Neurotoxicity refers to the direct or indirect effect of chemicals that disrupt the nervous syste... more Neurotoxicity refers to the direct or indirect effect of chemicals that disrupt the nervous system of humans or animals. Numerous chemicals can produce neurotoxic diseases in humans, and many more are used as experimental tools to disturb or damage the nervous system of animals. Some act directly on neural cells, others interfere with metabolic processes on which the nervous system is especially dependent. Some disrupt neural function, others induce maldevelopment or damage to the adult nervous system. Perturbations may appear and disappear rapidly, evolve slowly over days or weeks and regress over months or years, or cause permanent deficits. Neurotoxicity is usually self-limiting after exposure ceases and rarely progressive in the absence of continued exposure, although there may be a significant delay between exposure and manifestation of neurotoxic effects
The peripheral (axonal) neuropathy associated with repeated exposure to aliphatic and aromatic so... more The peripheral (axonal) neuropathy associated with repeated exposure to aliphatic and aromatic solvents that form protein-reactive γ-diketones shares some clinical and neuropathological features with certain metabolic neuropathies, including type-II diabetic neuropathy and uremic neuropathy, and with the largely sub-clinical nerve damage associated with old age. These conditions may be linked by metabolites that adduct and cross-link neuroproteins required for the maintenance of axonal transport and nerve fiber integrity in the peripheral and central nervous system.
Unknown environmental factors are thought to contribute to the etiology of sporadic forms of amyo... more Unknown environmental factors are thought to contribute to the etiology of sporadic forms of amyotrophic lateral sclerosis (ALS). Strong evidence supporting this view is found in the post-World War decline and disappearance of highincidence ALS in three Western Pacific populations that formerly utilized neurotoxic cycad seed as a traditional source of food and/or medicine. The principal toxins in cycads (cycasin) and in False Morel mushrooms (gyromitrin) generate methyl free radicals that damage DNA and cause mutation and uncontrolled division of cycling cells and degeneration of late-/postmitotic neurons. Since False Morels are scavenged for food in Finland, Russia, Spain, and USA, research studies are underway in Western Europe and USA to determine if the practice is associated with sporadic ALS.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has proved refracto... more Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has proved refractory to drug treatment. Given evidence of neuroprotection in animal models of ischemic stroke, we assessed the prenylflavonoid xanthohumol from the Common Hop ( L.) for therapeutic potential in murine neuroblastoma N2a cells stably expressing human Swedish mutant amyloid precursor protein (N2a/APP), a well-characterized cellular model of AD. The ELISA and Western-blot analysis revealed that xanthohumol (Xn) inhibited Aβ accumulation and APP processing, and that Xn ameliorated tau hyperphosphorylation via PP2A, GSK3β pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by Xn was also validated on HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis (2D-DIGE-coupled MS) revealed a total of 30 differentially expressed lysate proteins in N2a/APP vs. wild-type (WT) N2a cells (N2a/WT), and a total of 21 differentially expressed proteins in lysa...
Nodding syndrome (NS) is a debated scientific topic. A recently published study suggests that NS ... more Nodding syndrome (NS) is a debated scientific topic. A recently published study suggests that NS is an autoimmune disorder based on findings of cross-reacting antibodies between neuronal structures and a protein present in Onchocerca volvulus (OV). In our opinion, the proposed causal relationship between OV infection and NS has yet to be demonstrated and, instead, OV infection in NS may be opportunistic.
International Conference on Chemical, Agricultural and Medical Sciences (CAMS-2013) Dec. 29-30, 2013 Kuala Lumpur (Malaysia), 2013
ABSTRACT Contamination of food with fungal toxins is a plausible etiologic factor in Nodding Synd... more ABSTRACT Contamination of food with fungal toxins is a plausible etiologic factor in Nodding Syndrome, a form of epilepsy affecting thousands of children in east Africa. Children developed eating-and cold-induced atonic seizures (with head nodding) and generalized seizures during periods of community displacement when food sources were unreliable and food quality was compromised. Seed of Sorghum bicolor, an important food source during displacement, was collected in a region with Nodding Syndrome. Seed extracts were subjected to a multi-mycotoxin LS-MS/MS assay for 87 analytes. Among other mycotoxins, beauvericin (BEA) was identified and confirmed by comparison with a standard using both multiple reaction monitoring (MRM) and enhanced product ion scans. Principal component analysis of all positive-mode MRM transitions revealed clustering of BEA-positive samples (328-744 µg/kg) in "old" sorghum seed samples. BEA is an apolar lipophilic cyclohexadepsipeptide that forms ionophores in membranes, disturbs intracellular calcium ion homeostasis, disrupts cellular metabolism and induces apoptosis.
The causes and the mechanisms of neuronal death in Alzheimer's disease are not el... more The causes and the mechanisms of neuronal death in Alzheimer's disease are not elucidated, although some new insights have been proposed over the past years, including free-radical toxicity, beta-amyloid toxicity, excitotoxicity, and disturbed cellular calcium metabolism. Some authors have also pointed out that apoptosis could play a role in neuronal degeneration, but it is still largely debated. Here, we review some recent data linking the induction of experimental neuronal apoptosis in vitro and the molecular pathology of the tau protein and amyloid precursor protein (APP). In cultures exposed to mild glutamate toxicity, tau mRNA expression, not beta-actin, is enhanced in stressed neurons. The Guam cycad toxin metabolite methylazoxymethanol also produces an increase of tau gene transcription that exacerbates changes induced by glutamate. In serum-deprived cultures or glutamate-exposed cultures, neurons committed to apoptosis have a reduced tau gene expression, whereas resistant neurons display a stable or even augmented tau mRNA expression accompanied by a persistent tau phosphorylation near serine 202. In the same conditions, stressed neurons produce membrane blebbings strongly immunopositive for APP and putative amyloidogenic fragments that are subsequently released in the extracellular space. Experimental apoptosis in neurons can recapitulate tau and APP modifications that could be associated with a selective vulnerability and a progression of cellular degeneration along the neuronal network.
The western Pacific parkinsonism-dementia and amyotrophic lateral sclerosis complex is a prototyp... more The western Pacific parkinsonism-dementia and amyotrophic lateral sclerosis complex is a prototypical neurodegenerative disorder found among inhabitants of Guam, New Guinea (Irian Jaya, Indonesia) and Japan (Kii Peninsula, Honshu). Nonviral environmental factors peculiar to the affected populations seem to play a prominent etiologic role. Although cause-effect relationships cannot be established by epidemiologic studies alone, we have shown in all three affected population groups that individuals develop the amyotrophic lateral sclerosis variant of this disorder after heavy exposure to the raw or incompletely detoxified seed of neurotoxic cycad plants. Since long periods may elapse between cycad exposure and the appearance of neurological disease in humans, cycads may harbor a "slow toxin" that causes the postmitotic neuron to undergo slow irreversible degeneration. Two cycad neurotoxins are recognized, one of which (cycasin) is known to have long-latency effects (tumorige...
This case-control study adds to the growing body of knowledge on the medical, nutritional, and en... more This case-control study adds to the growing body of knowledge on the medical, nutritional, and environmental factors associated with Nodding Syndrome (NS), a seizure disorder of children and adolescents in northern Uganda. Past research described a significant association between NS and prior history of measles infection, dependence on emergency food and, at head nodding onset, subsistence on moldy maize, which has the potential to harbor mycotoxins. We used LC-MS/MS to screen for current mycotoxin loads by evaluating nine analytes in urine samples from age-and-gender matched NS cases (n = 50) and Community Controls (CC, n = 50). The presence of the three mycotoxins identified in the screening was not significantly different between the two groups, so samples were combined to generate an overall view of exposure in this community during the study. Compared against subsequently run standards, α-zearalenol (43 ± 103 µg/L in 15 samples > limit of quantitation (LOQ); 0 (0/359) µg/L),...
Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) is a di... more 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 schizophren...
Plants and mushrooms bioconcentrate metals/metalloids from soil and water such that high levels o... more Plants and mushrooms bioconcentrate metals/metalloids from soil and water such that high levels of potentially neurotoxic elements can occur in cultivated and wild species used for food. While the health effects of excessive exposure to metals/metalloids with neurotoxic potential are well established, overt neurological disease from prolonged ingestion of contaminated botanicals has not been recognized. However, the presence of metal elements may affect levels of botanical neurotoxins in certain plants and mushrooms that are established causes of acute and chronic neurological disease.
Neurotoxicity refers to the direct or indirect effect of chemicals that disrupt the nervous syste... more Neurotoxicity refers to the direct or indirect effect of chemicals that disrupt the nervous system of humans or animals. Numerous chemicals can produce neurotoxic diseases in humans, and many more are used as experimental tools to disturb or damage the nervous system of animals. Some act directly on neural cells, others interfere with metabolic processes on which the nervous system is especially dependent. Some disrupt neural function, others induce maldevelopment or damage to the adult nervous system. Perturbations may appear and disappear rapidly, evolve slowly over days or weeks and regress over months or years, or cause permanent deficits. Neurotoxicity is usually self-limiting after exposure ceases and rarely progressive in the absence of continued exposure, although there may be a significant delay between exposure and manifestation of neurotoxic effects
The peripheral (axonal) neuropathy associated with repeated exposure to aliphatic and aromatic so... more The peripheral (axonal) neuropathy associated with repeated exposure to aliphatic and aromatic solvents that form protein-reactive γ-diketones shares some clinical and neuropathological features with certain metabolic neuropathies, including type-II diabetic neuropathy and uremic neuropathy, and with the largely sub-clinical nerve damage associated with old age. These conditions may be linked by metabolites that adduct and cross-link neuroproteins required for the maintenance of axonal transport and nerve fiber integrity in the peripheral and central nervous system.
Unknown environmental factors are thought to contribute to the etiology of sporadic forms of amyo... more Unknown environmental factors are thought to contribute to the etiology of sporadic forms of amyotrophic lateral sclerosis (ALS). Strong evidence supporting this view is found in the post-World War decline and disappearance of highincidence ALS in three Western Pacific populations that formerly utilized neurotoxic cycad seed as a traditional source of food and/or medicine. The principal toxins in cycads (cycasin) and in False Morel mushrooms (gyromitrin) generate methyl free radicals that damage DNA and cause mutation and uncontrolled division of cycling cells and degeneration of late-/postmitotic neurons. Since False Morels are scavenged for food in Finland, Russia, Spain, and USA, research studies are underway in Western Europe and USA to determine if the practice is associated with sporadic ALS.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has proved refracto... more Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has proved refractory to drug treatment. Given evidence of neuroprotection in animal models of ischemic stroke, we assessed the prenylflavonoid xanthohumol from the Common Hop ( L.) for therapeutic potential in murine neuroblastoma N2a cells stably expressing human Swedish mutant amyloid precursor protein (N2a/APP), a well-characterized cellular model of AD. The ELISA and Western-blot analysis revealed that xanthohumol (Xn) inhibited Aβ accumulation and APP processing, and that Xn ameliorated tau hyperphosphorylation via PP2A, GSK3β pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by Xn was also validated on HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis (2D-DIGE-coupled MS) revealed a total of 30 differentially expressed lysate proteins in N2a/APP vs. wild-type (WT) N2a cells (N2a/WT), and a total of 21 differentially expressed proteins in lysa...
Nodding syndrome (NS) is a debated scientific topic. A recently published study suggests that NS ... more Nodding syndrome (NS) is a debated scientific topic. A recently published study suggests that NS is an autoimmune disorder based on findings of cross-reacting antibodies between neuronal structures and a protein present in Onchocerca volvulus (OV). In our opinion, the proposed causal relationship between OV infection and NS has yet to be demonstrated and, instead, OV infection in NS may be opportunistic.
International Conference on Chemical, Agricultural and Medical Sciences (CAMS-2013) Dec. 29-30, 2013 Kuala Lumpur (Malaysia), 2013
ABSTRACT Contamination of food with fungal toxins is a plausible etiologic factor in Nodding Synd... more ABSTRACT Contamination of food with fungal toxins is a plausible etiologic factor in Nodding Syndrome, a form of epilepsy affecting thousands of children in east Africa. Children developed eating-and cold-induced atonic seizures (with head nodding) and generalized seizures during periods of community displacement when food sources were unreliable and food quality was compromised. Seed of Sorghum bicolor, an important food source during displacement, was collected in a region with Nodding Syndrome. Seed extracts were subjected to a multi-mycotoxin LS-MS/MS assay for 87 analytes. Among other mycotoxins, beauvericin (BEA) was identified and confirmed by comparison with a standard using both multiple reaction monitoring (MRM) and enhanced product ion scans. Principal component analysis of all positive-mode MRM transitions revealed clustering of BEA-positive samples (328-744 µg/kg) in "old" sorghum seed samples. BEA is an apolar lipophilic cyclohexadepsipeptide that forms ionophores in membranes, disturbs intracellular calcium ion homeostasis, disrupts cellular metabolism and induces apoptosis.
The causes and the mechanisms of neuronal death in Alzheimer's disease are not el... more The causes and the mechanisms of neuronal death in Alzheimer's disease are not elucidated, although some new insights have been proposed over the past years, including free-radical toxicity, beta-amyloid toxicity, excitotoxicity, and disturbed cellular calcium metabolism. Some authors have also pointed out that apoptosis could play a role in neuronal degeneration, but it is still largely debated. Here, we review some recent data linking the induction of experimental neuronal apoptosis in vitro and the molecular pathology of the tau protein and amyloid precursor protein (APP). In cultures exposed to mild glutamate toxicity, tau mRNA expression, not beta-actin, is enhanced in stressed neurons. The Guam cycad toxin metabolite methylazoxymethanol also produces an increase of tau gene transcription that exacerbates changes induced by glutamate. In serum-deprived cultures or glutamate-exposed cultures, neurons committed to apoptosis have a reduced tau gene expression, whereas resistant neurons display a stable or even augmented tau mRNA expression accompanied by a persistent tau phosphorylation near serine 202. In the same conditions, stressed neurons produce membrane blebbings strongly immunopositive for APP and putative amyloidogenic fragments that are subsequently released in the extracellular space. Experimental apoptosis in neurons can recapitulate tau and APP modifications that could be associated with a selective vulnerability and a progression of cellular degeneration along the neuronal network.
The western Pacific parkinsonism-dementia and amyotrophic lateral sclerosis complex is a prototyp... more The western Pacific parkinsonism-dementia and amyotrophic lateral sclerosis complex is a prototypical neurodegenerative disorder found among inhabitants of Guam, New Guinea (Irian Jaya, Indonesia) and Japan (Kii Peninsula, Honshu). Nonviral environmental factors peculiar to the affected populations seem to play a prominent etiologic role. Although cause-effect relationships cannot be established by epidemiologic studies alone, we have shown in all three affected population groups that individuals develop the amyotrophic lateral sclerosis variant of this disorder after heavy exposure to the raw or incompletely detoxified seed of neurotoxic cycad plants. Since long periods may elapse between cycad exposure and the appearance of neurological disease in humans, cycads may harbor a "slow toxin" that causes the postmitotic neuron to undergo slow irreversible degeneration. Two cycad neurotoxins are recognized, one of which (cycasin) is known to have long-latency effects (tumorige...
This case-control study adds to the growing body of knowledge on the medical, nutritional, and en... more This case-control study adds to the growing body of knowledge on the medical, nutritional, and environmental factors associated with Nodding Syndrome (NS), a seizure disorder of children and adolescents in northern Uganda. Past research described a significant association between NS and prior history of measles infection, dependence on emergency food and, at head nodding onset, subsistence on moldy maize, which has the potential to harbor mycotoxins. We used LC-MS/MS to screen for current mycotoxin loads by evaluating nine analytes in urine samples from age-and-gender matched NS cases (n = 50) and Community Controls (CC, n = 50). The presence of the three mycotoxins identified in the screening was not significantly different between the two groups, so samples were combined to generate an overall view of exposure in this community during the study. Compared against subsequently run standards, α-zearalenol (43 ± 103 µg/L in 15 samples > limit of quantitation (LOQ); 0 (0/359) µg/L),...
Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) is a di... more 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 schizophren...
Plants and mushrooms bioconcentrate metals/metalloids from soil and water such that high levels o... more Plants and mushrooms bioconcentrate metals/metalloids from soil and water such that high levels of potentially neurotoxic elements can occur in cultivated and wild species used for food. While the health effects of excessive exposure to metals/metalloids with neurotoxic potential are well established, overt neurological disease from prolonged ingestion of contaminated botanicals has not been recognized. However, the presence of metal elements may affect levels of botanical neurotoxins in certain plants and mushrooms that are established causes of acute and chronic neurological disease.
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