microRNAs and Gene–Environment Interactions in Autism: Effects of Prenatal Maternal Stress and the SERT Gene on Maternal microRNA Expression

Background: Genetics and environment both are critical in autism spectrum disorder (ASD), but their interaction (G × E) is less understood. Numerous studies have shown higher incidence of stress exposures during pregnancies with children later diagnosed with ASD. However, many stress-exposed mothers have unaffected children. The serotonin transporter (SERT) gene affects stress reactivity. Two independent samples have shown that the association between maternal stress exposure and ASD is greatest with maternal presence of the SERT short (S)-allele (deletion in the promoter region). MicroRNAs play a regulatory role in the serotonergic pathway and in prenatal stress and are therefore potential mechanistic targets in this setting.Design/methods: We profiled microRNA expression in blood from mothers of children with ASD, with known stress exposure during pregnancy. Samples were divided into groups based on SERT genotypes (LL/LS/SS) and prenatal stress level (high/low).Results: Two thousand five hundred mature microRNAs were examined. The ANOVA analysis showed differential expression (DE) of 119 microRNAs; 90 were DE in high- vs. low-stress groups (stress-dependent). Two (miR-1224-5p, miR-331-3p) were recently reported by our group to exhibit stress-dependent expression in rodent brain samples from embryos exposed to prenatal stress. Another, miR-145-5p, is associated with maternal stress. Across SERT genotypes, with high stress exposure, 20 significantly DE microRNAs were detected, five were stress-dependent. These microRNAs may be candidates for stress × SERT genotype interactions. This is remarkable as these changes were from mothers several years after stress-exposed pregnancies.Conclusions: Our study provides evidence for epigenetic alterations in relation to a G × E model (prenatal maternal stress × SERT gene) in ASD.

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Prenatal Stress and Maternal Immune Dysregulation in Autism Spectrum Disorders: Potential Points for Intervention

Current Pharmaceutical Design ◽

10.2174/1381612825666191119093335 ◽

2020 ◽

Vol 25 (41) ◽

pp. 4331-4343 ◽

Cited By ~ 3

Author(s):

David Q. Beversdorf ◽

Hanna E. Stevens ◽

Kara Gross Margolis ◽

Judy Van de Water

Keyword(s):

Environmental Factors ◽

Prenatal Stress ◽

Maternal Stress ◽

Significant Proportion ◽

Fetal Brain ◽

Immune Dysregulation ◽

Autism Spectrum ◽

Stress Exposure ◽

Stress Susceptibility ◽

The Impact

Background: Genetics is a major etiological contributor to autism spectrum disorder (ASD). Environmental factors, however, also appear to contribute. ASD pathophysiology due to gene x environment is also beginning to be explored. One reason to focus on environmental factors is that they may allow opportunities for intervention or prevention. Methods And Results: Herein, we review two such factors that have been associated with a significant proportion of ASD risk, prenatal stress exposure and maternal immune dysregulation. Maternal stress susceptibility appears to interact with prenatal stress exposure to affect offspring neurodevelopment. We also explore how maternal stress may interact with the microbiome in the neurodevelopmental setting. Additionally, understanding of the impact of maternal immune dysfunction on ASD has recently been advanced by recognition of specific fetal brain proteins targeted by maternal autoantibodies, and identification of unique mid-gestational maternal immune profiles. This might also be interrelated with maternal stress exposure. Animal models have been developed to explore pathophysiology targeting each of these factors. Conclusions: We are beginning to understand the behavioral, pharmacopathological, and epigenetic effects related to these interactions, and we are beginning to explore potential mitigating factors. Continued growth in understanding of these mechanisms may ultimately allow for the identification of multiple potential targets for prevention or intervention for this subset of environmental-associated ASD cases.

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Failure of Saliva Sampling in the QF2011 Queensland Flood Study Examining the Effects of Prenatal Maternal Stress on Neonatal Stress Reactivity

International Journal of Childbirth ◽

10.1891/2156-5287.7.1.31 ◽

2017 ◽

Vol 7 (1) ◽

pp. 31-39

Author(s):

Gabrielle Simcock ◽

Helen Stapleton ◽

Sue Kildea ◽

Laura Shoo ◽

David P. Laplante ◽

...

Keyword(s):

Stress Reactivity ◽

Maternal Stress ◽

Sudden Onset ◽

Stressful Events ◽

Prenatal Maternal Stress ◽

Research Activities ◽

Newborn Screen ◽

Hospital Policies ◽

Heel Prick ◽

The Impact

The study was designed to investigate the impact of disaster-related prenatal maternal stress on neonates’ reactivity to the routinely administered, painful, newborn screen procedure (heelstick or heel prick). We hypothesized that pregnancy exposure to a flood stressor would affect fetal developmental pathways and subsequently neonatal responses to other stressful events, including the newborn screen. The pregnant women we recruited were affected by sudden onset floods in Queensland, Australia in 2011. Using methods similar to those described in the literature, we collected neonatal saliva immediately prior to the newborn screen and +20 and +40 min afterwards. Saliva sampling was halted after failed saliva collection attempts by trained research staff on 17 newborns. This article discusses reasons for our failure, including the influence of bioethical concerns and the requirement that research activities are compliant with hospital policies as well as the necessity of publishing studies that fail to replicate prior research.

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FinnBrain Birth Cohort Study: Effects of prenatal maternal stress and neonatal intensive care on stress reactivity of the 10-week-old infants

Psychoneuroendocrinology ◽

10.1016/j.psyneuen.2017.07.312 ◽

2017 ◽

Vol 83 ◽

pp. 28

Author(s):

Susanna Kortesluoma ◽

Kalle Korhonen ◽

Laura Korhonen ◽

Linnea Karlsson ◽

Hasse Karlsson

Keyword(s):

Cohort Study ◽

Intensive Care ◽

Birth Cohort ◽

Neonatal Intensive Care ◽

Stress Reactivity ◽

Maternal Stress ◽

Birth Cohort Study ◽

Prenatal Maternal Stress

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Prenatal maternal stress and risk of neurodevelopmental disorders in the offspring: A systematic review and meta-analysis protocol

HRB Open Research ◽

10.12688/hrbopenres.12827.1 ◽

2018 ◽

Vol 1 ◽

pp. 15

Author(s):

Nicla Manzari ◽

Karen Matvienko-Sikar ◽

Franco Baldoni ◽

Gerard W. O'Keeffe ◽

Ali S. Khashan

Keyword(s):

Systematic Review ◽

Maternal Stress ◽

Data Extraction ◽

Meta Analysis ◽

Autism Spectrum ◽

Prenatal Maternal Stress ◽

Cross Sectional ◽

Increased Risk ◽

Meta Analyses ◽

The Impact

Background: Prenatal maternal stress (PNMS) is defined as the experience of significant levels of prenatal stress, depression or anxiety during pregnancy. PNMS has been associated with increased risk of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) in exposed offspring. However, these findings are inconsistent and other studies found no association, meaning a clear consensus on the impact of PNMS on ASD and ADHD risk is required. The purpose of this systematic review and meta-analysis is to summarize and critically review the existing literature on the effects of PNMS on ASD and ADHD risk. Methods: Electronic databases (PubMed, PsycINFO, Web of Science, Scopus and EMBASE) will be searched for articles following a detailed search strategy. We will include cohort, case-control and cross-sectional studies that assessed maternal exposure to psychological and/or environmental stress and had ASD or ADHD as an outcome. Two reviewers will independently screen the titles, abstracts and full articles to identify eligible studies. We will use a standardised data extraction form for extracting data and a bias classification tool for assessing study quality. This systematic review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). The generic inverse variance method will be used if possible to perform meta-analyses. Ethics and dissemination: Ethical approval is not required for this study because it will not involve the conduct or inclusion of any experimental or personal data that would require informed consent. The systematic review will be disseminated in peer-reviewed journals. PROSPERO registration number: CRD42018084222.

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Prenatal maternal stress and risk of neurodevelopmental disorders in the offspring: A systematic review and meta-analysis protocol

HRB Open Research ◽

10.12688/hrbopenres.12827.2 ◽

2019 ◽

Vol 1 ◽

pp. 15 ◽

Cited By ~ 1

Author(s):

Nicla Manzari ◽

Karen Matvienko-Sikar ◽

Franco Baldoni ◽

Gerard W. O'Keeffe ◽

Ali S. Khashan

Keyword(s):

Systematic Review ◽

Maternal Stress ◽

Data Extraction ◽

Meta Analysis ◽

Autism Spectrum ◽

Prenatal Maternal Stress ◽

Case Control Studies ◽

Increased Risk ◽

Meta Analyses ◽

The Impact

Background: Prenatal maternal stress (PNMS) is defined as the experience of significant levels of prenatal stress, depression or anxiety during pregnancy. PNMS has been associated with increased risk of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) in exposed offspring. However, these findings are inconsistent and other studies found no association, meaning a clear consensus on the impact of PNMS on ASD and ADHD risk is required. The purpose of this systematic review and meta-analysis is to summarize and critically review the existing literature on the effects of PNMS on ASD and ADHD risk. Methods: Electronic databases (PubMed, PsycINFO, Web of Science, Scopus and EMBASE) will be searched for articles following a detailed search strategy. We will include cohort and case-control studies that assessed maternal exposure to psychological and/or environmental stress and had ASD or ADHD as an outcome. Two reviewers will independently screen the titles, abstracts and full articles to identify eligible studies. We will use a standardised data extraction form for extracting data and a bias classification tool for assessing study quality. This systematic review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). The generic inverse variance method will be used if possible to perform meta-analyses. Ethics and dissemination: Ethical approval is not required for this study because it will not involve the conduct or inclusion of any experimental or personal data that would require informed consent. The systematic review will be disseminated in peer-reviewed journals. PROSPERO registration number: CRD42018084222.

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The 5-HTTLPR polymorphism of the serotonin transporter gene and child's sex moderate the relationship between disaster-related prenatal maternal stress and autism spectrum disorder traits: The QF2011 Queensland flood study

Development and Psychopathology ◽

10.1017/s0954579418000871 ◽

2018 ◽

Vol 31 (04) ◽

pp. 1395-1409 ◽

Cited By ~ 3

Author(s):

David P. Laplante ◽

Gabrielle Simcock ◽

Lei Cao-Lei ◽

Maya Mouallem ◽

Guillaume Elgbeili ◽

...

Keyword(s):

Serotonin Transporter ◽

Rating Scales ◽

Maternal Stress ◽

Short Form ◽

Autism Spectrum ◽

Prenatal Maternal Stress ◽

Peritraumatic Dissociation ◽

Two Factors ◽

Spectrum Disorders ◽

The Relationship

AbstractThe 5-HTTLPR polymorphism of the serotonin transporter has been shown to play a role in autism spectrum disorders (ASD). Moreover, disaster-related prenatal maternal stress (PNMS) has also been shown to be associated with ASD. However, no study to date has examined whether these two factors, either individually or in combination, are predictive of ASD traits in the same sample. We hypothesized that children, particularly boys, with the LL genotype exposed to high levels of disaster-related PNMS would exhibit higher levels of ASD traits compared to boys with the LS or SS genotypes and girls regardless of genotype. Genotype and ASD levels obtained using the Australian normed Autism Spectrum Rating Scales – Short Form were available for 105 30-month-old children exposed to varying levels of PNMS following the 2011 Queensland Flood. For boys, higher ASD traits were associated with the 5-HTTLPR LL genotype in combination with either a negative maternal appraisal of the flood, or high levels of maternal composite subjective stress, PSTD-like or peritraumatic dissociation symptoms. For girls, maternal peritraumatic dissociation levels in combination with the 5-HTTLPR LS or SS genotype were associated with higher ASD traits. The present findings are the first to demonstrate that children’s genotype moderates effects of disaster-related PNMS on ASD traits, with different pattern according to child sex.

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Stress reactivity in preschool-aged children: Evaluation of a social stress paradigm and investigation of the impact of prenatal maternal stress

Psychoneuroendocrinology ◽

10.1016/j.psyneuen.2018.11.002 ◽

2019 ◽

Vol 101 ◽

pp. 223-231 ◽

Cited By ~ 2

Author(s):

T.S. Send ◽

S. Bardtke ◽

M. Gilles ◽

I.A.C. Wolf ◽

M.W. Sütterlin ◽

...

Keyword(s):

Social Stress ◽

Stress Reactivity ◽

Maternal Stress ◽

Prenatal Maternal Stress ◽

The Impact ◽

Preschool Aged Children

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Prenatal maternal stress exposure and immune function in the offspring

Stress ◽

10.3109/10253890.2013.876404 ◽

2014 ◽

Vol 17 (2) ◽

pp. 133-148 ◽

Cited By ~ 84

Author(s):

Franz Veru ◽

David P. Laplante ◽

Giamal Luheshi ◽

Suzanne King

Keyword(s):

Immune Function ◽

Maternal Stress ◽

Prenatal Maternal Stress ◽

Stress Exposure

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Effects of maternal exposure to social stress during pregnancy: consequences for mother and offspring

Reproduction ◽

10.1530/rep-13-0258 ◽

2013 ◽

Vol 146 (5) ◽

pp. R175-R189 ◽

Cited By ~ 100

Author(s):

Paula J Brunton

Keyword(s):

Hpa Axis ◽

Prenatal Stress ◽

Social Stress ◽

Maternal Stress ◽

Reproductive Potential ◽

Maternal Behaviour ◽

Stress Exposure ◽

Prenatally Stressed ◽

In Pregnancy

A suboptimalin uteroenvironment, for example, as a result of maternal stress, can have detrimental effects on the pregnancy and long-term adverse ‘programming’ effects on the offspring. This article focuses on the effects of prenatal social stress on the mother, her pregnancy and the offspring, since these issues have ethological relevance in both animals and humans. The consequences of social stress exposure depend on when during pregnancy the stress occurs, and many of the effects on the offspring are sex specific. Social stress during early pregnancy tends to result in pregnancy loss, whereas stress exposure later in pregnancy, when the mother has already invested considerable resources in the foetuses, results in programmed offspring of low birth weight: a risk factor for various adulthood diseases. Neuroendocrine and behavioural responses to stress in the offspring are particularly sensitive to foetal programming by prenatal stress, indicated by enhanced hypothalamo-pituitary–adrenal (HPA) axis responses and increased anxiety behaviour, which result from permanent changes in the offspring's brain. The dysregulation of HPA axis function may also interfere with other systems, for example, the hypothalamic–pituitary–gonadal axis, as there is evidence for alterations in steroidogenesis, reproductive potential and impaired reproductive/social behaviours in prenatally stressed offspring. Prenatal social stress also programmes future maternal behaviour, highlighting the potential for negative phenotypes to be transmitted to future generations. The possible mechanisms through which maternal stress during pregnancy is transmitted to the foetuses and the foetal brain is programmed by prenatal stress and the potential to overwrite programming of the offspring are discussed.

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