Adolescent exposure to neurotoxic metals adversely impacts cognitive, motor, and behavioral development. Few studies have addressed the underlying brain mechanisms of these metal-associated developmental outcomes. Furthermore, metal exposure occurs as a mixture, yet previous studies most often consider impacts of each metal individually. In this cross-sectional study, we investigated the relationship between exposure to neurotoxic metals and topological brain metrics (global and local efficiency) in adolescents. In 193 participants (53% females, ages: 15-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study, we measured concentrations of four metals (manganese, lead, copper and chromium) in multiple biological media (blood, urine, hair, and saliva) and acquired resting-state functional magnetic resonance imaging scans. Using graph theory metrics, we computed global and local efficiency (global:GE; local:LE) in 111 brain areas (Harvard Oxford Atlas). We used weighted quantile sum (WQS) regression models to examine association between metal mixtures and each graph metric (GE or LE), adjusted for sex and age. We observed significant negative associations between the metal mixture and GE and LE (βGE = -0.076, 95% CI [-0.122, -0.031]; βLE= -0.051, 95% CI [-0.095, -0.006]). Lead and chromium measured in blood contributed most to this association for GE, while chromium measured in hair contributed the most for LE. Our results suggest that exposure to this metal mixture during adolescence reduces the efficiency of integrating information in brain networks at both local and global levels, informing potential neural mechanisms underlying the developmental toxicity of metals. Results further suggest these associations are due to combined joint effects to different metals, rather than to a single metal.

The authors have declared no competing interest.

The authors would like to acknowledge support from the National Institutes of Environmental Health Sciences (NIEHS) grants numbers R01 ES019222, R01 ES013744, P30ES023515, and the European Union through its Sixth Framework Programme for RTD (contract number FOOD-CT-2006-016253).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Study procedures were approved by the Institutional Review Board of the University of California, Santa Cruz and the ethical committees of the University of Brescia, and the Icahn School of Medicine at Mount Sinai.

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