Early life critical windows of metal exposure associated with whole brain white matter changes in children

Abstract

BACKGROUND AND AIM: The brain white matter (WM) connects gray matter regions into functional networks and is critical for human cognition and behavior. Early-life exposure to metals may impact fetal WM development. Most environmental studies consider single exposures, potentially missing the combined effects of mixtures. In addition, the developmental timing of exposure may be as important as the dose. Little is known about critical windows to nutritive and toxicant metal mixtures on the developing brain. In this study, we investigated associations between early life exposure to a mixture of metals and whole brain white matter in children. METHODS: In preliminary analysis of 30 subjects (6-10 years; 19 females) enrolled in a neuroimaging follow-up visit of the ongoing Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, we estimated weekly early life exposure (12th gestation week through one year of age) to 10 nutritive and toxicant metals (Mn, Zn, Pb, Mg, Li, Ca, Cr, Cu, Sr, Ba) in deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. Whole brain WM microstructure integrity was estimated 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 a time-varying mixture effect of multiple metals on whole brain FA. Models were adjusted for age. RESULTS:We observe a potential critical window to metal exposure during the postnatal period (0 - 13 weeks) showing positive association with whole brain FA. This association is driven mainly by Li, Mg, and Ca. Negative associations were not detected. CONCLUSIONS:WM microstructure integrity may demonstrate a postnatal critical window to essential elements. These results may help understand the role of exposure timing in driving neurodevelopmental effects, thereby pointing to future optimal, efficient, and properly timed public health interventions. KEYWORDS: Neurodevelopmental outcomes, Mixtures analysis, Mixtures