Early-life critical windows of metal exposure associated with internalizing symptoms in young adolescents

Abstract

Introduction and Aim: Internalizing disorders, such as anxiety and depression, affect 10 – 20% of children and increase the risk for later-life psychopathology. The neural circuitry subserving internalizing phenotypes begins developing in utero and is vulnerable to early-life environmental exposures. Although early-life exposure to metals can adversely impact children’s neurodevelopment and have lifelong impacts on mental health, little is known about critical windows to metal exposures and adolescent internalizing disorders. In this study, we hypothesized that early-life exposure to a mixture of metals is associated with increased internalizing problems in early adolescence. Methods: Among 431 (8-12 years; 216 females) pre-adolescents enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) longitudinal birth cohort study in Mexico City, we estimated weekly concentrations of 15 metals in naturally shed deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry (i.e., Ba, Bi, Cd, Co, Cr, Cu, Li, Mg, Mn, Mo, Ni, Pb, Sn, Sr, and Zn) from the 14th gestation week through one year of age). Internalizing problems were assessed using the Behavior Assessment System for Children, 2nd edition (BASC-2). We used lagged weighted quantile sum (lWQS) regression to estimate a time-varying mixture effect of multiple metals on internalizing problems. Models were adjusted for age and sex. Results: A higher metal mixture index in the 22nd-43rd postnatal weeks was associated with increased internalizing problems (maximum β = 0.37 [95% CI 0.06, 0.69]), driven mainly by Mg, As, Sn, and Bi. Conclusions: This study supports the hypothesis that mixed metal exposure during specific critical windows in early life may associate with mental health disorders in childhood and adolescence. Our lWQS modeling approach and results may inform the role of exposure timing in driving neurodevelopmental outcomes, thereby pointing to future optimal, efficient, and properly timed public health interventions.