Foreword:
JEM Spotlight: Metal speciation related to neurotoxicity in humans
Michael Aschner
Vanderbilt University Department of Pediatrics and Pharmacology, TN, USA
 Michael Aschner | Michael Aschner is the Gray E. B. Stahlman Professor of Neuroscience, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN. A neurotoxicologist by training, he has served on national and international committees and editorial boards, authoring >300 peer-reviewed publications. He has worked on brain metal uptake, developmental neurotoxicity and molecular mechanisms of neurodegeneration. |
Michalke and colleagues succinctly describe the potential role played by several metals in the etiology of common neurodegenerative disorders, with special emphasis on metal speciation or valence. The authors advance a strong argument for the paucity of data and lack of contemporary methodologies to determine the valence of various metals in biological media, especially in the brain, as metal speciation may directly be linked to neurotoxic outcome. Examples of the differential toxicity of several metals that can assume a number of valence states in biological media are discussed. It is elegantly documented that metals, such as manganese and mercury, have more than one biologically relevant valence state, and as such their absorption, distribution, biotransformation and elimination, and by inference toxicity will be directly linked to their valence. Within a broader perspective, the review is especially illuminating, as the rate of common diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD) has increased. It is now appreciated that the pattern of inheritance of many of the neurodegenerative disorders rarely follows Mendelian laws, and reflects a complex interaction among multiple predisposing genes and environmental contributions. As pointed out by the authors, identifying metal valences will serve to better understand the etiologic process and pathogenesis of common forms of disease and the role of various metals in this process. Identifying the chain of events leading to metal-induced neurological damage may also improve understanding of the etiology of other neurodegenerative conditions, thus having broad application for the development of potential treatment modalities.
A major focus of the review is the application of speciation analysis for metals in neurologically relevant biological media in humans. The authors justifiably argue for the need of better speciation data, especially from the cerebrospinal fluid (CSF). A case can also be made for the potential utilization of postmortem tissue where available techniques may be instrumental not only in determining metal levels but also their speciation. However, it needs to be considered that elevated metals per se, if and where found, should be cautiously interpreted, given that an increase or decrease in metal levels by themselves do not necessarily establish causality. Notably, brain homeostasis of metals is intertwined with changes in a single metal leading to profound changes in the levels of other metals. This is well established for manganese (Mn) and iron (Fe), where Fe deficiency leads to significant increases in brain Mn levels. Nevertheless, biological media, such as CSF, especially if collected along a temporal axis during disease progression, will be more informative and provide data on changes in metal ion brain concentrations, especially if such data are gathered for multiple metals.
A strong case is made for the lack of adequate methods for the determination of metal valence in tissues. Methods such as graphite furnace atomic absorption spectrometry (GFAAS) [(also known as electrothermal atomic absorption spectrometry (ETAAS)] or inductively coupled plasma mass spectrometry (ICP-MS), and others, are analytical techniques that are quite routinely employed for the determination of the elemental composition of samples. Electrospray ionization (ESI) is also based on mass spectrometry to produce ions and has been also useful in producing ions from macromolecules overcoming the propensity of these molecules to fragment when ionized. None of the above, however, will speciate the metal valence. The importance of recognizing a metal's valence within the context of neurodegenerative potential is perhaps best exemplified with Mn. The specificity for Mn accumulation in various brain regions, such as globus pallidus (GP) and striatum is known to be related to transporter expression [divalent metal transporter-1 (DMT) for Mn2+vs. transferrin receptor (TfR) for Mn3+], as well as the metabolic activity of the basal ganglia nuclei. Furthermore, given that Mn2+ is readily oxidized by superoxide to Mn3+, a strong pro-oxidant, and since the mitochondrial electron transport chain (ETC) is the largest producer of superoxide in the cell, it has been hypothesized that oxidation of Mn2+ to Mn3+ in mitochondria leads to the proximate species of Mn-induced neurodegeneration.
X-ray absorption near edge structure (XANES), a technique also discussed by Michalke and colleagues, has received little attention in neurodegenerative studies, yet it may offer new insights into the role of metal valence in triggering neurodegenerative injuries. The technique is also a type of absorption spectroscopy, which, to my knowledge, offers the most definitive means for speciating metals. While the GFAAS, ICP-MS, or ESI are very sensitive and may provide pertinent information on the amount of metal ions in biological media, they provide no information about the oxidation state. On the other hand, by fitting experimental XANES spectra to phantom complexes of metals, one can unambiguously distinguish within cells or media, metal-containing complexes and establish the metal's oxidation state, as we have recently reported (K. K. Gunter, M. Aschner, L. M. Miller, R. Eliseev, J. Salter, K. Anderson, S. Hammond and T. E. Gunter, Free Radical Biol. Med., 2005, 39, 164–181). The increasing sensitivity of XANES, owing to the more intense synchrotron beams and efficient focusing optics (R. Lobinski, C. Moulin and R. Ortega, Biochimie, 2006, 88, 1591–1604), should enable researchers to more readily gather pertinent information about metal oxidation state, fingerprint speciation of metal sites and metal-site structures, all of which will be instrumental in understanding the role of metals and their oxidation states in neurodegeneration. However, the availability of technology by itself will not bring about additional knowledge unless it is met with enthusiasm by basic scientists and clinicians. As such, the present article stipulates the need and provides a level of objectivity that will be necessary to move the field forward and highlights the timeliness of future research in this area of neuroscience.
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