Genome-wide association study identifies a novel maternal gene × stress interaction associated with spontaneous preterm birth (original) (raw)
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Background: Chronic stress is considered to be one of many causes of human preterm birth (PTB), but no direct evidence has yet been provided. Here we show in rats that stress across generations has downstream effects on endocrine, metabolic and behavioural manifestations of PTB possibly via microRNA (miRNA) regulation. Methods: Pregnant dams of the parental generation were exposed to stress from gestational days 12 to 18. Their pregnant daughters (F1) and grand-daughters (F2) either were stressed or remained as non-stressed controls. Gestational length, maternal gestational weight gain, blood glucose and plasma corticosterone levels, litter size and offspring weight gain from postnatal days 1 to 30 were recorded in each generation, including F3. Maternal behaviours were analysed for the first hour after completed parturition, and offspring sensorimotor development was recorded on postnatal day (P) 7. F0 through F2 maternal brain frontal cortex, uterus and placenta miRNA and gene expression patterns were used to identify stress-induced epigenetic regulatory pathways of maternal behaviour and pregnancy maintenance. Results: Progressively up to the F2 generation, stress gradually reduced gestational length, maternal weight gain and behavioural activity, and increased blood glucose levels. Reduced offspring growth and delayed behavioural development in the stress cohort was recognizable as early as P7, with the greatest effect in the F3 offspring of transgenerationally stressed mothers. Furthermore, stress altered miRNA expression patterns in the brain and uterus of F2 mothers, including the miR-200 family, which regulates pathways related to brain plasticity and parturition, respectively. Main miR-200 family target genes in the uterus, Stat5b, Zeb1 and Zeb2, were downregulated by multigenerational stress in the F1 generation. Zeb2 was also reduced in the stressed F2 generation, suggesting a causal mechanism for disturbed pregnancy maintenance. Additionally, stress increased placental miR-181a, a marker of human PTB.
N Eurobiology of Stress: Bridging the Genotype- Phenotype Gap
2008
The biological response to stress is concerned with the maintenance of homeostasis in the presence of real or perceived challenges. This process requires numerous adaptive responses involving changes in the central nervous and neuroendocrine systems. When a situation is perceived as stressful, the brain activates many neuronal circuits linking centers involved in sensory, motor, autonomic, neuroendocrine, cognitive, and emotional functions in order to adapt to the demand. However, the details of the pathways by which the brain translates stressful stimuli into the final, integrated biological response are presently incompletely understood. Nevertheless, it is clear that dysregulation of these physiological responses to stress can have severe psychological and physiological consequences, and there is much evidence to suggest that inappropriate regulation, disproportional intensity, or chronic and/or irreversible activation of the stress response is linked to the etiology and pathophy...
Cognition, 2014
Maternal stress during pregnancy has been associated with a range of adverse outcomes in offspring and the catechol-O-methyltransferase (COMT) gene has been linked to differential susceptibility to the consequences of antenatal stress. This study examined two functional polymorphisms of the COMT gene (rs4680 and rs165599) in relation to maternal perceived stress and childhood cognitive performance. Data from the longitudinal Auckland Birthweight Collaborative (ABC) study was used. Maternal perceived stress over the prior month was measured at birth, 3.5 and 7 years. Full-Scale IQ (FSIQ) was measured at ages 7 and 11. At age 11, a total of 546 DNA samples were collected from the child participants. Data were subjected to a series of split-plot ANCOVAs with birthweight for gestational age and maternal school leaving age as covariates. There were direct effects of maternal stress during the last month of pregnancy on offspring FSIQ at ages 7 and 11 years. A significant interaction revealed that children exposed to high maternal antenatal stress had significantly lower FSIQ scores at both 7 and 11 years of age than those exposed to low stress, only when they were carriers of the rs165599 G allele. At each age, this difference was of approximately 5 IQ points. The G allele of the rs165599 polymorphism may confer genetic susceptibility to negative cognitive outcomes arising from exposure to antenatal stress. This finding highlights the need to consider gene-environment interactions when investigating the outcomes of antenatal stress exposure.
Cohort Profile: Stress in Pregnancy (SIP) Study
International journal of epidemiology, 2017
to understand the extent to which an adverse environment in utero can alter fetal growth and development, with potential lifelong impacts on health and disease, based on the theoretical framework of the 'Developmental Origins of Health and Diseases (DoHaD) Hypothesis'. 1-6 Growing evidence 7-9 suggests that not only the genome but also the epigenome, the heritable, quasi-stable yet dynamic control of gene expression, can be modulated by the environment, and plays a vital role in defining health and disease in growing offspring. 10-12 Preclinical studies demonstrated that antenatal stress leads to dysregulated neurobehavioural functioning and problems with development, providing a solid platform for hypothesis testing in human studies. Human studies have also demonstrated that antenatal exposure to broadly defined stress (i.e. stressful life events and psychological problems) is linked to long-term neurobehavioural problems in offspring, 13,14 such as autism, 15,16 schizophrenia 17-20 and attention deficit/hyperactivity disorder, 21-23 as well as growth-related suboptimal reproductive outcomes such as intra-uterine growth restriction (IUGR) 24-26 and obesity, 27-29 through epigenetic mechanisms. Human studies remain hampered by methodological restrictions, including: (i) the inability to randomize pregnant women in varying stressful condition and to systematically control for the level and timing of any exposure; (ii) stressful c A graduate/professional degree includes higher level postgraduate degrees (Master's, MD, JD, PhD etc).
Placental transcriptomic signatures of prenatal and preconceptional maternal stress
Molecular Psychiatry, 2024
Prenatal exposure to maternal psychological stress is associated with increased risk for adverse birth and child health outcomes. Accumulating evidence suggests that preconceptional maternal stress may also be transmitted intergenerationally to negatively impact offspring. However, understanding of mechanisms linking these exposures to offspring outcomes, particularly those related to placenta, is limited. Using RNA sequencing, we identified placental transcriptomic signatures associated with maternal prenatal stressful life events (SLEs) and childhood traumatic events (CTEs) in 1 029 mother-child pairs in two birth cohorts from Washington state and Memphis, Tennessee. We evaluated individual gene-SLE/CTE associations and performed an ensemble of gene set enrichment analyses combing across 11 popular enrichment methods. Higher number of prenatal SLEs was significantly (FDR < 0.05) associated with increased expression of ADGRG6, a placental tissue-specific gene critical in placental remodeling, and decreased expression of RAB11FIP3, an endocytosis and endocytic recycling gene, and SMYD5, a histone methyltransferase. Prenatal SLEs and maternal CTEs were associated with gene sets related to several biological pathways, including upregulation of protein processing in the endoplasmic reticulum, protein secretion, and ubiquitin mediated proteolysis, and down regulation of ribosome, epithelial mesenchymal transition, DNA repair, MYC targets, and amino acid-related pathways. The directional associations in these pathways corroborate prior non-transcriptomic mechanistic studies of psychological stress and mental health disorders, and have previously been implicated in pregnancy complications and adverse birth outcomes. Accordingly, our findings suggest that maternal exposure to psychosocial stressors during pregnancy as well as the mother's childhood may disrupt placental function, which may ultimately contribute to adverse pregnancy, birth, and child health outcomes.
STRESS AND THE BRAIN: FROM ADAPTATION TO DISEASE
| In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation. In genetically predisposed individuals, an imbalance in this binary control mechanism can introduce a bias towards stress-related brain disease after adverse experiences. New candidate susceptibility genes that serve as markers for the prediction of vulnerable phenotypes are now being identified.
Stress risk factors and stress-related pathology: Neuroplasticity, epigenetics and endophenotypes
Stress, 2011
This paper highlights a symposium on stress risk factors and stress susceptibility, presented at the Neurobiology of Stress workshop in Boulder, CO, in June 2010. This symposium addressed factors linking stress plasticity and reactivity to stress pathology in animal models and in humans. Dr. J. Radley discussed studies demonstrating prefrontal cortical neuroplasticity and prefrontal control of hypothalamo -pituitary -adrenocortical axis function in rats, highlighting the emerging evidence of the critical role that this region plays in normal and pathological stress integration. Dr. M. Kabbaj summarized his studies of possible epigenetic mechanisms underlying behavioral differences in rat populations bred for differential stress reactivity. Dr. L. Jacobson described studies using a mouse model to explore the diverse actions of antidepressants in brain, suggesting mechanisms whereby antidepressants may be differentially effective in treating specific depression endophenotypes. Dr. R. Yehuda discussed the role of glucocorticoids in post-traumatic stress disorder (PTSD), indicating that low cortisol level may be a trait that predisposes the individual to development of the disorder. Furthermore, she presented evidence indicating that traumatic events can have transgenerational impact on cortisol reactivity and development of PTSD symptoms. Together, the symposium highlighted emerging themes regarding the role of brain reorganization, individual differences, and epigenetics in determining stress plasticity and pathology.
NeuroToxicology, 2008
We previously demonstrated potentiated effects of maternal Pb exposure producing blood Pb(PbB) levels averaging 39 μg/dl combined with prenatal restraint stress (PS) on stress challenge responsivity of female offspring as adults. The present study sought to determine if: 1) such interactions occurred at lower PbBs, 2) exhibited gender specificity, and 3) corticosterone and neurochemical changes contributed to behavioral outcomes. Rat dams were exposed to 0, 50 or 150 ppm Pb acetate drinking water solutions from 2 mos prior to breeding through lactation (pup exposure ended at weaning; mean PbBs of dams at weaning were <1, 11 and 31 μg/dl, respectively); a subset in each Pb group underwent prenatal restraint stress (PS) on gestational days 16-17. The effects of variable intermittent stress challenge (restraint, cold, novelty) on Fixed Interval (FI) schedule controlled behavior and corticosterone were examined in offspring when they were adults. Corticosterone changes were also measured in non-behaviorally tested (NFI) littermates. PS alone was associated with FI rate suppression in females and FI rate enhancement in males; Pb exposure blunted these effects in both genders, particularly following restraint stress. PS alone produced modest corticosterone elevation following restraint stress in adult females, but robust enhancements in males following all challenges. Pb exposure blunted these corticosterone changes in females, but further enhanced levels in males. Pb-associated changes showed linear concentration dependence in females, but non-linearity in males, with stronger or selective changes at 50 ppm. Statistically, FI performance was associated with corticosterone changes in females, but with frontal cortical dopaminergic and serotonergic changes in males. Corticosterone changes differed markedly in FI vs. NFI groups in both genders, demonstrating a critical role for behavioral history and raising caution about extrapolating biochemical markers across such conditions. These findings demonstrate that maternal Pb interacts with prenatal stress to further modify both behavioral and corticosterone responses to stress challenge, thereby suggesting that studies of Pb in isolation from other disease risk factors will not reveal the extent of its adverse effects. These findings also underscore the critical need to extend screening programs for elevated Pb exposure, now restricted to young children, to pregnant, at risk, women.