The Use of Metabolomics to Identify Biological Signatures of Manganese Exposure

Abstract

Objectives: Manganese (Mn) is a known neurotoxicant, and given its health effects and ubiquitous nature in metal-working settings, identification of a valid and reproducible biomarker of Mn exposure is of interest. Here, global metabolomics is utilized to determine metabolites that differ between groups defined by Mn exposure status, with the goal being to help inform a potential metabolite biomarker of Mn exposure.

Methods: Mn exposed subjects were recruited from a Mn steel foundry and Mn unexposed subjects were recruited from crane operators at a metal recycling facility. Over the course of a work day, each subject wore a personal inhalable dust sampler (IOM), and provided an end of shift urine sample that underwent global metabolomics profiling. Both exposed and unexposed subjects were divided into a training set and demographically similar validation set. Using a two-sided adjusted t-test, relative abundances of all metabolites found were compared between Mn exposed and unexposed training sets, and those with a false discovery rates (FDR) <0.1 were further tested in the validation sets.

Results: Fifteen ions were found to be significantly different (FDR < 0.1) between the exposed and unexposed training sets, and nine of these ions remained significantly different between the exposed and unexposed validation set as well. When further dividing exposure status into 'lower exposure' and 'higher exposure', several of these nine ions exhibited an apparent exposure-response relationship.

Conclusions: This is the first time that metabolomics has been used to distinguish between Mn exposure status in an occupational cohort, though additional work should be done to replicate these findings with a larger cohort. With metabolite identification by name, empirical formula, or pathway, a better understanding of the relationship between Mn exposure and neurotoxic effects could be elucidated, and a potential metabolite biomarker of Mn exposure could be determined.

Keywords: biomarkers of exposure; exposome; exposure assessment; manganese; metabolomics.

Figure 1.

Manganese exposure assessment by Mn exposure group (in µg/m³). For each exposure group, the middle line that divides the box into two parts represents the median value while the top and bottom line of the box represent the 75^th and 25^th percentiles, respectively. The box represents the interquartile range (IQR) of scores for the group. The whiskers are extended to all values that are no >1.5 × IQR from the edge of the box.

Figure 2.

Box plots of exposure–response relationships for ions identified as different between no Mn exposure, lower Mn exposure, and higher Mn exposure, in both training and validation sets.