Tremorgenic effects and functional metabolomics analysis of lolitrem B and its biosynthetic intermediates

Priyanka Reddy, Simone Rochfort, Elizabeth Read, Myrna Deseo, Emily Jaehne, Maarten Van Den Buuse, Kathryn Guthridge, Martin Combs, German Spangenberg, Jane Quinn

Research output: Contribution to journalArticle

Abstract

The neuroactive mycotoxin lolitrem B causes a neurological syndrome in grazing livestock resulting in hyperexcitability, muscle tremors, ataxia and, in severe cases, clonic seizures and death. To define the effects of the major toxin, lolitrem B in the brain, a functional metabolomic study was undertaken in which motor coordination and tremor were quantified and metabolomic profiling undertaken to determine relative abundance of both toxin and key neurotransmitters in various brain regions in male mice. Marked differences were observed in the duration of tremor and coordination between lolitrem B pathway members, with some showing protracted effects and others none at all. Lolitrem B was identified in liver, kidney, cerebral cortex and thalamus but not in brainstem or cerebellum which were hypothesised previously to be the primary site of action. Metabolomic profiling showed significant variation in specific neurotransmitter and amino acid profiles over time. This study demonstrates accumulation of lolitrem B in the brain, with non-detectable levels of toxin in the brainstem and cerebellum, inducing alterations in metabolites such as tyrosine, suggesting a dynamic catecholaminergic response over time. Temporal characterisation of key pathways in the pathophysiological response of lolitrem B in the brain was also identified.
Original languageEnglish
Article number9364
Pages (from-to)1-17
Number of pages17
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 27 Jun 2019

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Metabolomics
Tremor
Brain
Cerebellum
Brain Stem
Neurotransmitter Agents
Kidney Cortex
Mycotoxins
Livestock
Ataxia
Thalamus
Cerebral Cortex
Tyrosine
lolitrem B
Seizures
Amino Acids
Liver

Cite this

Reddy, Priyanka ; Rochfort, Simone ; Read, Elizabeth ; Deseo, Myrna ; Jaehne, Emily ; Van Den Buuse, Maarten ; Guthridge, Kathryn ; Combs, Martin ; Spangenberg, German ; Quinn, Jane. / Tremorgenic effects and functional metabolomics analysis of lolitrem B and its biosynthetic intermediates. In: Scientific Reports. 2019 ; Vol. 9, No. 1. pp. 1-17.
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abstract = "The neuroactive mycotoxin lolitrem B causes a neurological syndrome in grazing livestock resulting in hyperexcitability, muscle tremors, ataxia and, in severe cases, clonic seizures and death. To define the effects of the major toxin, lolitrem B in the brain, a functional metabolomic study was undertaken in which motor coordination and tremor were quantified and metabolomic profiling undertaken to determine relative abundance of both toxin and key neurotransmitters in various brain regions in male mice. Marked differences were observed in the duration of tremor and coordination between lolitrem B pathway members, with some showing protracted effects and others none at all. Lolitrem B was identified in liver, kidney, cerebral cortex and thalamus but not in brainstem or cerebellum which were hypothesised previously to be the primary site of action. Metabolomic profiling showed significant variation in specific neurotransmitter and amino acid profiles over time. This study demonstrates accumulation of lolitrem B in the brain, with non-detectable levels of toxin in the brainstem and cerebellum, inducing alterations in metabolites such as tyrosine, suggesting a dynamic catecholaminergic response over time. Temporal characterisation of key pathways in the pathophysiological response of lolitrem B in the brain was also identified.",
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Reddy, P, Rochfort, S, Read, E, Deseo, M, Jaehne, E, Van Den Buuse, M, Guthridge, K, Combs, M, Spangenberg, G & Quinn, J 2019, 'Tremorgenic effects and functional metabolomics analysis of lolitrem B and its biosynthetic intermediates', Scientific Reports, vol. 9, no. 1, 9364, pp. 1-17. https://doi.org/10.1038/s41598-019-45170-7

Tremorgenic effects and functional metabolomics analysis of lolitrem B and its biosynthetic intermediates. / Reddy, Priyanka; Rochfort, Simone; Read, Elizabeth; Deseo, Myrna; Jaehne, Emily; Van Den Buuse, Maarten; Guthridge, Kathryn ; Combs, Martin; Spangenberg, German; Quinn, Jane.

In: Scientific Reports, Vol. 9, No. 1, 9364, 27.06.2019, p. 1-17.

Research output: Contribution to journalArticle

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T1 - Tremorgenic effects and functional metabolomics analysis of lolitrem B and its biosynthetic intermediates

AU - Reddy, Priyanka

AU - Rochfort, Simone

AU - Read, Elizabeth

AU - Deseo, Myrna

AU - Jaehne, Emily

AU - Van Den Buuse, Maarten

AU - Guthridge, Kathryn

AU - Combs, Martin

AU - Spangenberg, German

AU - Quinn, Jane

PY - 2019/6/27

Y1 - 2019/6/27

N2 - The neuroactive mycotoxin lolitrem B causes a neurological syndrome in grazing livestock resulting in hyperexcitability, muscle tremors, ataxia and, in severe cases, clonic seizures and death. To define the effects of the major toxin, lolitrem B in the brain, a functional metabolomic study was undertaken in which motor coordination and tremor were quantified and metabolomic profiling undertaken to determine relative abundance of both toxin and key neurotransmitters in various brain regions in male mice. Marked differences were observed in the duration of tremor and coordination between lolitrem B pathway members, with some showing protracted effects and others none at all. Lolitrem B was identified in liver, kidney, cerebral cortex and thalamus but not in brainstem or cerebellum which were hypothesised previously to be the primary site of action. Metabolomic profiling showed significant variation in specific neurotransmitter and amino acid profiles over time. This study demonstrates accumulation of lolitrem B in the brain, with non-detectable levels of toxin in the brainstem and cerebellum, inducing alterations in metabolites such as tyrosine, suggesting a dynamic catecholaminergic response over time. Temporal characterisation of key pathways in the pathophysiological response of lolitrem B in the brain was also identified.

AB - The neuroactive mycotoxin lolitrem B causes a neurological syndrome in grazing livestock resulting in hyperexcitability, muscle tremors, ataxia and, in severe cases, clonic seizures and death. To define the effects of the major toxin, lolitrem B in the brain, a functional metabolomic study was undertaken in which motor coordination and tremor were quantified and metabolomic profiling undertaken to determine relative abundance of both toxin and key neurotransmitters in various brain regions in male mice. Marked differences were observed in the duration of tremor and coordination between lolitrem B pathway members, with some showing protracted effects and others none at all. Lolitrem B was identified in liver, kidney, cerebral cortex and thalamus but not in brainstem or cerebellum which were hypothesised previously to be the primary site of action. Metabolomic profiling showed significant variation in specific neurotransmitter and amino acid profiles over time. This study demonstrates accumulation of lolitrem B in the brain, with non-detectable levels of toxin in the brainstem and cerebellum, inducing alterations in metabolites such as tyrosine, suggesting a dynamic catecholaminergic response over time. Temporal characterisation of key pathways in the pathophysiological response of lolitrem B in the brain was also identified.

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KW - neurotoxin

KW - metabolomic profiling

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DO - 10.1038/s41598-019-45170-7

M3 - Article

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