Sonja Entringer

Stress exposure in intrauterine life is associated with shorter telomere length in young adulthood

Leukocyte telomere length (LTL) is a predictor of age-related disease onset and mortality. The association in adults of psychosocial stress or stress biomarkers with LTL suggests telomere biology may represent a possible underlying mechanism linking stress and health outcomes. It is, however, unknown whether stress exposure in intrauterine life can produce variations in LTL, thereby potentially setting up a long-term trajectory for disease susceptibility. We, therefore, as a first step, tested the hypothesis that stress exposure during intrauterine life is associated with shorter telomeres in adult life after accounting for the effects of other factors on LTL. LTL was assessed in 94 healthy young adults. Forty-five subjects were offspring of mothers who had experienced a severe stressor in the index pregnancy (prenatal stress group; PSG), and 49 subjects were offspring of mothers who had a healthy, uneventful index pregnancy (comparison group; CG). Prenatal stress exposure was a significant predictor of subsequent adult telomere length in the offspring (178-bp difference between prenatal stress and CG; d = 0.41 SD units; P < 0.05). The effect was substantially unchanged after adjusting for potential confounders (subject characteristics, birth weight percentile, and early-life and concurrent stress level), and was more pronounced in women (295-bp difference; d = 0.68 SD units; P < 0.01). To the best of our knowledge, this study provides the first evidence in humans of an association between prenatal stress exposure and subsequent shorter telomere length. This observation may help shed light on an important biological pathway underlying the developmental origins of adult health and disease risk.

Prenatal exposure to maternal psychosocial stress and HPA axis regulation in young adults

Epidemiological studies have reported associations between measures of size and weight at birth and disease risk in later life. Alteration in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis in response to prenatal stress has been proposed as one underlying mechanism. The present study investigated in humans the association of prenatal psychosocial stress exposure with subsequent HPA axis regulation in adult life, with a focus on measures of response to challenge and feedback sensitivity. Healthy young adults whose mothers experienced severe stress during their pregnancy in form of major negative life events (e.g. death of someone close; prenatal stress (PS) group, n=31) and an age-matched comparison group (CG, n=30) underwent the Trier Social Stress Test (TSST) and a 1 microg ACTH(1-24) stimulation test. In addition, a diurnal cortisol profile was assessed. ACTH concentrations following a standardized behavioural challenge paradigm (TSST) were marginally significantly higher in PS subjects than in CG subjects (p=.06). Pre-TSST adrenocortical (cortisol) levels were lower (p=.007), whereas the increase in cortisol in response to the TSST was higher (p=.03) in PS subjects compared to CG subjects. Cortisol concentrations following a pharmacological stimulation test simulating pituitary activity (ACTH(1-24) test) were significantly lower in PS than in CG subjects (p=.006). No differences emerged between the two groups in basal diurnal cortisol levels. This study provides first evidence in humans of an association between prenatal psychosocial stress exposure and subsequent alterations in the regulation of the HPA axis.

Stress and telomere biology: A lifespan perspective

In the past decade, the growing field of telomere science has opened exciting new avenues for understanding the cellular and molecular substrates of stress and stress-related aging processes over the lifespan. Shorter telomere length is associated with advancing chronological age and also increased disease morbidity and mortality. Emerging studies suggest that stress accelerates the erosion of telomeres from very early in life and possibly even influences the initial (newborn) setting of telomere length. In this review, we highlight recent empirical evidence linking stress and mental illnesses at various times across the lifespan with telomere erosion. We first present findings in the developmental programming of telomere biology linking prenatal stress to newborn and adult telomere length. We then present findings linking exposure to childhood trauma and to certain mental disorders with telomere shortening. Last, we review studies that characterize the relationship between related health-risk behaviors with telomere shortening over the lifespan, and how this process may further buffer the negative effects of stress on telomeres. A better understanding of the mechanisms that govern and regulate telomere biology throughout the lifespan may inform our understanding of etiology and the long-term consequences of stress and mental illnesses on aging processes in diverse populations and settings.

Sex Specific Associations between Common Glucocorticoid Receptor Gene Variants and Hypothalamus-Pituitary-Adrenal Axis Responses to Psychosocial Stress

BACKGROUND Alterations in glucocorticoid (GC) signaling have been associated with a number of psychiatric disorders. Genetic variation of the glucocorticoid receptor (GR) might be one of the factors underlying susceptibility to stress related disease. METHODS We investigated 206 healthy subjects and assessed associations between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress (Trier Social Stress Test, TSST) and glucocorticoid sensitivity measured by a dexamethasone suppression test (DST). RESULTS Male 9beta AG carriers displayed the highest adrenocorticotropic hormone (ACTH) and total cortisol TSST responses (for ACTH: main effect genotype p = .02) whereas male BclI GG carriers showed diminished responses. Remarkably, the BclI GG genotype in women (all using oral contraceptives) was associated with the highest total cortisol TSST responses, resulting in a significant sex by genotype interaction (p = .03). Following the DST, male 9beta AG carriers had elevated ACTH levels (sex by genotype interaction p = .03). CONCLUSIONS We observed significant sex specific associations between GR gene polymorphisms and HPA axis responses to psychosocial stress as well as GC sensitivity. These findings support the relevance of GR gene polymorphisms in HPA axis regulation. Genetic variations of the GR might constitute a risk factor in development of HPA axis related disorders.

The Contribution of Maternal Stress to Preterm Birth: Issues and Considerations

Preterm birth represents the most significant problem in maternal-child health, with maternal stress identified as a variable of interest. The effects of maternal stress on risk of preterm birth may vary as a function of context. This article focuses on select key issues and questions highlighting the need to develop a better understanding of which particular subgroups of pregnant women may be especially vulnerable to the potentially detrimental effects of maternal stress, and under what circumstances and at which stages of gestation. Issues related to the characterization and assessment of maternal stress and candidate biologic mechanisms are addressed.

Prenatal stress and developmental programming of human health and disease risk: concepts and integration of empirical findings.

Purpose of reviewThe concept of the developmental origins of health and disease susceptibility is rapidly attracting interest and gaining prominence as a complementary approach to understanding the causation of many complex common disorders that confer a major burden of disease; however several important issues and questions remain to be addressed, particularly in the context of humans. Recent findingsIn this review we enunciate some of these questions and issues, review empirical evidence primarily from our own recent studies on prenatal stress and stress biology, and discuss putative maternal–placental–fetal endocrine and immune/inflammatory candidate mechanisms that may underlie and mediate short-term and long-term effects of prenatal stress on the developing human embryo and fetus, with a specific focus on body composition, metabolic function, and obesity risk. SummaryThe implications for research and clinical practice are discussed with a summary of recent advances in noninvasive methods to characterize fetal, newborn, infant, and child developmental and health-related processes that, when coupled with available state-of-the-art statistical modeling approaches for longitudinal, repeated measures time series analysis, now afford unprecedented opportunities to explore and uncover the developmental origins of human health and disease.

Covariance between psychological and endocrine responses to pharmacological challenge and psychosocial stress: a question of timing

Objective: To test if the covariance of hypothalamus-pituitary-adrenal (HPA) axis and subjective-psychological responses to stress is dependent on different dynamics of these systems. Although stress theories typically assume substantial correlations of psychological and endocrine stress responses, studies have produced inconsistent results. One reason for this might be imperfect coupling of the different stress response systems. However, inconsistent correlations might also be a result of different on-/offsets of these stress responses, i.e., specific dynamics of the systems. Methods: HPA axis indicators and subjective-psychological states were repeatedly and synchronously measured in a pharmacological challenge test (injection of corticotropin-releasing hormone and infusion of arginine vasopressin; Study 1; n = 42) and a psychosocial stress situation (Trier Social Stress Test; Study 2; n = 219). Cross-correlation analysis was used to test for lag effects in HPA axis reactivity and psychoendocrine responses. Results: Analyses revealed high cross-correlations of adrenocorticotropic hormone with cortisol responses (up to r = .80 in Study 1 and r = .56 in Study 2) and positive associations of psychological with endocrine stress responses (up to r = .48 in Study 1 and r = .54 in Study 2) at nonzero lags. Subjective-psychological responses preceded HPA axis responses. Moreover, high levels of cortisol were associated with lower later levels of anxiety and activation. Conclusions: The findings suggest that psychoendocrine stress responses are more closely coupled than previous studies suggested. Due to different dynamics of the systems, endocrine responses lag behind psychological responses. ACTH = adrenocorticotropic hormone; AD-ACL = Activation-Deactivation Adjective Checklist; AVP = arginine vasopressin; BMI = body mass index; CRH = corticotropin-releasing hormone; ELISA = enzyme-linked immunosorbent assay; EDTA = ethylene diamine tetraacetic acid; HPA = hypothalamus-pituitary-adrenal; STAI-S = State-Trait Anxiety Inventory-State Version; TSST = Trier Social Stress Test.

Developmental origins of health and disease: environmental exposures.

The developmental origins of health and disease (DOHaD) approach has evolved over the past 20 years, and the current hypothesis proposes that fetal adaptations to intrauterine and maternal conditions during development shape structure and function of organs. Here we present a review of some environmental exposures that may trigger fetal maladaptations in these processes, including three examples: exposures to tobacco smoke, antidepressant medication, and folic acid deficits in the food supply. We provide a selected review of current research on the effects of each of these exposures on fetal development and birth outcomes, and use the DOHaD approach to suggest how these exposures may alter long-term outcomes. In the interpretation of this literature, we review the evidence of gene-environment interactions based on evaluation of biological pathways and evidence that some exposures to the fetus may be moderated by maternal and fetal genotypes. Finally, we use the design of the National Childrens Study (now in progress) to propose how the DOHaD approach could be used to address questions that have emerged in this area that are relevant to reproductive medicine and subsequent health outcomes.

Sex-specific association between the 5-HTT gene-linked polymorphic region and basal cortisol secretion

OBJECTIVE A key regulator of serotonergic neurotransmission is the serotonin transporter (5-HTT) and a common 5HTT gene promoter polymorphism, termed 5HTTLPR, is associated with phenotypes related to anxiety and depression. Furthermore, the serotonergic system influences hypothalamus-pituitary-adrenal (HPA) axis activity, which, in turn, is related to psychiatric diseases. METHODS To explore the association between the 5-HTTLPR and HPA axis regulation we performed a detailed endophenotyping in 216 healthy subjects (all 126 females used oral contraceptives). RESULTS While ACTH and cortisol responses to an established psychosocial stress paradigm (Trier Social Stress Test) were not found to be related to the 5-HTTLPR, we observed a significant and sex-specific association with the cortisol awakening response, which is a reliable marker of basal cortisol secretion, and with ACTH levels after dexamethasone administration. The supplementary inclusion of a 5-HTT A/G polymorphism (rs25531) in the analyses did not substantially modify our results. CONCLUSION These findings support the view that the 5-HTTLPR is associated with a major neuroendocrine stress system. It could be speculated that the sex-specific nature of this association contributes to the distinct gender differences in the vulnerability for depression.

Attenuation of maternal psychophysiological stress responses and the maternal cortisol awakening response over the course of human pregnancy

The effects of maternal stress during pregnancy may depend, in part, on the timing in gestation of the occurrence of stress. The aim of the present study was to examine the effect of stage of gestation on maternal psychophysiological responses to stress using a standardized laboratory paradigm and on the cortisol response to awakening (CAR). A longitudinal design was employed to quantify maternal psychophysiological stress reactivity [changes in heart rate (HR), blood pressure, salivary cortisol, and psychological distress in response to the trier social stress test (TSST)] and the CAR at approximately 17 and 31 weeks gestation in a sample of 148 women. To account for the possible effects of habituation when being exposed to the same stress protocol twice, a non-pregnant comparison group (CG, N = 36) also underwent these assessments at two time points, with a comparable time interval between the assessments. In both groups, the TSST elicited significant changes in maternal HR, mean arterial pressure, and psychological distress levels but not a significant increase in cortisol levels. Among the pregnant women (pregnant group(PG)), the stressor-induced increases in HR, blood pressure, and psychological distress were significantly lower at the second (31 weeks gestation) compared to the first (17 weeks gestation) assessment of pregnancy (all p < 0.01). The maternal CAR was also significantly attenuated in later compared to earlier gestation (p = 0.003). In the CG, there were no significant differences in psychophysiological stress responses and in the CAR across the two assessments. Among pregnant women there is a progressive attenuation of psychophysiological stress responses with advancing gestation. This attenuation is unlikely to be attributable to habituation. Individual differences in the degree of attenuation of stress responses over gestation may represent a novel marker of stress susceptibility in human pregnancy.