Julia Anglen Bauer1, Roberta F White2, Brent A Coull3, Christine Austin4, Manuela Oppini5, Silvia Zoni5, Chiara Fedrighi5, Giuseppa Cagna5, Donatella Placidi5, Stefano Guazzetti6, Qiong Yang7, David C Bellinger8, Thomas F Webster9, Robert O Wright4, Donald Smith10, Megan Horton4, Roberto G Lucchini11, Manish Arora4, Birgit Claus Henn9. 1. Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA. Electronic address: julia.a.bauer@dartmouth.edu. 2. Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA. 3. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 4. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 5. Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Italy. 6. Azienda USL - IRCCS - di Reggio Emilia, Italy. 7. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. 8. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Departments of Neurology and Psychiatry, Boston Children's Hospital, Boston, MA, USA; Departments of Neurology and Psychiatry, Harvard Medical School, Boston, MA, USA. 9. Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA. 10. Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, CA, USA. 11. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Italy; School of Public Health, Florida International University, Miami, FL, USA.
Abstract
INTRODUCTION: Understanding the neurodevelopmental effects of manganese (Mn) is complicated due to its essentiality for growth and development. While evidence exists for the harmful effects of excess Mn, pediatric epidemiologic studies have observed inconsistent associations between Mn and child cognition. OBJECTIVE: We sought to estimate prospective associations between Mn measured in three different early-life time windows with adolescent cognition using deciduous teeth biomarkers. METHODS: Deciduous teeth were collected from 195 participants (ages 10-14 years) of the Public Health Impact of Manganese Exposure (PHIME) study in Brescia, Italy. Measurements of tooth Mn represented prenatal (∼14 weeks gestation - birth), early postnatal (birth - 1.5 years) and childhood (∼1.5 - 6 years) time windows. Neuropsychologists administered the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), to obtain composite IQ and subtest scores. Associations between tooth Mn at each time window and adolescent WISC-III scores were estimated using multivariable linear regression. We tested differences in associations between Mn and outcomes across time windows using multiple informant models. Sex-specific associations were explored in stratified models. RESULTS: Adjusted associations between tooth Mn and composite IQ scores were positive in the prenatal period and negative in the childhood period. Associations were strongest for subtest scores that reflect working memory, problem solving, visuospatial ability and attention: prenatal Mn was positively associated with Digits backward [SD change in score per interquartile range increase in Mn: β = 0.20 (95 % CI: 0.02, 0.38)] and Block design [β = 0.21 (0.01, 0.41)] and early postnatal Mn was positively associated with Digits forward [β = 0.24 (0.09, 0.40)], while childhood Mn was negatively associated with Coding [β = -0.14 (-0.28, -0.001)]. Sex-stratified analyses suggested different Mn-cognition associations for boys and girls and was also dependent on the time window of exposure. CONCLUSION: Our results suggest that exposure timing is critical when evaluating Mn associations between Mn and cognition. Higher prenatal Mn was beneficial for adolescent cognition; however, these beneficial associations shifted towards harmful effects in later time windows. Cognitive domains most sensitive to Mn across time windows included visuospatial ability, working memory, attention and problem-solving.
INTRODUCTION: Understanding the neurodevelopmental effects of manganese (Mn) is complicated due to its essentiality for growth and development. While evidence exists for the harmful effects of excess Mn, pediatric epidemiologic studies have observed inconsistent associations between Mn and child cognition. OBJECTIVE: We sought to estimate prospective associations between Mn measured in three different early-life time windows with adolescent cognition using deciduous teeth biomarkers. METHODS: Deciduous teeth were collected from 195 participants (ages 10-14 years) of the Public Health Impact of Manganese Exposure (PHIME) study in Brescia, Italy. Measurements of tooth Mn represented prenatal (∼14 weeks gestation - birth), early postnatal (birth - 1.5 years) and childhood (∼1.5 - 6 years) time windows. Neuropsychologists administered the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), to obtain composite IQ and subtest scores. Associations between tooth Mn at each time window and adolescent WISC-III scores were estimated using multivariable linear regression. We tested differences in associations between Mn and outcomes across time windows using multiple informant models. Sex-specific associations were explored in stratified models. RESULTS: Adjusted associations between tooth Mn and composite IQ scores were positive in the prenatal period and negative in the childhood period. Associations were strongest for subtest scores that reflect working memory, problem solving, visuospatial ability and attention: prenatal Mn was positively associated with Digits backward [SD change in score per interquartile range increase in Mn: β = 0.20 (95 % CI: 0.02, 0.38)] and Block design [β = 0.21 (0.01, 0.41)] and early postnatal Mn was positively associated with Digits forward [β = 0.24 (0.09, 0.40)], while childhood Mn was negatively associated with Coding [β = -0.14 (-0.28, -0.001)]. Sex-stratified analyses suggested different Mn-cognition associations for boys and girls and was also dependent on the time window of exposure. CONCLUSION: Our results suggest that exposure timing is critical when evaluating Mn associations between Mn and cognition. Higher prenatal Mn was beneficial for adolescent cognition; however, these beneficial associations shifted towards harmful effects in later time windows. Cognitive domains most sensitive to Mn across time windows included visuospatial ability, working memory, attention and problem-solving.
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