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

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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356 Microbial origins in the developmental programming of offspring health

Journal of Animal Science ◽

10.1093/jas/skaa278.170 ◽

2020 ◽

Vol 98 (Supplement_4) ◽

pp. 93-94

Author(s):

Eldin Jašarević

Keyword(s):

Caesarean Section ◽

Gut Microbiota ◽

Prenatal Stress ◽

Growth And Development ◽

Maternal Stress ◽

Fetal Brain ◽

Vaginal Microbiota ◽

Stress Exposure ◽

Prenatally Stressed ◽

Stress Experience

Abstract Adverse parental lifetime experiences, such as stress and malnutrition, are implicated in the risk for offspring metabolic, cardiovascular, and neurodevelopmental disorders. In recent years, the maternal microbiome has emerged as an important factor that affects maternal health and infant development during pregnancy and beyond. Using mouse models of maternal stress experience during pregnancy, we examined the hypothesis that maternal stress experience alters the composition of the maternal microbiota and this altered community is transmitted to offspring to mediate effects of prenatal stress. As maternal stress exposure exhibits disruptive effects on both in utero environment and maternal microbiota, it has been difficult to assess the mechanistic involvement of the maternal microbiome to the prenatal stress phenotype independent of stress effects on the fetal environment. To circumvent this, we developed a maternal microbiota transplantation method in which embryonic day 18.5 mouse pups were delivered by caesarean section, thereby preventing natural colonization, and then transplanted with various maternal microbiota communities via orogastric gavage. Transplantation of maternal microbiota from stressed dams into naïve pups delivered by caesarean section recapitulated phenotypes that resembled those seen in prenatally stressed males, including reduced body weight and increased neuroendocrine response to acute stressors. However, transplantation of control maternal vaginal microbiota into prenatally stressed pups delivered by caesarean section did not rescue the prenatal stress phenotype. We showed that the inability to rescue the prenatal stress phenotype is related to transcriptional reprogramming to pathways involved in the regulation of innate immunity in the fetal gut and brain prior to birth and colonization by maternal microbiota. These results are interesting in light of recent studies demonstrating a critical role of the maternal microbiome on homeostasis of immune cell populations in the offspring brain. As an important requirement for normal growth and development, metabolites produced by the maternal gut microbiota cross the placental barrier and gain access to fetal circulation. Thus, we examined the hypothesis that maternal stress experience during pregnancy significantly alters the availability of maternal gut microbiota-derived metabolites, thereby shifting the availability of these metabolites required for the developing brain. Metabolomic profiling of the maternal compartment and fetal brain showed stress-induced reduction in a class of microbiota-derived metabolites involved in immune homeostasis and chromatin remodeling. Indeed, functional profiling of immune populations in the fetal brain revealed an association between reduced metabolite availability and increased infiltration of proinflammatory monocytes in the fetal brain. Further, as the gut microbiome is fairly accessible within clinical settings, we are now also asking how our mouse model translates to humans in a cohort of pregnant women exposed to childhood adversity. Collectively, our results suggest that intergenerational transmission of stress exposure occur via the maternal microbiota through two novel mechanisms. First, stress alterations during pregnancy impact the available pool of maternal gut microbiota-derived metabolites necessary for normal prenatal growth and development. Second, transmission of stress-altered vaginal microbiota may alter critical immune and metabolic processes underlying neurodevelopment.

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

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.668577 ◽

2021 ◽

Vol 12 ◽

Author(s):

David Q. Beversdorf ◽

Ayten Shah ◽

Allison Jhin ◽

Janelle Noel-MacDonnell ◽

Patrick Hecht ◽

...

Keyword(s):

Prenatal Stress ◽

Stress Reactivity ◽

Maternal Stress ◽

High Stress ◽

Autism Spectrum ◽

Microrna Expression ◽

Prenatal Maternal Stress ◽

Stress Exposure ◽

Maternal Presence ◽

Stress Dependent

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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The Effects of Maternal Interleukin-17A on Social Behavior, Cognitive Function, and Depression-Like Behavior in Mice with Altered Kynurenine Metabolites

International Journal of Tryptophan Research ◽

10.1177/11786469211026639 ◽

2021 ◽

Vol 14 ◽

pp. 117864692110266

Author(s):

Yuki Murakami ◽

Yukio Imamura ◽

Yoshiyuki Kasahara ◽

Chihiro Yoshida ◽

Yuta Momono ◽

...

Keyword(s):

Neuronal Development ◽

Fetal Brain ◽

Autism Spectrum ◽

Maternal Serum ◽

Fetal Plasma ◽

Maternal Inflammation ◽

Interleukin 17A ◽

Behavioral Abnormalities ◽

Neuroactive Compounds ◽

The Impact

Viral infection and chronic maternal inflammation during pregnancy are correlated with a higher prevalence of autism spectrum disorder (ASD). However, the pathoetiology of ASD is not fully understood; moreover, the key molecules that can cross the placenta following maternal inflammation and contribute to the development of ASD have not been identified. Recently, the pro-inflammatory cytokine, interleukin-17A (IL-17A) was identified as a potential mediator of these effects. To investigate the impact of maternal IL-17A on offspring, C57BL/6J dams were injected with IL-17A-expressing plasmids via the tail vein on embryonic day 12.5 (E12.5), and maternal IL-17A was expressed continuously throughout pregnancy. By adulthood, IL-17A-injected offspring exhibited behavioral abnormalities, including social and cognitive defects. Additionally, maternal IL-17A promoted metabolism of the essential amino acid tryptophan, which produces several neuroactive compounds and may affect fetal neurodevelopment. We observed significantly increased levels of kynurenine in maternal serum and fetal plasma. Thus, we investigated the effects of high maternal concentration of kynurenine on offspring by continuously administering mouse dams with kynurenine from E12.5 during gestation. Obviously, maternal kynurenine administration rapidly increased kynurenine levels in the fetal plasma and brain, pointing to the ability of kynurenine to cross the placenta and change the KP metabolites which are affected as neuroactive compounds in the fetal brain. Notably, the offspring of kynurenine-injected mice exhibited behavioral abnormalities similar to those observed in offspring of IL-17A-conditioned mice. Several tryptophan metabolites were significantly altered in the prefrontal cortex of the IL-17A-conditioned and kynurenine-injected adult mice, but not in the hippocampus. Even though we cannot exclude the possibility or other molecules being related to ASD pathogenesis and the presence of a much lower degree of pathway activation, our results suggest that increased kynurenine following maternal inflammation may be a key factor in changing the balance of KP metabolites in fetal brain during neuronal development and represents a therapeutic target for inflammation-induced ASD-like phenotypes.

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Mindfulness-based Stress Reduction in Pregnancy: an App-Based Programme to Improve the Health of Mothers and Children (MINDFUL/PMI Study)

Geburtshilfe und Frauenheilkunde ◽

10.1055/a-0677-2630 ◽

2018 ◽

Vol 78 (12) ◽

pp. 1283-1291 ◽

Cited By ~ 8

Author(s):

Bernd Lenz ◽

Anna Eichler ◽

Eva Schwenke ◽

Verena Buchholz ◽

Charlotte Hartwig ◽

...

Keyword(s):

Environmental Factors ◽

Pregnant Women ◽

Tobacco Use ◽

Infant Development ◽

Maternal Stress ◽

Self Regulation ◽

Ring Finger ◽

Childhood Development ◽

Modifiable Factors ◽

The Impact

AbstractUnfavourable intrauterine environmental factors increase the risk of delivery complications as well as postpartum developmental and behavioural problems in children and adolescents with ongoing effects into older age. Biomarker studies show that maternal stress and the use of alcohol and tobacco during pregnancy are associated with a higher intrauterine testosterone exposure of the child. The antenatal testosterone load, in turn, is a risk factor for lasting adverse health effects which extend into adulthood. A 15-week, mindfulness-oriented, app-based programme for the reduction of stress as well as for the reduction of alcohol and tobacco use in pregnant women is established. In the monocentre, prospective, controlled, and investigator-blinded MINDFUL/PMI (Maternal Health and Infant Development in the Follow-up after Pregnancy and a Mindfulness Intervention) study, pregnant women carry out the programme. Its effect on antenatal testosterone exposure of the child is examined by assessing the index/ring finger length ratio and other biomarkers in the 1-year-old children. In addition, the programmeʼs effects on self-regulation, the developmental status and the mental health of the children at the age of one year will be investigated. Additional aspects of the course of the pregnancy and delivery represent exploratory study objectives. This longitudinal study project is intended to improve the understanding of the impact of intrauterine environmental factors on early childhood development and health. Maternal stress as well as alcohol and tobacco use during pregnancy are modifiable factors and represent potential preventive targets.

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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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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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Impact of MicroRNAs in Interaction With Environmental Factors on Autism Spectrum Disorder: An Exploratory Pilot Study

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.715481 ◽

2021 ◽

Vol 12 ◽

Author(s):

LiHua Cui ◽

WenRan Du ◽

Ning Xu ◽

JingYi Dong ◽

BingJie Xia ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Environmental Factors ◽

Neonatal Jaundice ◽

Maternal Stress ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Control Group ◽

Psychiatric History ◽

Healthy Children ◽

Threatened Abortion

Background: This study aimed to explore the main effects of environmental risk factors as well as their interaction effects with miRNA on the risk of autism spectrum disorder (ASD).Methods: One hundred fifty-nine ASD children (ASD group) and 159 healthy children (control group), aged 2–6 years, were included in this study. ASD diagnoses were based on DSM-5 criteria. The extensive medical and demographic characterization of the two groups were recorded. MicroRNAs (miRNAs) in serum were detected by qRT-PCR.Results: Compared with the control group, the ASD group had significantly higher rates of maternal stress during pregnancy (p < 0.001), maternal drinking during pregnancy (p = 0.006), threatened abortion (p = 0.011), pregnancy-induced hypertension (p = 0.032), gestational diabetes (p = 0.039), maternal anemia during pregnancy (p < 0.001), umbilical cord knot (p < 0.001), neonatal jaundice (p < 0.001), family psychiatric history (p = 0.001), and much lower birth weight (p = 0.012). Furthermore, the ASD group had much lower expression levels of hsa-miR-181b-5p (p < 0.001) and hsa-miR-320a (p < 0.001) and significantly higher levels of hsa-miR-19b-3p (p < 0.001). The interactions of hsa-miR-320a and maternal stress during pregnancy (OR = 39.42, p < 0.001), hsa-miR-19b-3p and neonatal jaundice (OR = 2.44, p < 0.001), and hsa-miR-181b-5p and family psychiatric history (OR = 8.65, p = 0.001) could increase ASD risk.Conclusions: The dysregulation of hsa-miR-181b-5p, hsa-miR-320a, and hsa-miR-19b-3p could interact with environmental factors, such as maternal stress during pregnancy, neonatal jaundice, and family psychiatric history, to impact the risk of ASD.

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Maternal prenatal stress during the first trimester and infant birthweight in Soweto, South Africa

10.1101/2021.01.11.21249590 ◽

2021 ◽

Author(s):

Andrew Wooyoung Kim ◽

Rihlat Said Mohamed ◽

Christopher W. Kuzawa ◽

Shane A. Norris

Keyword(s):

South Africa ◽

Birth Outcomes ◽

Prenatal Stress ◽

Maternal Stress ◽

First Trimester ◽

Growth Restriction ◽

Early Gestation ◽

Maternal Prenatal Stress ◽

Infant Birth ◽

The Impact

ABSTRACTBackgroundApproximately 14.2% of newborns are estimated to be born low birth weight (LBW) in South Africa. Past work has implicated maternal prenatal stress as a potent predictor of poor birth outcomes, including preterm birth, intrauterine growth restriction, and LBW. However, less is presently known about the impacts of prenatal stress during early gestation in low- and middle-income contexts, where public health burdens due to LBW are much higher.ObjectiveWe assess the effects of psychosocial stress during the first trimester on birthweight in a large sample of women (n = 657) in Soweto, South Africa, a peri-urban township located in the Greater Johannesburg area.MethodsData come from the Soweto First 1000 Days Cohort, a study of maternal and fetal predictors of infant birth outcomes. Multiple regression models were used to examine the impact of prenatal stress on infant birthweight.ResultsThe prevalence of LBW was 16.6%. Adjusting for maternal age, gestational age, fetal gender, body mass index, and parity, maternal prenatal stress during the first trimester was a borderline predictor of lower birthweight in this sample (β = 12.7, p = 0.071, 95% CI [-26.4, 1.10]). Women who reported greater levels of stress appeared to have non-significantly longer gestations, and the negative impact of maternal stress on birthweight only appeared after adjusting for this pattern.ConclusionsThese results suggest that fetal growth restriction associated with first trimester maternal stress may contribute to lower birthweights in this sample. Our findings report modest relationships between maternal stress specific to early gestation as likely important to birth outcomes in this urban South African sample.

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Prenatal stress exposure as a risk factor for anorexia nervosa: A controlled study

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.800 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S557-S557

Author(s):

S. Michelon ◽

E. Tenconi ◽

E. Bonello ◽

D. Degortes ◽

M. De Toffol ◽

...

Keyword(s):

Anorexia Nervosa ◽

Risk Factor ◽

Prenatal Stress ◽

Stressful Life Events ◽

Stressful Events ◽

Controlled Study ◽

Stress Exposure ◽

Neuropsychological Battery ◽

Competing Interest ◽

The Impact

IntroductionPrenatal risk factors, such as gestational complications and exposure to stress during pregnancy, may have a role in the development of many psychiatric disorders including eating disorders.AimTo investigate the impact of prenatal stress exposure on the development and clinical features of anorexia nervosa.MethodsOne hundred and nine patients with a lifetime diagnosis of anorexia nervosa and 118 healthy controls underwent a clinical assessment, which included interviews, questionnaires and a neuropsychological battery. The mothers of the patients and controls underwent a specific interview focused on stressful life events, which occurred during pregnancy. Obstetric and neonatal records were consulted.ResultsThe mothers of patients experienced more severe stressful episodes during pregnancy than the mothers of controls and the perceived distress showed significant positive correlation with both total number of obstetrical complications and placental weight. In patients, the severity of stressful events was strongly associated to cognitive rigidity and perseverance.ConclusionsPrenatal stress exposure might be a risk factor for the development of anorexia nervosa and it is associated with cognitive traits of rigidity and perseverance.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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