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

Childhood 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 (EDs) is associated with internalizing behaviours in infants, the associations with prenatal exposure to EDs in mixture remain poorly addressed. In addition, the biological mediators of EDs in mixture effects on internalizing behaviours remain unexplored. EDs 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 prenatal exposure to EDs in mixture could operate to influence offspring internalizing behaviours. Based on the EDEN birth cohort, we investigated whether exposure to a mixture of EDs 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 were mediators of this effect. To determine both the joint and individual associations of prenatal exposure to EDs 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 mixture of EDs 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 in boys at age 3. Further studies on larger cohorts are warranted to refine the deleterious effects of EDs in mixtures on internalizing behaviours and identify possible mediating pathways.