The hypothalamic–pituitary–adrenal (HPA) axis coordinates an organism's response to environmental stress. The responsiveness and sensitivity of an offspring's stress response may be shaped not only by stressors encountered in their early post‐natal environment but also by stressors in their parent's environment. Yet, few studies have considered how stressors encountered in both of these early life environments may function together to impact the developing HPA axis. Here, we manipulated stressors in the parental and post‐natal environments in a population of house sparrows (
- Award ID(s):
- 1840903
- NSF-PAR ID:
- 10129457
- Date Published:
- Journal Name:
- Integrative and Comparative Biology
- Volume:
- 59
- Issue:
- 2
- ISSN:
- 1540-7063
- Page Range / eLocation ID:
- 264 to 272
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Passer domesticus ) to assess their impact on changes in DNA methylation (and corresponding gene expression) in a suite of genes within the HPA axis. We found that nestlings that experienced early life stress across both life‐history periods had higher DNA methylation in a critical HPA axis gene, the glucocorticoid receptor (NR3C1 ). In addition, we found that the life‐history stage when stress was encountered impacted some genes (HSD11B1, NR3C1 andNR3C2 ) differently. We also found evidence for the mitigation of parental stress by post‐natal stress (inHSD11B1 andNR3C2 ). Finally, by assessing DNA methylation in both the brain and blood, we were able to evaluate cross‐tissue patterns. While some differentially methylated regions were tissue‐specific, we found cross‐tissue changes inNR3C2 andNR3C1 , suggesting that blood is a suitable tissue for assessing DNA methylation as a biomarker of early life stress. Our results provide a crucial first step in understanding the mechanisms by which early life stress in different life‐history periods contributes to changes in the epigenome of the HPA axis. -
null (Ed.)Stress is known to affect health throughout life and into future generations, but the underlying molecular mechanisms are unknown. We tested the hypothesis that maternal psychosocial stress influences DNA methylation (DNAm), which in turn impacts newborn health outcomes. Specifically, we analyzed DNAm at individual, regional, and genome-wide levels to test for associations with maternal stress and newborn birth weight. Maternal venous blood and newborn cord blood (n = 24 and 22, respectively) were assayed for methylation at ∼450,000 CpG sites. Methylation was analyzed by examining CpG sites individually in an epigenome-wide association study (EWAS), as regional groups using variably methylated region (VMR) analysis in maternal blood only, and through the epigenome-wide measures using genome-wide mean methylation (GMM), Horvath's epigenetic clock, and mitotic age. These methylation measures were tested for association with three measures of maternal stress (maternal war trauma, chronic stress, and experience of sexual violence) and one health outcome (newborn birth weight). We observed that maternal experiences of war trauma, chronic stress, and sexual assault were each associated with decreased newborn birth weight (p < 1.95 × 10-7 in all cases). Testing individual CpG sites using EWAS, we observed no associations between DNAm and any measure of maternal stress or newborn birth weight in either maternal or cord blood, after Bonferroni multiple testing correction. However, the top-ranked CpG site in maternal blood that associated with maternal chronic stress and sexual violence before multiple testing correction is located near the SPON1 gene. Testing at a regional level, we found increased methylation of a VMR in maternal blood near SPON1 that was associated with chronic stress and sexual violence after Bonferroni multiple testing correction (p = 1.95 × 10-7 and 8.3 × 10-6, respectively). At the epigenomic level, cord blood GMM was associated with significantly higher levels of war trauma (p = 0.025) and was suggestively associated with sexual violence (p = 0.053). The other two epigenome-wide measures were not associated with maternal stress or newborn birth weight in either tissue type. Despite our small sample size, we identified associations even after conservative multiple testing correction. Specifically, we found associations between DNAm and the three measures of maternal stress across both tissues; specifically, a VMR in maternal blood and GMM in cord blood were both associated with different measures of maternal stress. The association of cord blood GMM, but not maternal blood GMM, with maternal stress may suggest different responses to stress in mother and newborn. It is noteworthy that we found associations only when CpG sites were analyzed in aggregate, either as VMRs or as a broad summary measure of GMM.more » « less
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ABSTRACT Epigenetic mechanisms may play a central role in mediating phenotypic plasticity, especially during range expansions, when populations face a suite of novel environmental conditions. Individuals may differ in their epigenetic potential (EP; their capacity for epigenetic modifications of gene expression), which may affect their ability to colonize new areas. One form of EP, the number of CpG sites, is higher in introduced house sparrows (Passer domesticus) than in native birds in the promoter region of a microbial surveillance gene, Toll-like Receptor 4 (TLR4), which may allow invading birds to fine-tune their immune responses to unfamiliar parasites. Here, we compared TLR4 gene expression from whole blood, liver and spleen in house sparrows with different EP, first challenging some birds with lipopolysaccharide (LPS), to increase gene expression by simulating a natural infection. We expected that high EP would predict high inducibility and reversibility of TLR4 expression in the blood of birds treated with LPS, but we did not make directional predictions regarding organs, as we could not repeatedly sample these tissues. We found that EP was predictive of TLR4 expression in all tissues. Birds with high EP expressed more TLR4 in the blood than individuals with low EP, regardless of treatment with LPS. Only females with high EP exhibited reversibility in gene expression. Further, the effect of EP varied between sexes and among tissues. Together, these data support EP as one regulator of TLR4 expression.
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Abstract Objective Infancy is both a critical window for hypothalamic–pituitary–adrenal (HPA) axis development, and a sensitive period for social–emotional influences. We hypothesized that the social–emotional quality of maternal–infant interactions are associated with methylation of HPA‐axis gene
NR3C1 later in childhood.Methods Using a subsample of 114 mother‐infant pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC), linear regression models were created to predict variance in methylation of seven selected CpG sites from
NR3C1 in whole blood at age 7 years, including the main predictor variable of the first principal component score of observed maternal–infant interaction quality (derived from the Thorpe Interaction Measure at 12 months of age) and covariates of cell‐type proportion, maternal financial difficulties and marital status at 8 months postnatal, child birthweight, and sex.Results CpG site cg27122725 methylation was negatively associated with warmer, more positive maternal interaction with her infant (
β = 0.19,p = .02,q = 0.13). In sensitivity analyses, the second highest quartile of maternal behavior (neutral, hesitant behavior) was positively associated with cg12466613 methylation. The other five CpG sites were not significantly associated with maternal–infant interaction quality.Conclusions Narrow individual variation of maternal interaction with her infant is associated with childhood methylation of two CpG sites on
NR3C1 that may be particularly sensitive to environmental influences. Infancy may be a sensitive period for even small influences from the social–emotional environment on the epigenetic determinants of HPA‐axis function. -
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Abstract Objectives Candidate gene methylation studies of NR3C1 have identified associations with psychosocial adversity, including war trauma. This pilot study (sample sizes from 22 to 45 for primary analyses) examined NR3C1 methylation in a group of Kenyan pastoralist young men in relation to culturally relevant traumatic experiences, including participation in coalitional lethal gun violence.
Methods Adolescent and young adult Samburu men (“warriors”) were recruited for participation. DNA was obtained from whole saliva and methylation analyses performed using mass spectrometry. We performed a data reduction of variables from a standardized instrument of lifetime stress using a factor analysis and we assessed the association between the extracted factors with culturally relevant and cross‐culturally comparative experiences.
Results Cumulative lifetime trauma exposure and forms of violence to which warriors are particularly susceptible were associated with DNA methylation changes in the NR3C1 1Fpromoter region but not in the NR3C1 1Dpromoter region. However, sensitivity analyses revealed significant associations between individual CpG sites in both regions and cumulative stress exposures, war exposure timing, and war fatalities.
Conclusions This study supports the importance of NR3C1 methylation changes in response to challenging life circumstances, including in a global south cultural context that contrasts in notable ways from global north contexts and from the starkly tragic examples of the Rwandan genocide and war‐associated rape explored in recent studies. Timing of traumatic exposure and culturally salient means to measure enduring symptoms of trauma remain important considerations for DNA methylation studies.
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1093/icb/icz034
