Manganese: Recent advances in understanding its transport and neurotoxicity

Abstract

The present review is based on presentations from the meeting of the Society of Toxicology in San Diego, CA (March 2006). It addresses recent developments in the understanding of the transport of manganese (Mn) into the central nervous system (CNS), as well as brain imaging and neurocognitive studies in non-human primates aimed at improving our understanding of the mechanisms of Mn neurotoxicity. Finally, we discuss potential therapeutic modalities for treating Mn intoxication in humans.

Introduction

Mn exists in a number of physical and chemical forms in the Earth's crust, in water and in the atmosphere's particulate matter. Because its outer electron shell can donate up to 7 electrons (USEPA, 1984), Mn can assume 11 different oxidation states. Of environmental importance are Mn²⁺, Mn⁴⁺ and Mn⁷⁺. In living tissue, Mn has been found as Mn²⁺, Mn³⁺ and possibly as Mn⁴⁺ (Archibald and Tyree, 1987). Mn⁵⁺, Mn⁶⁺, Mn⁷⁺ and other complexes of Mn at higher oxidation states are generally unrecognized in biological materials (Keen, 1995). Mn plays an essential role as a cofactor in many enzymatic reactions in humans, but in excess quantities, can cause damage to the nervous system. Typically found in compounds with a coordination number of 6 and lacking octahedral coordination complexes, Mn tends to form very tight complexes with other substances (Keen, 1995). As a result, its free plasma and tissue concentrations tend to be extremely low (Cotzias et al., 1968).

Manganese (Mn) is an essential metal found in a variety of biological tissues and is necessary for normal functioning of a variety of physiological processes including amino acid, lipid, protein and carbohydrate metabolism (Erikson et al., 2005). Mn also plays an essential role in immune system functioning, regulation of cellular energy, bone and connective tissue growth and blood clotting (Erikson and Aschner, 2003). In the brain, Mn is an important cofactor for a variety of enzymes, including the anti-oxidant enzyme superoxide dismutase (Hurley and Keen, 1987), as well as enzymes involved in neurotransmitter synthesis and metabolism (Golub et al., 2005).

Despite its essentiality, Mn has been known to be a neurotoxicant for at least 150 years (ATSDR, 2000). Mn neurotoxicity was first identified as an extra-pyramidal syndrome in miners exposed to high concentrations of Mn ore (Barbeau et al., 1976, Barbeau, 1984, Couper, 1837, Mena et al., 1967). Exposure to excessive amounts of Mn is associated with a variety of psychiatric and motor disturbances (Chia et al., 1993, Calne et al., 1994, Pal et al., 1999, Stredrick et al., 2004). The signs and symptoms from relatively high levels of exposure, as might occur in occupational settings, include postural instability, mood and psychiatric changes (i.e., depression, agitation, hallucinations) (Mena et al., 1967) and parkinsonian symptoms such as bradykinesia, rigidity, tremor, gait disturbance, postural instability and dystonia and/or ataxia (Josephs et al., 2005). Cognitive deficits such as memory impairment, reduced learning capacity, decreased mental flexibility, cognitive slowing (Josephs et al., 2005) and difficulty with visuomotor and visuospatial information processing (Bowler et al., 2003) have also been reported. It has been suggested that the earliest signs of Mn intoxication may be subtle (Bowler et al., 2006) and that psychomotor testing, in particular, may be more sensitive than standardized neurological examinations in detecting central nervous system (CNS) defects in exposed workers (Roels et al., 1987, Roels et al., 1992).

The primary source of Mn intoxication in humans is due to occupational exposure in miners, smelters, welders and workers in dry-cell battery factories (Bowler et al., 2006, Chandra et al., 1981, Huang et al., 1989, Jiang et al., 2006, Myers et al., 2003, Ono et al., 2002). Significant neurological dysfunction has been associated with the duration of Mn exposure (Roels et al., 1987). Other epidemiological studies of industrial workers have shown a positive correlation between neurological dysfunction and lifetime integrated or cumulative Mn exposure (Lucchini et al., 1995, Lucchini et al., 1999, Roels et al., 1992).

The present review is based on presentations from the meeting of the Society of Toxicology in San Diego, CA (March 2006). It addresses recent developments in the understanding of the transport of manganese (Mn) into the central nervous system (CNS), as well as brain imaging and neurocognitive studies in non-human primates aimed at improving our understanding of the mechanisms of Mn neurotoxicity. Finally, we discuss potential therapeutic modalities for treating Mn intoxication in humans.