Role of Hydrazine-Related Chemicals in Cancer and Neurodegenerative Disease

Spencer, Peter S.; Kisby, Glen E.

doi:10.1021/acs.chemrestox.1c00150

Cited by 30 publications

(18 citation statements)

References 222 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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“…Additionally, 4-hydroxymethyl) benzenediazonium salt, a carcinogen in A. bisporus , generates a carbon-centered radical, the 4-(hydroxymethyl)phenyl radical, which causes DNA strand breaks [ 59 ]. Similarly, methylazoxymethanol (MAM), the free-radical-generating aglycone of cycasin, increases DNA adducts (O 6 -mG, N7-mG) and elevates tau mRNA expression in rat neuronal cultures treated with glutamate [ 60 ] and, in mice, modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked manner [ 61 , 62 ]. MAM-β-D-glucoside (cycasin) is the principal toxin in cycad seed, the traditional food use of which by the Chamorro people of Guam is etiologically associated with the Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex, a tau-dominated polyproteinopathy that can begin early in life [ 63 ] and has a neuropathologic profile with some overlap with that of Nodding syndrome [ 12 ].…”

Section: Hydrazinic Fungimentioning

confidence: 99%

Nodding syndrome: A key role for sources of nutrition?

et al. 2022

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“…Gyromitrin may also have long-term toxic effects, including increased rates of cancer (Toth and Nagel 1978; Toth and Patil 1980). The genotoxic potential of gyromitrin informs the emerging hypothesis of its role in the development of neurodegenerative diseases such as sporadic amyotrophic lateral sclerosis (ALS) (Spencer 2020; Lagrange et al 2021; Spencer and Kisby 2021; Spencer and Palmer 2021).…”

Section: Introductionmentioning

confidence: 99%

Distribution of the gyromitrin mycotoxin in the lorchel family assessed by a pre-column-derivatization and ultra high-performance liquid chromatography method

Dirks

Mohamed

Schultz

et al. 2022

Preprint

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Gyromitrin (acetaldehyde N-methyl-N-formylhydrazone) and its homologs are deadly mycotoxins produced most infamously by the lorchel (also known as false morel) Gyromitra esculenta, which is paradoxically consumed as a delicacy in some parts of the world. There is much speculation about the presence of gyromitrin in other species of the lorchel family (Discinaceae), but no studies have broadly assessed its distribution. Given the history of poisonings associated with the consumption of G. esculenta and G. ambigua, we hypothesized that gyromitrin evolved in the last common ancestor of these taxa and would be present in their descendants with adaptive loss of function in the nested truffle clade, Hydnotrya. To investigate this hypothesis, we developed a sensitive analytical derivatization method for the detection of gyromitrin using 2,4-dinotrobenzaldehyde as the derivatization reagent. In total, we analyzed 66 specimens for the presence of gyromitrin over 105 tests. Moreover, we sequenced the nuc rDNA ITS1-5.8S-ITS2 region (ITS barcode) and nuc 28S rDNA to assist in species identification and to infer a supporting phylogenetic tree. We detected gyromitrin in all tested specimens from the G. esculenta group as well as G. leucoxantha. This distribution is consistent with a model of rapid evolution coupled with horizontal transfer, which is typical for secondary metabolites. We clarified that gyromitrin production in Discinaceae is both discontinuous and more limited than previously thought. Further research is required to elucidate the gyromitrin biosynthesis gene cluster and its evolutionary history in lorchels.

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Role of Hydrazine-Related Chemicals in Cancer and Neurodegenerative Disease

Cited by 30 publications

References 222 publications

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Nodding syndrome: A key role for sources of nutrition?

Distribution of the gyromitrin mycotoxin in the lorchel family assessed by a pre-column-derivatization and ultra high-performance liquid chromatography method

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