Exposure to an environmental toxicant as a risk factor in the development of amyotrophic lateral sclerosis (ALS) was first hinted (demonstrated) in the Chamorro indigenous people of Guam. During the 1950s and 1960s these indigenous people presented an extremely high incidence of ALS which was presumed to be associated with the consumption of flying fox and cycad seeds. No other strong association between ALS and environmental toxicants has since been reported, although circumstantial epidemiological evidence has implicated exposure to heavy metals such as lead and mercury, industrial solvents and exposure to pesticides especially organophosphates and certain occupations such as playing soccer. Given that only ~10% of all ALS diagnosis has a genetic basis, a gene-environmental interaction provides a plausible explanation for the other 90% of cases. This mini-review provides an overview of our current knowledge of environmental etiologies of ALS with emphasis on the effects of mercury, lead and pesticides as potential risk factors in developing ALS. Epidemiologic and experimental evidence from animal models investigating the possible association between exposure to environmental toxicant and ALS disease has proven inconclusive. Nonetheless, there are indications that there may be causal links, and a need for more research.

Although the use of organophosphate (OP) insecticides has been restricted, sufficient exposure can occur to induce detrimental neurobehavioral effects. In this study, we measured physical and reflex development and spatial learning and memory in rats repeatedly exposed to incremental doses of chlorpyrifos (CPS) and methyl parathion (MPS) from postnatal day (PND) 1 to PND21. Other than decreased body weight in the higher dosage groups, no effects on physical or reflex development were observed. Significant hippocampal cholinesterase inhibition was induced in all treatment groups for up to 19 days following exposure. Beginning on PND36, working and reference memory was tested using a 12-arm radial maze, with subject animals trained and tested 4 days a week for 4 weeks. In males, working memory was decreased with the medium and high dosage of MPS but only the high dosage of CPS; while in females, no deficits were observed. For reference memory, errors were significantly increased in males exposed to the high dosage of CPS and all dosages of MPS. In females, enhanced performance was observed within the medium and high dosages of CPS but not with MPS. These data show that repeated developmental exposure to OP insecticides can induce sex-selective alterations and long-lasting changes in spatial learning and memory formation when measured using a radial arm maze and that MPS and CPS induce different neurobehavioral outcomes.

Mice expressing the human Cu 2ϩ /Zn 2ϩ superoxide dismutase 1 (hSOD1) gene mutation (hSOD1 G93A; G93A) were exposed to methylmercury (MeHg) at concentrations that did not cause overt motor dysfunction. We hypothesized that low concentrations of MeHg could hasten development of the amyotrophic lateral sclerosis (ALS)-like phenotype in G93A mice. MeHg (1 or 3 ppm/day in drinking water) concentration-dependently accelerated the onset of rotarod failure in G93A, but not wild-type, mice. At the time of rotarod failure, MeHg increased Fluo-4 fluorescence (free intracellular calcium concentration [Ca 2ϩ ] i ) in soma of brainstemhypoglossal nucleus. These motor neurons control intrinsic and some extrinsic tongue function and exhibit vulnerability in bulbaronset ALS. The ␣-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA)/kainic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione reduced [Ca 2ϩ ] i in all G93A mice, irrespective of MeHg treatment. N-acetyl spermine, which antag- -permeable AMPA receptors and may contribute to the hastened development of ALS-like phenotypes by subjecting motor neurons to excessive elevation of [Ca 2ϩ ] i , leading to excitotoxic cell death.

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