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Diss Factsheets

Toxicological information


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Administrative data

neurotoxicity, other
in vitro
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:
Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals
Chun-Hung Chen CH, Chen SJ, Suc CC, Yend CC, Tseng TJ, Jinng TR, Tangh FC, Chen KL, Sug YC, Lee K,
Hung DZ, Huang CF
Bibliographic source:
Toxicol. 303, 72–82

Materials and methods

Test guideline
no guideline followed
Principles of method if other than guideline:
The cytotoxicity of MCA was examined . In addition, mechanisms were examined by which MCA induced the generation of ROS and the depletion of glutathione (GSH), the disruption of mitochondrial function, the activations of caspase cascades, and the phosphorylation of JNK/ERK1/2/p38-MAPK in neuro-2a cells. Furthermore, the potential protective effects of antioxidant NAC, SP600125 (specific JNK inhibitor), and SB203580 (specific p38-MAPK inhibitor), which used at different stages to confirm the involvement of major signal pathways on CA-induced Neuro-2a cell death, were also investigated.
GLP compliance:
not specified

Test material

Specific details on test material used for the study:
0.1 - 10 mM was tested

Test animals

other: Murine neuroblastoma Neuro-2a cells


The significance of difference was evaluated by the Student’s t-test. When more than one group was compared with one control, significance was evaluated according to one-way analysis of variance (ANOVA), and the Duncans’s post hoc test was applied to identify group differences. The p value less than 0.05 was considered to be significant.

Results and discussion

Results of examinations

Details on results:
Treatment of Neuro-2a cells with MCA statistically significantly reduced the number of viable cells (starting at 0.5 mM and up to 10 mM). Levels >= 0.5 mM increased the generation of ROS, and reduced the intracellular levels of glutathione depletion. MCA also increased the number of sub-G1 hypodiploid cells; increased mitochondrial dysfunction (loss of MMP, cytochrome c release, and accompanied by Bcl-2 and Mcl-1 down-regulation and Bax up-regulation), and activated the caspase cascades activations, which displayed features of mitochondria-dependent apoptosis pathway. These MCA-induced apoptosis-related signals were markedly prevented by the antioxidant N-acetylcysteine (NAC).
Moreover, CA activated the JNK and p38-MAPK pathways, but did not that ERK1/2 pathway, in treated Neuro-2a cells. Pretreatment with NAC and specific p38-MAPK inhibitor (SB203580), but not JNK inhibitor (SP600125) effectively abrogated the phosphorylation of p38-MAPK and attenuated the apoptotic signals (including: decrease in cytotoxicity, caspase-3/-7 activation, the cytosolic cytochrome c release, and the reversed alteration of Bcl-2 and Bax mRNA) in CA-treated Neuro-2a cells. Taken together, these data suggest that oxidative stress-induced p38-MAPK activated pathway-regulated mitochondria-dependent apoptosis plays an important role in MCA-caused neuronal cell death.

Any other information on results incl. tables

The results of this study provide evidence that MCA is capable of inducing neuronal cell death at levels >= 0.5 mM; In addition, MCA triggers cell death through mitochondria dysfunction, which leads to activations of PARP and caspase cascades resulting in neuronal cells apoptosis. Furthermore, this adverse outcome can be prevented by antioxidant NAC and specific p38 inhibitor, suggesting that oxidative stress-induced p38 -MAPK activated pathway plays an important role in CA-caused neuronal cell apoptosis.

Applicant's summary and conclusion

It was concluded that oxidative stress induces the p38-MAPK-activated signaling pathway that increases the mitochondrial-dependent apoptosis in the cells. Thus oxidative stress-induced p38-MAPK activated pathway plays an important role in MCA-caused neuronal cell death.