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Altered maternal immune networks are associated with adverse child neurodevelopment: Impact of alcohol consumption during pregnancy.

ABSTRACT: Cytokines and chemokines are potent modulators of brain development and as such, dysregulation of the maternal immune system can result in deviations in the fetal cytokine balance, altering the course of typical brain development, and putting the individual on a "pathway to pathology". In the current study, we used a multi-variate approach to evaluate networks of interacting cytokines and investigated whether alterations in the maternal immune milieu could be linked to alcohol-related and alcohol-independent child neurodevelopmental delay. This was achieved through the measurement of 40 cytokines/chemokines from maternal blood samples collected during the second and third trimesters of pregnancy. Importantly, during the second trimester we identified network enrichment in levels of cytokines including IFN-?, IL-10, TNF-?, TNF-?, and CRP associated with offspring neurodevelopmental delay. However, as elevations in levels of these cytokines have previously been reported in a wide range of neurodevelopmental disorders including autism spectrum disorder and schizophrenia, we suggest that this cytokine profile is likely not disorder specific, but rather may be an indicator of neurodevelopmental delay in general. By contrast, distinct clusters of activated/inhibited cytokines were identified based on maternal alcohol consumption and child neurodevelopmental outcome. Specifically, cytokines including IL-15, IL-10, MDC, and members of the VEGF sub-family were highest in alcohol-consuming mothers of children with neurodevelopmental delay and were identified in both network analyses and examination of individual cytokines, whereas a differential and unique cytokine profile was identified in the case of alcohol-independent child neurodevelopmental delay. We propose that the current findings could provide a critical step towards the development of early biomarkers and possibly interventions for alcohol-related neurodevelopmental delay. Importantly, the current approach could be informative for understanding mechanisms linking maternal immune system dysfunction and adverse child outcomes in a range of other neurodevelopmental disorders.

SUBMITTER: Bodnar TS

PROVIDER: S-EPMC6344127 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Altered maternal immune networks are associated with adverse child neurodevelopment: Impact of alcohol consumption during pregnancy.

Bodnar Tamara S TS Raineki Charlis C Wertelecki Wladimir W Yevtushok Lyubov L Plotka Larisa L Zymak-Zakutnya Natalya N Honerkamp-Smith Gordon G Wells Alan A Rolland Matthieu M Woodward Todd S TS Coles Claire D CD Kable Julie A JA Chambers Christina D CD Weinberg Joanne J

Brain, behavior, and immunity 20180505

Cytokines and chemokines are potent modulators of brain development and as such, dysregulation of the maternal immune system can result in deviations in the fetal cytokine balance, altering the course of typical brain development, and putting the individual on a "pathway to pathology". In the current study, we used a multi-variate approach to evaluate networks of interacting cytokines and investigated whether alterations in the maternal immune milieu could be linked to alcohol-related and alcoho ...[more]

PMID: 29738852

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Project description:BackgroundGestational exposure to polychlorinated biphenyls (PCBs) has been associated with elevated risk for neurodevelopmental disorders. Placental epigenetics may serve as a potential mechanism of risk or marker of altered placental function. Prior studies have associated differential placental DNA methylation with maternal PCB exposure or with increased risk of autism spectrum disorder (ASD). However, sequencing-based placental methylomes have not previously been tested for simultaneous associations with maternal PCB levels and child neurodevelopmental outcomes.ObjectivesWe aimed to identify placental DNA methylation patterns associated with maternal PCB levels and child neurodevelopmental outcomes in the high-risk ASD MARBLES cohort.MethodsWe measured 209 PCB congeners in 104 maternal serum samples collected at delivery. We identified networks of DNA methylation from 147 placenta samples using the Comethyl R package, which performs weighted gene correlation network analysis for whole genome bisulfite sequencing data. We tested placental DNA methylation modules for association with maternal serum PCB levels, child neurodevelopment, and other participant traits.ResultsPCBs 153 + 168, 170, 180 + 193, and 187 were detected in over 50% of maternal serum samples and were highly correlated with one another. Consistent with previous findings, maternal age was the strongest predictor of serum PCB levels, alongside year of sample collection, pre-pregnancy BMI, and polyunsaturated fatty acid levels. Twenty seven modules of placental DNA methylation were identified, including five which significantly correlated with one or more PCBs, and four which correlated with child neurodevelopment. Two modules associated with maternal PCB levels as well as child neurodevelopment, and mapped to CSMD1 and AUTS2, genes previously implicated in ASD and identified as differentially methylated regions in mouse brain and placenta following gestational PCB exposure.ConclusionsPlacental DNA co-methylation modules were associated with maternal PCBs and child neurodevelopment. Methylation of CSMD1 and AUTS2 could be markers of altered placental function and/or ASD risk following maternal PCB exposure.

Project description:The developing fetus is especially vulnerable to environmental toxicants, including tobacco constituents. The aim of this study was to assess the impact of environmental tobacco smoke (ETS) exposure during pregnancy on child neurodevelopment within the first two years of life. The study population consisted of 461 non-smoking pregnant women (saliva cotinine level <10 ng/mL). Maternal passive smoking was assessed based on the cotinine level in saliva analyzed by the use of high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-ESI + MS/MS) and by questionnaire data. The cotinine cut-off value for passive smoking was established at 1.5 ng/mL (sensitivity 63%, specificity 71%). Psychomotor development was assessed in children at the age of one- and two-years using the Bayley Scales of Infant and Toddler Development. Approximately 30% of the women were exposed to ETS during pregnancy. The multivariate linear regression model indicated that ETS exposure in the 1st and the 2nd trimesters of pregnancy were associated with decreasing child language functions at the age of one (? = -3.0, p = 0.03, and ? = -4.1, p = 0.008, respectively), and two years (? = -3.8, p = 0.05, and ? = -6.3, p = 0.005, respectively). A negative association was found for cotinine level ?1.5 ng/mL in the 2nd trimester of pregnancy and child cognition at the age of 2 (? = -4.6, p = 0.05), as well as cotinine levels ?1.5 ng/mL in all trimesters of pregnancy and child motor abilities at two years of age (? = -3.9, p = 0.06, ? = -5.3, p = 0.02, and ? = -4.2, p = 0.05, for the 1st, the 2nd, and the 3rd trimester of pregnancy, respectively; for the 1st trimester the effect was of borderline statistical significance). This study confirmed that ETS exposure during pregnancy can have a negative impact on child psychomotor development within the first two years of life and underscore the importance of public health interventions aiming at reducing this exposure.

Project description:Background and aimsHazardous drinking (i.e. alcohol consumption that places drinkers at risk for adverse health outcomes) during pregnancy is associated with adverse child outcomes. To address whether the associations are causal, we aimed to estimate the effect of maternal hazardous drinking during the first trimester on offspring emotional and behavioural problems throughout the pre-school age. We adjusted for: (1) measured confounding (e.g. smoking), (2) familial risk factors by sibling control design and (3) non-shared environmental risk factors by using hazardous drinking the 3 months before pregnancy as an instrumental variable.DesignProspective cohort study. Participants were recruited between 1999 and 2009 at ultrasound examination offered to all pregnant women in Norway. Data were collected during the 17th and the 30th weeks of gestation, and when the children were aged 1.5, 3 and 5 years.SettingNorway, 1999-2015.ParticipantsThe sample consisted of 14 639 mothers with 25 744 offspring siblings from the Norwegian Mother and Child Cohort Study.MeasurementsRespondents self-reported on: alcohol consumption, children's emotional problems (i.e. emotional reactive, anxiety/depression, somatic complaints) and children's behavioural problems (i.e. attention and aggressive behaviour) throughout pre-school age. We used longitudinal latent growth curve models to estimate the effect of maternal drinking during the first trimester on offspring emotional and behavioural problems.FindingsMost associations were strongly reduced after controlling for both familial and measured environmental risk factors. After adjustment, exposed children were more emotionally reactive [β = 2.33; 95% confidence interval (CI) = 0.13-4.53] and had more somatic complaints (β = 1.93; 95% CI = 0.09-3.77) at age 3, but not at age 5. Exposed children were less aggressive than unexposed siblings at age 5 (β = -2.27; 95% CI = -4.02 to -0.52).ConclusionsChildren exposed to their mothers' hazardous drinking during the first trimester appear to be more emotionally reactive and have more somatic complaints at age 3, but not at age 5, and are less aggressive at age 5 compared with unexposed siblings.

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Altered maternal immune networks are associated with adverse child neurodevelopment: Impact of alcohol consumption during pregnancy.

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Altered maternal immune networks are associated with adverse child neurodevelopment: Impact of alcohol consumption during pregnancy.

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