Basic & Clinical Pharmacology & Toxicology
Volume 111, Issue 2, pages 126–132, August 2012
Roos P.M., Dencker L.
Amyotrophic lateral sclerosis (ALS) affects anterior horn cells of the spinal cord causing an indolent slow and steady deterioration of muscle strength leading inevitably to death in respiratory failure. ALS is a model condition for neurodegenerative disorders. Exposure to different agents dispersed in the environment has been suggested to cause neurodegeneration but no convincing evidence for such a link has yet been presented. Respiratory exposure to metallic mercury (Hg(0) ) from different sources may be suspected.
Body distribution of metallic mercury is fast and depends on solubility properties. Routes of transport, metabolism, excretion and biological half-life determine the overall toxic effects.
Inhalation experiments were performed in 1984 where small marmoset monkeys (Callithrix jacchus) were exposed to (203) Hg(0 vapour) mixed into the breathing air (4-5 μg/l). After 1 hr of exposure, they were killed and whole body autoradiograms prepared to study the distribution of mercury within organs.
Autoradiograms showed that Hg was deposited inside the spinal cord.
Areas of enhanced accumulation anatomically corresponding to motor nuclei could be observed. This study describes a reinvestigation, with new emphasis on the spinal cord, of these classical metal exposure data in a primate, focusing on their relevance for the causation of neurodegenerative disorders. A comparison with more recent rodent experiments with similar findings is included.
The hypothesis that long-time low-dose respiratory exposure to metals, for example, Hg, contributes to neurodegenerative disorders is forwarded and discussed.
Degenerative disorders of the nervous system affect an increasing number of individuals throughout the world. Genetic causes for this observed increase have been put forward. However, genetics alone cannot explain the observed rise in present prevalence of Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Environmental factors have been suggested as causative in all of these diagnoses, but no convincing evidence for such a link has to date been presented for these multifactorial diseases. ALS has been associated with metal exposure, and toxic metals such as mercury (Hg) are possible candidate substances in the complex causation of ALS.
Use of compounds with recognized neurotoxicity in human exposure experiments is not easily justified for ethical reasons. Because of that, animal experiments have been performed to study the possible contribution of toxic agents from different routes of exposure to the nervous system. Exposure data from rodent experiments are, however, in some cases hard to interpret as the metabolism of the rat for certain toxic agents, for example, mercury, is different from the metabolism of primates and absorption routes and elimination patterns may vary. Timing of dosage and exposure is also critical for the outcome. A low-dose exposure over long time of an accumulating toxic agent, albeit naturally occurring in the environment, causes different types of effects in the nervous system than a high-dose short-time exposure to the same substance.
Respiratory exposure causes a unique distribution pattern within tissues, when compared to intravenous exposure or dermal exposure; however, the overall systemic effects might be the same.
Route of exposure and chemical species of a toxic compound determines the degree of tissue binding. Distribution to organs depends on solubility properties and oxidation in the blood and is for Hg very fast. The whole body distribution also depends on the rate of blood flow in the organs and the capacity to oxidize Hg intracellulary. Local or systemic toxicity occurs for metallic Hg upon application to the skin. Absorption, distribution, metabolism and excretion and chemical properties of the substance explain the delayed observed toxicity upon exposure to elementary mercury (Hg0) where effects may be noted several months after exposure. Absorbed metallic Hg vapour is rapidly oxidized in the blood, and Hg ions are transported via blood to the kidney where renal toxicity will develop at critical concentrations. However, mercury vapour that passes the blood brain barrier (BBB) and is not oxidized until after uptake in the brain will remain in this organ for various time and cause adverse effects in this critical organ. The effects are seen after some time.
Among neurodegenerative disorders, ALS is considered the model condition for neurodegeneration. The motor systems are affected, and indolent slow and steady deterioration of muscle strength leading to death in respiratory failure is caused. In ALS, the anterior horn cells of the spinal cord are selectively affected and atrophy of these cells is seen in every case of ALS.
Possible exposure routes for noxious metal agents that might give rise to ALS consist of dermal exposure, gastrointestinal exposure, mercury vapour from dental amalgam fillings, axonal routes and respiratory exposure, all of which are valid in the discussion of possible environmental impact in causing neurodegenerative disorders. Long-time low-dose respiratory exposure to a toxic agent with long biological half-life absorbed and accumulated in specific cells will give rise to cellular toxicity which will have an impact on the detoxification systems and release of the agent from those cells. Respiratory exposure is unique in this context as it comprises high turnover of large volumes of possibly contaminated air during life-time. To what extent low doses of inhaled mercury vapour can be transported to the spinal cord remains to be elucidated.
This study describes a reinvestigation, with new emphasis on the spinal cord, of some classical metal exposure data in a primate, focusing on their relevance for the causation of ALS. A comparison with more recent rodent experiments with inhaled Hg is included. The hypothesis that long-time lowdose respiratory exposure to metals contributes to ALS is forwarded and discussed with Hg0 as an example.
Inhalation experiments such as the two Hg vapour inhalation studies described in this retrospective discussion show accumulation of Hg in anterior horn cells of the spinal cord after respiratory exposure to Hg vapour. The spread of Hg from respiratory organs to the spinal cord seem to be rapid and passing protective barriers.
Case reports on accidental or occupational respiratory exposure to Hg have described a clinical picture of widespread muscle atrophy and weakness as in ALS. To what extent low-dose respiratory Hg exposure contributes to ALS is still an open question. Small size particulate Hg might add to the respiratory exposure of Hg vapour and ALS-like clinical pictures have been described following inhalation of mercuric oxide dust. Mercury alone may not be responsible for the invariably deadly course in ALS but the possible contribution of inhaled Hg in the causation of this multifactorial disease cannot be neglected.
Inhalation experiments in rats and primates show deposition of Hg in spinal cord following single high-dose short-time exposure. Mercury accumulation in anterior horn cells is followed by axonal atrophy and distal weakness similar to the clinical picture in human ALS.
Protective mechanisms against central nervous system Hg toxicity include induction of MT and catalase in astrocytes supporting anterior horn cells in the spinal cord, however, lack of MT expression in anterior horn cells per se may leave these structures unprotected from Hg toxicity.
Respiratory Hg exposure could contribute to elevated concentrations of Hg found in cerebrospinal fluid from patients with ALS.
Further studies into the contribution from inhaled metal dust or vapour in the causation of neurodegenerative disorders are warranted.