Early life metal exposure is associated with reduced fractional anisotropy in the corpus callosum in children

Abstract

Background: The corpus callosum (CC) is the largest white matter structure in the brain, connecting the left and right hemispheres into functional networks subserving cognition and behavior. Neuroimaging studies demonstrate rapid CC development during the first years of life. During these early-life critical windows, the CC is vulnerable to perturbation by neurotoxicants including heavy metals. Most environmental studies consider single neurotoxicant exposures at a single time point, potentially missing the effects of joint exposure across a developmental stage. Here, we investigated associations between early life metal mixture exposure and CC white matter microstructure integrity in children. Methods: In a preliminary analysis of 47 children (8-13 years; 22 females) enrolled in a neuroimaging substudy within the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, we estimated weekly exposure (22nd-week gestation through 43rd week postnatal) to manganese (Mn), zinc (Zn), and lead (Pb) using laser ablation-inductively coupled plasma-mass spectrometry of teeth. We estimated CC white matter microstructure integrity using fractional anisotropy (FA) from diffusion tensor imaging (DTI) acquired in a 3T Siemens scanner. We used lagged weighted quantile sum (lWQS) regression to estimate the time-varying mixture effect on FA in the CC. Results: A higher metal mixture index in the 24th-43rd postnatal weeks was associated with decreased FA in the CC genu, body, and splenium (maximum β = -0.65 [95% CI -0.25, -1.07]), driven mainly by Zn and Pb. Conclusion: The CC may demonstrate a postnatal critical window to metals, with higher exposure to Zn and Pb associated with reduced FA. These results may help understand the role of exposure timing in driving neurodevelopmental outcomes, pointing to future optimal and timely public health interventions.