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Environmental insults: critical triggers for amyotrophic lateral sclerosis.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by a rapid loss of lower and upper motor neurons. As a complex disease, the ageing process and complicated gene-environment interactions are involved in the majority of cases.Significant advances have been made in unravelling the genetic susceptibility to ALS with massively parallel sequencing technologies, while environmental insults remain a suspected but largely unexplored source of risk. Several studies applying the strategy of Mendelian randomisation have strengthened the link between environmental insults and ALS, but none so far has proved conclusive. We propose a new ALS model which links the current knowledge of genetic factors, ageing and environmental insults. This model provides a mechanism as to how ALS is initiated, with environmental insults playing a critical role.The available evidence has suggested that inherited defect(s) could cause mitochondrial dysfunction, which would establish the primary susceptibility to ALS. Further study of the underlying mechanism may shed light on ALS pathogenesis. Environmental insults are a critical trigger for ALS, particularly in the aged individuals with other toxicant susceptible genes. The identification of ALS triggers could lead to preventive strategies for those individuals at risk.

SUBMITTER: Yu B

PROVIDER: S-EPMC5472994 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Environmental insults: critical triggers for amyotrophic lateral sclerosis.

Yu Bing B Pamphlett Roger R

Translational neurodegeneration 20170616

<h4>Background</h4>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by a rapid loss of lower and upper motor neurons. As a complex disease, the ageing process and complicated gene-environment interactions are involved in the majority of cases.<h4>Main body</h4>Significant advances have been made in unravelling the genetic susceptibility to ALS with massively parallel sequencing technologies, while environmental insults remain a suspected but largely unexplor ...[more]

PMID: 28638596

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Project description:IMPORTANCE:Persistent environmental pollutants may represent a modifiable risk factor involved in the gene-time-environment hypothesis in amyotrophic lateral sclerosis (ALS). OBJECTIVE:To evaluate the association of occupational exposures and environmental toxins on the odds of developing ALS in Michigan. DESIGN, SETTING, AND PARTICIPANTS:Case-control study conducted between 2011 and 2014 at a tertiary referral center for ALS. Cases were patients diagnosed as having definitive, probable, probable with laboratory support, or possible ALS by revised El Escorial criteria; controls were excluded if they were diagnosed as having ALS or another neurodegenerative condition or if they had a family history of ALS in a first- or second-degree blood relative. Participants completed a survey assessing occupational and residential exposures. Blood concentrations of 122 persistent environmental pollutants, including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and brominated flame retardants (BFRs), were measured using gas chromatography-mass spectrometry. Multivariable models with self-reported occupational exposures in various exposure time windows and environmental toxin blood concentrations were separately fit by logistic regression models. Concordance between the survey data and pollutant measurements was assessed using the nonparametric Kendall ? correlation coefficient. MAIN OUTCOMES AND MEASURES:Occupational and residential exposures to environmental toxins, and blood concentrations of 122 persistent environmental pollutants, including OCPs, PCBs, and BFRs. RESULTS:Participants included 156 cases (mean [SD] age, 60.5 [11.1] years; 61.5% male) and 128 controls (mean [SD] age, 60.4 [9.4] years; 57.8% male); among them, 101 cases and 110 controls had complete demographic and pollutant data. Survey data revealed that reported pesticide exposure in the cumulative exposure windows was significantly associated with ALS (odds ratio [OR]?=?5.09; 95% CI, 1.85-13.99; P?=?.002). Military service was also associated with ALS in 2 time windows (exposure ever happened in entire occupational history: OR?=?2.31; 95% CI, 1.02-5.25; P?=?.046; exposure ever happened 10-30 years ago: OR?=?2.18; 95% CI, 1.01-4.73; P?=?.049). A multivariable model of measured persistent environmental pollutants in the blood, representing cumulative occupational and residential exposure, showed increased odds of ALS for 2 OCPs (pentachlorobenzene: OR?=?2.21; 95% CI, 1.06-4.60; P?=?.04; and cis-chlordane: OR?=?5.74; 95% CI, 1.80-18.20; P?=?.005), 2 PCBs (PCB 175: OR?=?1.81; 95% CI, 1.20-2.72; P?=?.005; and PCB 202: OR?=?2.11; 95% CI, 1.36-3.27; P?=?.001), and 1 BFR (polybrominated diphenyl ether 47: OR?=?2.69; 95% CI, 1.49-4.85; P?=?.001). There was modest concordance between survey data and the measurements of persistent environmental pollutants in blood; significant Kendall ? correlation coefficients ranged from -0.18 (Dacthal and "use pesticides to treat home or yard") to 0.24 (trans-nonachlor and "store lawn care products in garage"). CONCLUSIONS AND RELEVANCE:In this study, persistent environmental pollutants measured in blood were significantly associated with ALS and may represent modifiable ALS disease risk factors.

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Environmental insults: critical triggers for amyotrophic lateral sclerosis.

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Environmental insults: critical triggers for amyotrophic lateral sclerosis.

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