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Integrated metabolic models for xenobiotic induced mitochondrial toxicity in skeletal muscle (compound 177 experiments)

ABSTRACT: There is a need for robust in vitro models to sensitively capture skeletal muscle adverse toxicities early in the research and development of novel xenobiotics. To this end, an in vitro rat skeletal muscle model (L6) was used to study the translation of transcriptomics data generated from an in vivo rat model. Novel sulfonyl isoxazoline herbicides were associated with skeletal muscle toxicity in an in vivo rat model. Gene expression pathway analysis on skeletal muscle tissues taken from in vivo repeat dose studies identified enriched pathways associated with mitochondrial dysfunction, oxidative stress, energy metabolism, protein regulation and cell cycle. Mitochondrial dysfunction and oxidative stress were further explored in an in vitro L6 model. This model demonstrated that the sulfonyl isoxazoline compounds induced mitochondrial dysfunction, mitochondrial superoxide production and apoptosis. These in vitro findings accurately concurred with the in vivo transcriptomics data, thereby confirming the ability of the L6 skeletal muscle model to identify relevant in vivo mechanisms of xenobiotic-induced toxicity. Moreover, these results highlight the sensitivity of the L6 galactose media model to study mitochondrial perturbation associated with skeletal muscle toxicity; this model may be utilised to rank the potency of novel xenobiotics upon further validation.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE101844 | GEO | 2017/07/26

SECONDARY ACCESSION(S): PRJNA395695

REPOSITORIES: GEO

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Integrated metabolic models for xenobiotic induced mitochondrial toxicity in skeletal muscle (compound 177 experiments)

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