Association between prenatal manganese exposure and long-term neuropsychological development at 4 years old in a population-based birth cohort

摘要

Background: Manganese is an essential micronutrient that plays a critical role in normal growth and development. Nevertheless, overexposure to Mn can also be detrimental to health and accumulation of Mn in the brain may result in neurotoxic effects. Previous studies reveal the complexity of the association given the differences in the child's age or developmental and nutritional status (1). While in various transversal studies a negative association has been found with cognitive development (2, 3, 4), in cohort studies a positive trend has been observed with cognitive development and a lack of consistency with motor development (5, 6). There is also limited and inconsistent evidence of gender-specific neurological effects; generally greater effects in girls (2, 7), but also found in boys (8). The goal of the study was to assess the association between Mn levels in hair at birth, derived from prenatal exposure, and longer-term neurodevelopment in a population based birth cohort derived from the INMA Project (Environment and Childhood). Methods: Study subjects were 249 children, participants in the INMA (Environment and Childhood) birth cohort study. Pregnant women were recruited at the first trimester of pregnancy between 2006-2008 in Gipuzkoa, Spain (http://www. proyectoinma.org). Sociodemographic variables were collected through questionnaires in the 1st and 3rd trimesters of pregnancy. Atomic Absorption Spectrometry-furnace technique was used for Mn determination. The cognitive and psycho-motor development was assessed at 4 years of age by using a standardized version of the McCarthy Scales of Children's Abilities (9). The MSCA comprises 18 subtests that yield standardized test scores for six conventional domains (Verbal, Quantitative, Perceptive, Memory, Motor and General Cognitive). MSCA raw scores were centered to a mean of 100 and a standard deviation (SD) of 15 to homogenize the scales. Mul-tivariate linear regression models were built for each cognitive and psychomotor scale. The sex specific association was also analysed by interaction analysis. Results: Complete information was available for 249 children for whom we had data on both the Mn hair levels and neurodevelopment. The new-born hair Mn mean levels were 0.41μg/g (SD = 0.34μg/g). Overall results show no association between Mn levels and longer-term neurodevelopment. General cognitive score increases 0.93 points [IC95% = -4.67 to 6.53] and motor scale decreases points [IC95% = -6.36 to 4.35] per each Mn 1 μg/g increase but the associations are not statistically significant. A statistically significant interaction was found between sex and manganese for the Quantitative scale. While a positive association was found in boys (β = 6.84; 95% IC = -1.95 to 15.63) a negative association was found in girls. (β= -2.02; 95%IC= -10.06 to 6.02). This sex specific trend was found for all the neuropsychological scales except for Fine motor in boys and Gross motor in girls. Conclusions: No statistically significant association has been found between prenatal Mn levels and longer-term neuropsychological development. There is a lack of consistency in the association between Mn and the different neuropsychological scales. Results suggest an opposite sex specific trend in the association between Mn and neurodevelopment, positive for boys and negative for girls.