Critical windows of metal mixture exposure on functional connectivity in adolescents

Abstract

BACKGROUND AND AIM: Exposure to neurotoxic metals occurs as a mixture, yet most studies consider single exposures, potentially missing the combined effects of environmental metals. Further, health impacts of mixtures may be missed if studied at a single developmental timepoint. In this study, we investigated associations between early life exposure to a mixture of neurotoxic metals and developmental trajectories of brain networks associated with executive functions (EF) among young adults. We hypothesize that associations between early-life metal mixture exposure and developmental trajectories depend upon the timing of exposure and the developmental stage of the outcome. METHODS: In preliminary analysis of 32 subjects enrolled in the Public Health Impact of Metals Exposure (PHIME) study, we generated prenatal (2nd week of gestation to birth), early postnatal (birth to one year) and childhood (1-6 years of age) concentrations of 5 toxic and nutritive metals including manganese, lead, zinc, copper and chromium in naturally shed deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. We acquired resting state functional magnetic resonance imaging scans at ages 16-22 years. We used generalized weighted quantile sum (gWQS) regression to examine associations between metal mixtures at each developmental timepoint and functional connectivity in resting state networks. RESULTS:We observed a significant inverse association between the postnatal metal mixture and connectivity in the attention network, i.e., higher metals associated with reduced connectivity (β = -0.029 [95% CI - 0.046, -0.012]). Mn (29%) and Cu (42%) contributed most to the mixture association, suggesting both that these metals were key components and that Mn does not act alone on the brain but is a key part of a larger mixture. CONCLUSIONS:Our preliminary results suggest that postnatal Mn disrupts the trajectory of development in the neural circuitry supporting EF and that the association may be specific to the timing of exposure. KEYWORDS: Heavy metals, Children's environmental health, Mixtures, Mixtures analysis, Neurodevelopmental outcomes