Manganese in teeth and neurobehavior: Sex-specific windows of susceptibility

Background: Manganese (Mn) is an essential element required for growth and development, but higher body burdens have been associated with neurobehavioral decrements in children. Objectives: We examined whether prenatal or postnatal Mn measured in deciduous teeth was associated with scores on a test of visuospatial learning and memory. Methods: Deciduous teeth were collected from 142 participants (ages 10-14 years) residing near varied ferro-manganese industry in Italy. Mn concentrations were measured in prenatal and postnatal tooth regions by laser ablation inductively coupled plasma mass spectrometry (ICP-MS). The Virtual Radial Arm Maze (VRAM), an animal-human analogue task, was used to assess visuospatial learning and memory. We used generalized additive, linear and zero-inflated Poisson mixed regression models to estimate associations between prenatal or postnatal Mn concentrations and repeated measures of all four VRAM outcomes: time, distance, working and reference memory errors. Effect measure modification by sex was examined in stratified models. Results: U-shaped associations between prenatal Mn and VRAM outcomes were observed among girls only (p(GAMM)=0.001 to 0.02 in stratified models). Compared to the mid-tertile of prenatal Mn, girls in the highest tertile took 7.7 s [95% CI: -6.1, 21.5] longer to complete the task, traveled 2.3 maze units [0.1, 4.4] farther, and committed more working and reference memory errors (beta for count ratio =1.33 [1.01, 1.83]; 1.10 [0.98, 1.24], respectively). This association was not observed among boys. In contrast, for postnatal Mn, no significant associations were found, and patterns were similar for boys and girls. Conclusions: The prenatal period may be a critical window for the impact of environmental Mn on visuospatial ability and executive function, especially for females.