene in males, leaving the fetus less protected against maternal stress. The exact mechanism by which natural disaster-related PNMS acts on the placenta and the impact on fetal programming requires further investigation.

DNA methylation mediates the effect of maternal cognitive appraisal of a disaster in pregnancy on the child’s C-peptide secretion in adolescence: Project Ice Storm

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.