Sensitive windows of manganese exposure and frontal cortex function in adolescents

Introduction: Prior studies have reported Mn-associated decrements in IQ, a composite score computed from subtests. We examined patterns of IQ subtest scores to generate hypotheses about the underlying structural changes in the brain that may be produced by early life Mn exposure among adolescents living near ferromanganese industry. Methods: We analyzed deciduous teeth from 190 Italian children ages 10-14 years. Mn was measured in the tooth matrix to represent prenatal, postnatal (0-1 year) and childhood (~1-6 years) exposure periods. Neuropsychologists administered the Wechsler Intelligence Scale for Children, 3rd edition. Multivariable linear regression and generalized additive models were used to estimate adjusted associations between ln-tooth Mn and scores on seven subtests: Arithmetic, Comprehension, Information, Similarities, Vocabulary, Digits forward and Digits backward. Results: We observed varied patterns of adjusted associations between tooth Mn and subtest performance, depending on the window of exposure. Overall, subtests associated with Mn across exposure windows measure memory, problem solving and attention, suggesting frontal system and hippocampal involvement. We found inverted U-shaped associations between prenatal Mn and Arithmetic, Comprehension, Information and Digits forward (pgam=0.18-0.39). Early postnatal Mn was associated with better performance on Arithmetic (β=0.27 (95%CI=-0.63, 1.17)), Information (β=0.35 (95%CI=-0.42, 1.13)), and Digits forward (β=0.51 (95%CI=0.21, 0.81)). However, childhood Mn was associated with lower Information scores (β=-0.35 (95%CI=-1.11, 0.41)) and non-linearly associated with Digits forward (pgam=0.06). In these data, the shape of the Mn-subtest relationship was dependent on exposure timing. Conclusion: Our results suggest that frontal cortex function may be sensitive to Mn exposure. Higher Mn may be toxic in childhood, potentially identifying a window for intervention implementation