Metal(loid)s role in the pathogenesis of amyotrophic lateral sclerosis: Environmental, epidemiological, and genetic data

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. The etiology is still unknown and the pathogenesis remains unclear. ALS is familial in the 10% of cases with a Mendelian pattern of inheritance. In the remaining sporadic cases, a multifactorial origin is supposed in which several predisposing genes interact with environmental factors. The etiological role of environmental factors, such as pesticides, exposure to electromagnetic fields, and metals has been frequently investigated, with controversial findings. Studies in the past two decades have highlighted possible roles of metals, and ionic homeostasis dysregulation has been proposed as the main trigger to motor-neuron degeneration. This study aims at evaluating the possible role of environmental factors in etiopathogenesis of ALS, with a particular attention on metal contamination, focusing on the industrial Briga area in the province of Novara (Piedmont region, North Italy), characterized by: i) a higher incidence of sporadic ALS (sALS) in comparison with the entire province, and ii) the reported environmental pollution. Environmental data from surface, ground and discharge waters, and from soils were collected and specifically analyzed for metal content. Considering the significance of genetic mechanisms in ALS, a characterization for the main ALS genes has been performed to evaluate the genetic contribution for the sALS patients living in the area of study. The main findings of this study are the demonstration that in the Briga area the most common metal contaminants are Cu, Zn, Cr, Ni (widely used in tip-plating processes), that are above law limits in surface waters, discharge waters, and soil. In addition, other metals and metalloids, such as Cd, Pb, Mn, and As show a severe contamination in the same area. Results of genetic analyses show that sALS patients in the Briga area do not carry recurrent mutations or an excess of mutations in the four main ALS causative genes (SOD1, TARDBP, FUS, C9ORF72) and for ATXN2 CAG repeat locus. This study supports the hypothesis that the higher incidence of sALS in Briga area may be related to environmental metal(loid)s contamination, along with other environmental factors. Further studies, implementing analysis of genetic polymorphisms, as well as investigation with long term follow-up, may yield to key aspects into the etiology of ALS. The interplay between different approaches (environmental, chemical, epidemiological, genetic) of our work provides new insights and methodology to the comprehension of the disease etiology.

Risk of Amyotrophic Lateral Sclerosis and Exposure to Particulate Matter from Vehicular Traffic: A Case-Control Study

“…Clinical and lifestyle determinants have been widely investigated, especially smoking, military service, and traumatic events [9][10][11]. Additionally, exposure to several occupational and environmental factors has been addressed, including electromagnetic fields, cyanotoxins, and chemicals such as pesticides, solvents, heavy metals, and selenium [12][13][14][15][16][17][18][19][20]. Most recently, exposure to traffic-related air pollutants has been investigated [21].…”

Gastrointestinal Status and Microbiota Shaping in Amyotrophic Lateral Sclerosis: A New Frontier for Targeting?

“…The latter include occupational exposure to toxic substances, viral infections, lifestyle habits, habitual diet, and body mass index. However, contrasting results have been reported regarding environmental elements as being risk factors for disease progression (1).…”

Assessing the Causal Role of Selenium in Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

“…This multistep model empathizes the relevance of studying both genetic and environmental risk factors in ALS [9]. Among these environmental factors, studies in the past decades have highlighted the potential role of ionic homeostasis in the etiopathogenesis of ALS [10,11]. In particular, suggestive epidemiologic evidence seem to support an association between increased ASL incidence and selenium exposure [12][13][14].…”