Tooth manganese and neurobehavior in Italian children: sex-specific windows of susceptibility

Abstract

Introduction: Manganese (Mn) exposure can now be quantified using teeth, which can determine dose and exposure timing. Translation of epidemiologic research can be further facilitated by employing behavioral tasks that parallel animal studies, which in turn have access to neurologic tissue for mechanistic research. We examined associations of Mn exposure among Italian adolescents living near a ferromanganese plant with visuospatial learning assessed using the virtual radial arm maze (VRAM). Methods: We analyzed deciduous teeth from 137 children ages 10-15 years by laser ablation inductively coupled plasma mass spectrometry. Mn levels were measured in prenatal and postnatal exposure periods. We assessed performance on the VRAM, a computerized version of the rodent task, estimating latency, distance, working and reference memory errors. Linear mixed regression and generalized additive mixed regression were used to model associations between tooth Mn and VRAM performance and to assess interactions with sex. Results are compared to rodent research. Results: Adjusting for age, socioeconomic status, video game use, childhood blood lead, and tooth type, we observed sex-specific associations of tooth Mn with VRAM performance: among girls, there was a U-shaped association between prenatal Mn and latency, distance and working memory errors (pGAM=0.009-0.02). This result suggest both lower and higher prenatal tooth Mn predict worse performance among girls. Among boys, no association was observed in the prenatal period, but postnatal Mn was associated with latency, distance and reference memory in a non-linear manner (pGAM=0.004-0.08), which is consistent with a rodent study of Mn that also used a radial arm maze. Conclusions: Our sex specific results parallel a rodent study of postnatal Mn exposure demonstrating the utility of employing parallel phenotyping methods for translational research. Sensitive exposure windows appeared to be sex-specific.