Cytokines as mediators of the associations of prenatal exposure to phenols, parabens, and phthalates with internalizing behaviours at age 3 in boys: a mixture exposure and mediation approach

Abstract

ABSTRACTChildhood internalizing disorders refer to inwardly focused negative behaviours such as anxiety, depression, and somatic complains. Interactions between psychosocial, genetic, and environmental risk factors adversely impact neurodevelopment and can contribute to internalizing disorders. While prenatal exposure to single endocrine disruptors (ED) is associated with internalizing behaviours in infants, the associations with prenatal exposure to ED in mixture remain poorly addressed. In addition, the biological mediators of ED mixture effects on internalizing behaviours remain unexplored. ED do not only interfere with endocrine function, but also with immune function and inflammatory processes. Based on this body of evidence, we hypothetised that inflammation at birth is a plausible biological pathway through which ED prenatal exposure could operate to influence offspring internalizing behaviours. Based on the EDEN birth cohort, we investigated whether ED mixture exposure increased the odds of internalizing disorders in 459 boy infants at age 3, and whether the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α measured at birth are mediators of this effect. To determine both the joint and individual associations of ED prenatal exposure with infant internalizing behaviours and the possible mediating role of cytokines, we used the counterfactual hierarchical Bayesian Kernel Machine Regression (BKMR) regression-causal mediation analysis. We show that prenatal exposure to a complex ED mixture has limited effects on internalizing behaviours in boys at age 3. We also show that IL-1β, IL-6, and TNF-α are unlikely mediators or suppressors of ED mixture effects on internalizing behaviours. Further studies on larger cohorts are warranted to refine the deleterious effects of ED mixtures on internalizing behaviours and identify possible mediating pathways.