Abstract
Background: The brain white matter (WM) connects gray matter regions into functional networks and is critical for human cognition and behavior. Early-life metal exposure can disrupt WM maturation and lead to long-lasting changes in neuronal circuitry. Despite a growing literature suggesting associations between environmental levels of metal exposures and persistent neurodevelopmental effects, the underlying brain mechanisms of these associations are poorly understood. Furthermore, the influence of sex on these associations is understudied. The goal of the present study was to examine sex-specific associations between early-life exposure to manganese (Mn) and WM microstructure in young adults. Methods: Participants are adolescents and young adults enrolled in the ongoing Public Health Impact of Manganese Exposure (PHIME) study. Fractional anisotropy (FA) measures from diffusion tensor imaging (DTI) were acquired from 73 participants (16-23 years; 39 females) in a 3T Siemens scanner. Prenatal, early postnatal and childhood Mn concentrations were measured in deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. We generated an FA index (representing a combination of FA in 48 brain regions of the ICBM-DTI-81 atlas) using weighted quantile sum (WQS) regression and investigated associations between the FA index and Mn at each timepoint, controlling for socioeconomic status, sex, and age. To test our hypothesis that sex has a moderating effect on the association between early life Mn exposure and WM integrity, we included an interaction term between sex and Mn. Results: The FA index was positively associated with dentine Mn at all three timepoints. This association was driven by FA in the fornix, cerebral pedencule, tapetum and superior longitudinal fasciculus. Associations were stronger in males. Conclusion: These results suggest that a) early-life Mn exposure is associated with WM microstructure within regions involved in widespread motor and cognitive functions, and b) the effect of Mn exposure on the brain differs by sex.
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