Immune network dysregulation associated with child neurodevelopmental delay: modulatory role of prenatal alcohol exposure

Abstract

Background: Evidence suggests that cytokine imbalances may be at the root of deficits that occur in numerous neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Notably, while clinical studies have demonstrated maternal cytokine imbalances with alcohol consumption during pregnancy-and data from animal models have identified immune disturbances in alcohol-exposed offspring-to date, immune alterations in alcohol-exposed children have not been explored. Thus, here we hypothesized that perturbations in the immune environment as a result of prenatal alcohol exposure will program the developing immune system, and result in immune dysfunction into childhood. Due to the important role of cytokines in brain development/function, we further hypothesized that child immune profiles might be associated with their neurodevelopmental status.

Methods: As part of a longitudinal study in Ukraine, children of mothers reporting low/no alcohol consumption or moderate-to-heavy alcohol consumption during pregnancy were enrolled in the study and received neurodevelopmental assessments. Group stratification was based on maternal alcohol consumption and child neurodevelopmental status resulting in the following groups: A/TD, alcohol-consuming mother, typically developing child; A/ND, alcohol-consuming mother, neurodevelopmental delay in the child; C/TD, control mother (low/no alcohol consumption), typically development child; and C/ND, control mother, neurodevelopmental delay in the child. Forty cytokines/chemokines were measured in plasma and data were analyzed using regression and constrained principle component analysis.

Results: Analyses revealed differential cytokine network activity associated with both prenatal alcohol exposure and neurodevelopmental status. Specifically, alcohol-exposed children showed activation of a cytokine network including eotaxin-3, eotaxin, and bFGF, irrespective of neurodevelopmental status. However, another cytokine network was differentially activated based on neurodevelopmental outcome: A/TD showed activation of MIP-1β, MDC, and MCP-4, and inhibition of CRP and PlGF, with opposing pattern of activation/inhibition detected in the A/ND group. By contrast, in the absence of alcohol-exposure, activation of a network including IL-2, TNF-β, IL-10, and IL-15 was associated with neurodevelopmental delay.

Conclusions: Taken together, this comprehensive assessment of immune markers allowed for the identification of unique immune milieus that are associated with alcohol exposure as well as both alcohol-related and alcohol-independent neurodevelopmental delay. These findings are a critical step towards establishing unique immune biomarkers for alcohol-related and alcohol-independent neurodevelopmental delay.

Keywords: Cytokines; Development; Fetal alcohol spectrum disorders; Immune networks.

Fig. 1

Heatmaps showing the overall cytokine profile. Rows represent groups (C/TD, C/ND, A/TD, A/ND), as indicated, and columns represent mean cytokine levels (z-scored data), for each group. Colors demonstrate deviations from the mean of zero, as indicated in the color key. Abbreviations: C/TD, control mother (low to no alcohol), typically developing child (n = 15); C/ND, control mother (low to no alcohol), neurodevelopmental delay in the child (n = 12); A/TD, alcohol-consuming mother, typically developing child (n = 15); A/ND: alcohol-consuming mother, neurodevelopmental delay in the child (n = 17)

Fig. 2

Cytokines contributing to the three immune networks identified through constrained principle component analysis (CPCA). Network membership was defined based on component loadings from the CPCA. Activated cytokines are indicated in dark blue, and inhibited cytokines indicated in light blue, with color gradation depicting the value of the component loading. For each network, the strength (|r|) and the significance (p value) of the correlation between groups (C/TD, C/ND, A/TD, A/ND) and component scores are indicated. The cytokine networks indicated in white were not significantly correlated with the group, as indicated in the figure. Abbreviations: C/TD, control mother (low to no alcohol), typically developing child (n = 15); C/ND, control mother (low to no alcohol), neurodevelopmental delay in the child (n = 12); A/TD, alcohol-consuming mother, typically developing child (n = 15); A/ND, alcohol-consuming mother, neurodevelopmental delay in the child (n = 17)