The role of environmental mercury, lead and pesticide exposure in development of amyotrophic lateral sclerosis

Abstract

Exposure to an environmental toxicant as a risk factor in the development of amyotrophic lateral sclerosis (ALS) was first hinted at (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 pesticides especially organophosphates and certain occupations such as playing professional soccer. Given that only ∼10% of all ALS diagnosis have 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.

Introduction

Amyotrophic lateral sclerosis (ALS) is a lethal, progressive, adult onset motoneuron disease characterized by disintegration of corticospinal tract neurons and α-motor neurons in the brainstem and spinal cord (Morrison and Morrison, 1999, Sejvar et al., 2005, Schymick et al., 2007). ALS neuropathology is characterized by accumulation of insoluble proteins in the cytoplasm of disintegrating neuronal cells (Leigh et al., 1991). The sequelae of ALS include difficulty in performance of certain tasks within a single limb which progresses gradually to include disintegration in other muscle groups leading to loss of limb function, difficulty in speaking or swallowing. It ultimately ends in respiratory failure and death. Once diagnosed with ALS, the survival time is 2–5 years making ALS one of the most rapidly progressive and fatal neurological disorders. The worldwide incidence of ALS is ∼2–4/100,000 people affected per year with the exception of some high-risk areas around the Pacific Rim such as Guam or parts of Western New Guinea (Spencer et al., 1987, Iwami et al., 1993, Plato et al., 2003a, Plato et al., 2003b, Waring et al., 2004). Specifically, individuals of the Chamorro indigenous people of Guam had a high incidence rate, and men exhibit a 20–60% increased risk compared to women (Shoesmith and Strong, 2006, Schmidt et al., 2008). Additionally, 1991 Persian Gulf War veterans have been reported to have a twofold increase in risk of developing ALS, particularly among Air Force and Army personnel (Horner et al., 2008, Miranda et al., 2008). The basis for this enhanced susceptibility is yet unknown, however, several postulated causes have for the most part been ruled out. Age is certainly a risk factor for developing ALS; individuals older than 40 years present higher susceptibility rates, with a median age of 55 years. Moreover, within the last two decades the incidence and mortality rates in the general population have risen (Worms, 2001). However, it is quite striking that in the Persian Gulf War veterans the age of onset of ALS is dramatically earlier (Haley, 2003, Kasarskis et al., 2009).

ALS occurs either as a sporadic (sALS) or familial form (fALS); both forms present indistinguishable clinical symptoms. Approximately, 90% of the cases of ALS are of the sporadic (sALS) form with no known etiology, but 10% have a known genetic basis. Approximately, 20% of the familial cases are linked to mutations in Cu/Zn-superoxide dismutase 1 gene (SOD1) (Rosen et al., 1993, Gurney, 1997).

Shortly after World War II the Chamorro Guamanians experienced an extremely high incidence rate of ALS or ALS-like condition; in 1954 it was estimated to be 50–100× higher than the worldwide rate (Kurland and Mulder, 1987). Recent investigation suggests that the incidence and prevalence rate has declined precipitously over the last 4 decades to levels that correlate more closely to the rest of the world (7/100,000) and it is found only in older individuals and rarely in persons born after 1960 (Galasko et al., 2002, Plato et al., 2003a, Plato et al., 2003b). The reason for this decline is unknown. Plato et al., 2003a, Plato et al., 2003b conclude that it was not due to genetic factors, but most likely is the result of ethnographic changes, radical socioeconomic, and ecologic changes brought about by the rapid westernization of Guam. Galasko et al. (2002) conclude that it was due to modifying environmental factors. However, the emerging view seems to suggest that the initially high incidence rate of ALS among Chamorro Guamanians was the result of the cumulative consumption of cycad flour and flying fox (Spencer et al., 1987, Kisby et al., 1992, Cox and Sacks, 2002). The flying fox, which was a regular part of their diet, bioaccumulates toxic substances found in the cycad seed. One of these was identified as β-methylaminoalanine (BMAA) a known neurotoxin (Cox and Sacks, 2002). In addition, cycad flour made from the seed of cycad, Cycas rumphii, was well known to the Chamorro as acutely toxic, and they detoxified the flour with multiple washings during preparations (Sacks, 1993, Cox and Sacks, 2002, Murch et al., 2004). Collectively, the consumption of cycad flour and cycad-eating flying foxes, which biomagnifies the highly lipophilic BMAA, provide a causal environmental link to ALS or the ALS-like condition in Guam. Additionally, a combination of other environmental factors, superimposed, perhaps on genetic polymorphism yet to be identified, may have contributed to the high incidence rate of ALS among indigenous Chamorro of Guam. Due to the relatively high rates of sporadic as compared to familial ALS, the potential role of environmental factors to its etiology is suggestive.

The comparatively high rate of sALS as compared to fALS has led to the postulate that exposure to environmental pollutant is linked with potential genetic susceptibility to contribute to the pathogenesis of ALS. A growing list of potential environmental risk factors is proposed for developing sALS (McGuire et al., 1997, Weisskopf et al., 2004, Weisskopf et al., 2009, Sutedja et al., 2008). However, to date no definitive causal link has been consistently established. The most consistent associations are exposure to pesticides, heavy metals including lead and mercury, intense physical activity including playing professional soccer, head injury, cigarette smoking, and electromagnetic fields—EMF (Nelson et al., 2000, Håkansson et al., 2003, Morahan and Pamphlett, 2006, Qureshi et al., 2008). Physical activity is reported to have minimal, if any, effect as a risk factor for developing ALS (Longstreth et al., 1998, Veldink et al., 2005). There is some epidemiological evidence of an association between occupational exposure to EMF and the risk of developing ALS (Li and Sung, 2003, Håkansson et al., 2003). However, these risks have not been confirmed in the experimental mouse model of ALS (SOD1G93A) following exposure to extremely low frequency magnetic fields (Poulletier de Gannes et al., 2008).

Among the many forms of environmental exposure scenarios postulated, agricultural pesticides and heavy metals such as mercury and lead in particular are the most likely toxicants routinely encountered by humans and could potentially be a risk factor in the development of sALS. They are likely candidates because we encountered these toxicants in a plethora of environmental media such as air, water, wind drift, multiple dietary sources and volcanic eruptions. Specifically, the pathophysiology of agricultural pesticides, lead and mercury is not yet known but their human neurotoxicity is well studied, documented and is substantial (Roscoe et al., 2002, Thakur et al., 2008, Albanito et al., 2008, Mutter and Yeter, 2008). Mercury and lead exposure have each been associated with the risk of developing ALS (Praline et al., 2007, Kamel et al., 2008). However, inconsistent results have been reported between the concentration in tissue and cerebrospinal fluids and their correlation with the risk of developing ALS. For example, mercury, lead and other metals were found either in lower concentrations or unchanged in the blood and cerebrospinal fluid of ALS patients versus controls (Pierce-Ruhland and Patten, 1980, Foo et al., 1993). Conversely, Kurlander and Patten (1979), report that even after 1-year of chelation therapy the concentration of environmental metals in tissue after death was significantly increased. Retrospective and prospective epidemiological studies of ALS and environmental factors are also inconclusive. A large prospective study of chemical exposures and ALS did not uncover any evidence for an association with exposure to pesticides/herbicides; however, there was an increased risk of ALS with formaldehyde exposure (Weisskopf et al., 2009). Interestingly, this large prospective study examined many different chemicals but did not include heavy or transitional metals.