An amyotrophic lateral sclerosis hot spot in the French Alps associated with genotoxic fungi

Lagrange, É.; Vernoux, Jean-Paul; Reis, Jacques; Palmer, Valerie S.; Camu, William; Spencer, Peter S.

doi:10.1016/j.jns.2021.117558

Cited by 25 publications

(23 citation statements)

References 50 publications

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“…Finally, as discussed elsewhere, the molecular mechanisms utilized by MAM are shared by other genotoxic chemicals, including nitrosoureas, nitrosoamines, and hydrazines ( Spencer and Kisby, 2021b ), exposure to which has also been associated with neurodegenerative disease, notably sporadic ALS ( Spencer, 2019 ; Lagrange et al, 2021 ). This should encourage intense study of the lifetime exposure history of subjects with non-inherited neurodegenerative disorders that, like ALS/PDC, may be triggered by environmental genotoxins.…”

Section: Discussionmentioning

confidence: 99%

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Kisby

Spencer

2021

Front. Neurosci.

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Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) is a disappearing prototypical neurodegenerative disorder (tau-dominated polyproteinopathy) linked with prior exposure to phytogenotoxins in cycad seed used for medicine and/or food. The principal cycad genotoxin, methylazoxymethanol (MAM), forms reactive carbon-centered ions that alkylate nucleic acids in fetal rodent brain and, depending on the timing of systemic administration, induces persistent developmental abnormalities of the cortex, hippocampus, cerebellum, and retina. Whereas administration of MAM prenatally or postnatally can produce animal models of epilepsy, schizophrenia or ataxia, administration to adult animals produces little effect on brain structure or function. The neurotoxic effects of MAM administered to rats during cortical brain development (specifically, gestation day 17) are used to model the histological, neurophysiological and behavioral deficits of human schizophrenia, a condition that may precede or follow clinical onset of motor neuron disease in subjects with sporadic ALS and ALS/PDC. While studies of migrants to and from communities impacted by ALS/PDC indicate the degenerative brain disorder may be acquired in juvenile and adult life, a proportion of indigenous cases shows neurodevelopmental aberrations in the cerebellum and retina consistent with MAM exposure in utero. MAM induces specific patterns of DNA damage and repair that associate with increased tau expression in primary rat neuronal cultures and with brain transcriptional changes that parallel those associated with human ALS and Alzheimer’s disease. We examine MAM in relation to neurodevelopment, epigenetic modification, DNA damage/replicative stress, genomic instability, somatic mutation, cell-cycle reentry and cellular senescence. Since the majority of neurodegenerative disease lacks a solely inherited genetic basis, research is needed to explore the hypothesis that early-life exposure to genotoxic agents may trigger or promote molecular events that culminate in neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Kisby

Spencer

2021

Front. Neurosci.

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“…In addition to the study of experimental animal models, environmental factors need careful consideration . For example, comprehensive investigations of an ALS cluster in a small village in the French Alps indicated that consumption of Gyromitra gigas mushrooms was a common factor among those who developed ALS . This commonality provides support for a previously published hypothesis that NDDs could be induced by genotoxic hydrazine-based mycometabolites .…”

Section: Demonstrating 12-dehydropyrrolizidine Alkaloids As a Cause O...mentioning

confidence: 99%

1,2-Dehydropyrrolizidine Alkaloids: Their Potential as a Dietary Cause of Sporadic Motor Neuron Diseases

Edgar

Molyneux

Colegate

2022

Chem. Res. Toxicol.

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Sporadic motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS), can be caused by spontaneous genetic mutations. However, many sporadic cases of ALS and other debilitating neurodegenerative diseases (NDDs) are believed to be caused by environmental factors, subject to considerable debate and requiring intensive research. A common pathology associated with MND development involves progressive mitochondrial dysfunction and oxidative stress in motor neurons and glial cells of the central nervous system (CNS), leading to apoptosis. Consequent degeneration of skeletal and respiratory muscle cells can lead to death from respiratory failure. A significant number of MND cases present with cancers and liver and lung pathology. This Perspective explores the possibility that MNDs could be caused by intermittent, low-level dietary exposure to 1,2-dehydropyrrolizidine alkaloids (1,2-dehydroPAs) that are increasingly recognized as contaminants of many foods consumed throughout the world. Nontoxic, per se, 1,2-dehydroPAs are metabolized, by particular cytochrome P450 (CYP450) isoforms, to 6,7-dihydropyrrolizines that react with nucleophilic groups (−NH, −SH, −OH) on DNA, proteins, and other vital biochemicals, such as glutathione. Many factors, including aging, gender, smoking, and alcohol consumption, influence CYP450 isoform activity in a range of tissues, including glial cells and neurons of the CNS. Activation of 1,2-dehydroPAs in CNS cells can be expected to cause gene mutations and oxidative stress, potentially leading to the development of MNDs and other NDDs. While relatively high dietary exposure to 1,2-dehydroPAs causes hepatic sinusoidal obstruction syndrome, pulmonary venoocclusive disease, neurotoxicity, and diverse cancers, this Perspective suggests that, at current intermittent, low levels of dietary exposure, neurotoxicity could become the primary pathology that develops over time in susceptible individuals, along with a tendency for some of them to also display liver and lung pathology and diverse cancers co-occurring with some MND/NDD cases. Targeted research is recommended to investigate this proposal.

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“…Frequent ingestion of false morels was reported 30 years ago, causing “hepatitis and neurological diseases”, but the latter was never defined. However, in 2021, a progressive motor neuron disease (sporadic amyotrophic lateral sclerosis, sALS) was reported in 14 persons who consumed false morels (specifically G. gigas ), half of whom had a history of acute reversible illness following food use of these poisonous mushrooms . While this does not prove a causal relationship between sALS and repeated oral exposure to hydrazine-related compounds intrinsic to and derived from the culpable false morel ( G. gigas ), it adds to other evidence that strongly implicates a related food toxin, MAM, in the etiology of human neurodegenerative disease .…”

Section: Evidence For Neurotoxicity and Neurodegenerative Diseasementioning

confidence: 99%

Role of Hydrazine-Related Chemicals in Cancer and Neurodegenerative Disease

Spencer

Kisby

2021

Chem. Res. Toxicol.

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Hydrazine-related chemicals (HRCs) with carcinogenic and neurotoxic potential are found in certain mushrooms and plants used for food and in products employed in various industries, including aerospace. Their propensity to induce DNA damage (mostly O 6-, N7- and 8-oxo-guanine lesions) resulting in multiple downstream effects is linked with both cancer and neurological disease. For cycling cells, unrepaired DNA damage leads to mutation and uncontrolled mitosis. By contrast, postmitotic neurons attempt to re-enter the cell cycle but undergo apoptosis or nonapoptotic cell death. Biomarkers of exposure to HRCs can be used to explore whether these substances are risk factors for sporadic amyotrophic laterals sclerosis and other noninherited neurodegenerative diseases, which is the focus of this paper.

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An amyotrophic lateral sclerosis hot spot in the French Alps associated with genotoxic fungi

Cited by 25 publications

References 50 publications

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

1,2-Dehydropyrrolizidine Alkaloids: Their Potential as a Dietary Cause of Sporadic Motor Neuron Diseases

Role of Hydrazine-Related Chemicals in Cancer and Neurodegenerative Disease

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