Novel techniques for assessing manganese exposure and children's neurodevelopment
Bauer, Julia Anglen
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BACKGROUND: While manganese (Mn) is essential for growth and development, evidence for Mn as a developmental neurotoxicant is mounting. However, inconsistencies in exposure metrics, susceptibility factors and neurobehavioral outcomes muddle the understanding of Mn effects on the developing nervous system. OBJECTIVE: To estimate Mn-neurobehavioral associations in varied neurobehavioral tasks and evaluate susceptibility factors (sex differences, co-exposures, exposure timing). METHODS: Research aims were conducted using the Public Health Impact of Mixed element Exposure (PHIME) study, including 720 Italian adolescents living near ferro-manganese industry. Blood, hair, nails, urine and saliva were collected in adolescence and metals [Mn, lead (Pb), copper (Cu), chromium (Cr)] were measured using ICP-MS. Mn was measured in deciduous teeth in a subset of participants (n=195) using LA ICP-MS to represent prenatal, postnatal and childhood exposure periods. Trained neuropsychologists administered a neurobehavioral battery to adolescents. In the first aim, we estimated associations of early-life Mn levels measured in deciduous teeth with visuospatial learning and memory, assessed using the Virtual Radial Arm Maze (VRAM), a novel animal-human translational neurobehavioral task. The second aim estimated associations of prenatal, early postnatal (0-1 year) and childhood (1~6 years) Mn measured in deciduous teeth with IQ scores and subtests measured by the Wechsler Intelligence Scale for Children (WISC-III). The third aim evaluated the association of a mixture of metals (Mn, Pb, Cu, Cr) measured in multiple biomarkers (hair, blood, urine, nails, saliva) and IQ. Data analysis included generalized additive models, linear regression, zero-inflated Poisson regression (for VRAM count outcomes), and Bayesian kernel machine regression (BKMR). RESULTS: In the first aim we observed U-shaped associations between prenatal Mn and VRAM outcomes among girls only, suggesting that low and high prenatal Mn levels may be harmful to visuospatial learning and memory. In the second aim, several associations were found with specific subtests that assess visuospatial ability, working memory, problem solving and attention, wherein estimates from the prenatal period suggested beneficial Mn associations, unlike the early postnatal and childhood periods. For the third aim we found inverse associations of adolescent Mn, measured either in hair or saliva, with verbal IQ (VIQ) scores, and an inverted U-shaped association for hair Cu. Strongest associations for the overall metals mixture were estimated with VIQ, where the joint increase in metals concentrations was associated with lower VIQ scores.