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| Status |
Public on Jul 26, 2017 |
| Title |
Integrated metabolic models for xenobiotic induced mitochondrial toxicity in skeletal muscle (compound 197 experiments) |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
Total RNA obtained from isolated thigh skeletal muscle obtained from Han Wistar rats fed 150ppm sulfonyl isoxazoline 197 compounds for 28 days (repeat dose), n=4, compared to n-4 control rats fed standard lab chow.
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| Contributor(s) |
Herbert K, Dott W |
| Citation(s) |
28942197 |
| Submission date |
Jul 25, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Karl Eric Herbert |
| E-mail(s) |
keh3@le.ac.uk
|
| Organization name |
University of Leicester
|
| Department |
Cardiovascular Sciences
|
| Street address |
Glenfield Hospital
|
| City |
Leicester |
| ZIP/Postal code |
LE3 9QP |
| Country |
United Kingdom |
| |
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| Platforms (1) |
| GPL6101 |
Illumina ratRef-12 v1.0 expression beadchip |
|
| Samples (8)
|
| GSM2717155 |
skeletal_muscle_197_control_rep4 |
| GSM2717157 |
skeletal_muscle_150ppm SI compd 197_rep1 |
| GSM2717159 |
skeletal_muscle_150ppm SI compd 197_rep2 |
| GSM2717160 |
skeletal_muscle_150ppm SI compd 197_rep3 |
| GSM2717162 |
skeletal_muscle_150ppm SI compd 197_rep4 |
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| This SubSeries is part of SuperSeries: |
| GSE101847 |
Integrated metabolic models for xenobiotic induced mitochondrial toxicity in skeletal muscle |
|
| Relations |
| BioProject |
PRJNA395696 |
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