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. 2017 Oct 11;12(10):e0186250.
doi: 10.1371/journal.pone.0186250. eCollection 2017.

Susceptibility of different mouse strains to oxaliplatin peripheral neurotoxicity: Phenotypic and genotypic insights

Paola Marmiroli  1 , Beatrice Riva  2 , Eleonora Pozzi  1 , Elisa Ballarini  1 , Dmitry Lim  2 , Alessia Chiorazzi  1 , Cristina Meregalli  1 , Carla Distasi  2 , Cynthia L Renn  3 , Sara Semperboni  1 , Lavinia Morosi  4 , Federico A Ruffinatti  2 , Massimo Zucchetti  4 , Susan G Dorsey  3 , Guido Cavaletti  1 , Armando Genazzani  2 , Valentina A Carozzi  1
Affiliations

Susceptibility of different mouse strains to oxaliplatin peripheral neurotoxicity: Phenotypic and genotypic insights

Paola Marmiroli et al. PLoS One. .

Abstract

Peripheral neurotoxicity is one of the most distressing side effects of oxaliplatin therapy for cancer. Indeed, most patients that received oxaliplatin experience acute and/or chronic severe sensory peripheral neuropathy. However, despite similar co-morbidities, cancer stage, demographics and treatment schedule, patients develop oxaliplatin-induced peripheral neurotoxicity with remarkably different severity. This suggests individual genetic variability, which might be used to glean the mechanistic insights into oxaliplatin neurotoxicity. We characterized the susceptibility of different mice strains to oxaliplatin neurotoxicity investigating the phenotypic features of neuropathy and gene expression profiles in dorsal root ganglia of six genetically different mice strains (Balb-c, C57BL6, DBA/2J, AJ, FVB and CD1) exposed to the same oxaliplatin schedule. Differential gene expression in dorsal root ganglia from each mice strain were assayed using a genome-wide expression analysis and selected genes were validated by RT-PCR analysis. The demonstration of consistent differences in the phenotypic response to oxaliplatin across different strains is interesting to allow the selection of the appropriate strain based on the pre-defined read-out parameters. Further investigation of the correlation between gene expression changes and oxaliplatin-induced neurotoxicity phenotype in each strain will be useful to deeper investigate the molecular mechanisms of oxaliplatin neurotoxicity.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Cold Plate test.
The graphs report the number of events related to pain (withdrawal response) during thermal (cold) stimulation of oxaliplatin-treated animals versus naive animals at baseline, day 13 and day 26.
Fig 2
Fig 2. Morphological analysis at light microscope.
Naive DRG (A), caudal nerve (C), sciatic nerve (E) and skin (G) were compared to oxaliplatin treated ones (B, D, F, H) of Balb-c mice (explanatory of the neurotoxic damage). B: multiple (arrows) and eccentric (arrowhead) nucleoli can be observed; D and F: degenerating fibers (arrows) and myelin derangement (arrowheads) are indicated; H: arrows point at the site of unmyelinated fiber density reduction in the epidermis.
Fig 3
Fig 3. Dynamic test.
The graphs report the pressure (grams) evoking a withdrawal response during mechanical stimuli of oxaliplatin-treated animals versus naive animals at baseline, day 13 and day 26.
Fig 4
Fig 4. Correlation of the log-change of the 30 selected genes in the 4 strains as predicted by microarray analysis and RT-PCR.
See this image and copyright information in PMC

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