Resting-state functional connectivity patterns are associated with metal mixture exposure in young adolescents

Abstract

Background and Aim. Early-life metal mixture exposure may increase the risk for anxiety and depression in adolescence. The neural circuitry subserving internalizing phenotypes begins developing in utero and is vulnerable to early-life exposures. Resting state functional magnetic resonance imaging (rs-fMRI) provides a novel tool to examine underlying mechanisms of metal-associated neurodevelopmental outcomes. We investigate relationships between early-life metal exposure and functional connectivity in pre-adolescents. Methods. In preliminary analysis of 67 children (8-14years; 34 females) enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, we estimated weekly exposure (14th week gestation through one year of age) to 15 metals (Ba, Bi, Cd, Co, Cr, Cu, Li, Mg, Mn, Mo, Ni, Pb, Sn, Sr, Zn) in deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. Using graph theory analysis of rs-fMRI data, we computed global and local efficiency (GE, LE) and eigenvector centrality (EC) in 111 brain areas (Harvard Oxford Atlas). We used lagged weighted quantile sum (lWQS) regression to examine time-varying associations between metal mixtures and GE, LE or EC in the whole brain and anterior cingulate cortex (ACC), globus pallidus (GP), and insula, adjusting for sex and age. Results. We observed prenatal and postnatal windows between the metal mixture and LE; -13 to 4 weeks, peak βLE (week -2) = -0.23, 95%CI -0.02, -0.45 and 16 to 43 weeks; peak βLE (week 42) = -0.42, 95%CI -0.13, -0.70 and one prenatal window for GE at -18 to -11 weeks, peak βGE (week -18) = -0.35, 95%CI -0.07, -0.64. The metal mixture was significantly associated with decreased EC in the ACC, GP and insula at different critical windows spanning gestation and infancy. Conclusions. Our results combining lWQS modeling with graph theory analysis of rs-fMRI may inform mechanistic understanding of environmentally-associated neurodevelopmental outcomes.