Biomarkers of manganese intoxication

Abstract

Manganese (Mn), upon absorption, is primarily sequestered in tissue and intracellular compartments. For this reason, blood Mn concentration does not always accurately reflect Mn concentration in the targeted tissue, particularly in the brain. The discrepancy between Mn concentrations in tissue or intracellular components means that blood Mn is a poor biomarker of Mn exposure or toxicity under many conditions and that other biomarkers must be established. For group comparisons of active workers, blood Mn has some utility for distinguishing exposed from unexposed subjects, although the large variability in mean values renders it insensitive for discriminating one individual from the rest of the study population. Mn exposure is known to alter iron (Fe) homeostasis. The Mn/Fe ratio (MIR) in plasma or erythrocytes reflects not only steady-state concentrations of Mn or Fe in tested individuals, but also a biological response (altered Fe homeostasis) to Mn exposure. Recent human studies support the potential value for using MIR to distinguish individuals with Mn exposure. Additionally, magnetic resonance imaging (MRI), in combination with noninvasive assessment of γ-aminobutyric acid (GABA) by magnetic resonance spectroscopy (MRS), provides convincing evidence of Mn exposure, even without clinical symptoms of Mn intoxication. For subjects with long-term, low-dose Mn exposure or for those exposed in the past but not the present, neither blood Mn nor MRI provides a confident distinction for Mn exposure or intoxication. While plasma or erythrocyte MIR is more likely a sensitive measure, the cut-off values for MIR among the general population need to be further tested and established. Considering the large accumulation of Mn in bone, developing an X-ray fluorescence spectroscopy or neutron-based spectroscopy method may create yet another novel non-invasive tool for assessing Mn exposure and toxicity.

Introduction

Manganese (Mn) is a naturally occurring element abundantly present in the environment. While essential to human health, overexposure to Mn is associated with devastating neurologic impairment clinically known as “manganism,” a motor syndrome similar to, but partially distinguishable from idiopathic Parkinson's disease (IPD) (Aschner et al., 2007, Aschner et al., 2009, Barbeau et al., 1976, Calne et al., 1994, Jiang et al., 2006, Mena et al., 1967, Olanow, 2004). Because the symptoms of Mn intoxication, once established, usually become progressive and irreversible, reflecting permanent damage to neurologic structures, establishing a biomarker for Mn intoxication has become an immensely pressing issue.

According to the National Academy of Sciences (1989), a biological marker or biomarker is defined as an indicator that signifies an event in a biological system or in samples of biological origin. Biomarkers can be divided into three broad interrelated sub-categories: biomarkers of exposure, biomarkers of effect, and biomarkers of host susceptibility (Fowle and Sexton, 1992). The distinction between these three sub-categories is not always clear, as effect and susceptibility usually overlap, and exposure and effect, in many cases, are closely related. However, there are instances in which biological exposure is evident and measurable, and a latency period exists in which biological or physical alterations do not visibly manifest.

No reliable biomarkers have been established to evaluate the effect of Mn exposure or host susceptibility to the metal primarily because a complete scientific understanding of the mechanism of toxicity remains undiscovered. Over the past decade, extensive research using animal models and human populations has led to several potential indicators of Mn exposure and biological effect. The purpose of this review is to identify valid biological indicators of Mn exposure and toxicity, evaluate their feasibility in real-life assessment, and provide a critical comment on the future direction of Mn biomarker investigation.