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.

Prenatal alcohol-induced sex differences in immune, metabolic and neurobehavioral outcomes in adult rats

“…Moreover, sex differences in PAE-linked cytokine expression, and the suppression of splenic Tregs, may elevate the risk for autoimmune disorders and explain variations in FASD-associated behaviors. These data are consistent with a number of previous studies that link immune system dysfunction to neuropathy and to adverse behavioral outcomes due to PAE in animal models ( Pascual et al, 2017 , Raineki et al, 2017 , Sanchez et al, 2017 , Noor et al, 2020 ), and to adverse neurodevelopmental outcomes in children with FASD ( Bodnar et al, 2020 ). Moreover, they suggest either genetic sex and/or endocrine environment modify the relationship between immune system, metabolism and behavior as has been documented in other preclinical studies ( Yao and Gregoire Nyomba, 2007 , Bodnar et al, 2016 , Nguyen et al, 2019 ).…”

Altered Maternal Plasma Fatty Acid Composition by Alcohol Consumption and Smoking during Pregnancy and Associations with Fetal Alcohol Spectrum Disorders

“…We, along with others, have previously reported that alcohol-consuming women with FASD children selected from the same parent cohort have a higher ratio of proinflammatory to anti-inflammatory cytokines compared to alcohol-consuming women with normally developing children (27,39,40). Specifically, an increase in third trimester tumor necrosis factor-a (TNF-a) relative to interleukin (IL)À10 was associated with increased risk of FASD in alcohol-consuming women (27).…”

Oxidative stress marker aberrations in children with autism spectrum disorder: a systematic review and meta-analysis of 87 studies (N = 9109)

“…The social communication problem as the core diagnostic feature in ASD children has been extensively studied in the field. However, the non-diagnostic features in ASD children have attracted great attention over the past decade; these include gastrointestinal problem 7 , sleep disorders 8 , immune system aberration 9 , neurotrophic factor dysregulation 10 , mitochondrial dysfunction 11 , and oxidative stress 12 . Oxidative stress may cause damages to lipids, proteins, and DNAs in cells, with subsequent disease development in humans 13 .…”