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Toxicological information


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Administrative data

neurotoxicity, other
in vitro
Type of information:
read-across from supporting substance (structural analogue or surrogate)
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 triggers apoptosis in neuronal cells via a reactive oxygen species-induced endoplasmic reticulum stress signaling pathway
Lu TH, Su CCb, Tang FC, Chen CH, Yen CC, Fang KM, Lee K, Hung DZ, Chen YW
Bibliographic source:
Chem. Biol. Inter. 225, 1–12

Materials and methods

Test guideline
no guideline followed
Principles of method if other than guideline:
Investigation of cytotoxic effects in neuronal cells due to MCA.
GLP compliance:
not specified

Test material

Specific details on test material used for the study:
0-2 mM MCA was tested

Test animals

other: Murine neuroblastoma cell line: Neuro-2a (CCL-131)

Results and discussion

Results of examinations

Details on results:
Treatment of Neuro-2a cells with MCA for 24 h induced a significant increase in the release of LDH in a dose-dependent manner with a range from 0.5 to 2 mM. This effect of MCA-induced cytotoxicity was confirmed by examining cell viability using the MTT assay. It was also shown that the cell viability of Neuro-2a cells after exposure to MCA for 24 h was markedly reduced and the LD50 (lethal dose, 50%) was determined to be approximately 1.5 mM.
In the present study, MCA (0.5–2.0 mM) significantly increased LDH release, decreased the number of viable cells (cytotoxicity) and induced apoptotic events (including: increases in the numbers of apoptotic cells, the membrane externalization of phosphatidylserine (PS), and caspase-3/-7 activity) in Neuro-2a cells. MCA (1.5 mM; the approximate to LD50) also triggered ER stress, which was identified by monitoring several key molecules that are involved in the unfolded protein responses (including the increase in the expressions of p-PERK, p-IRE-1, p-eIF2a, ATF-4, ATF-6, CHOP, XBP-1, GRP 78, GRP 94, and caspase-12) and calpain activity. Transfection of GRP 78- and GRP 94-specific si-RNA effectively abrogated MCA-induced cytotoxicity, caspase-3/-7 and caspase-12 activity, and GRP 78 and GRP 94 expression in Neuro-2a cells. Additionally, pretreatment with 2.5 mM N-acetylcysteine (NAC; a glutathione (GSH) precursor) dramatically suppressed the increase in lipid peroxidation, cytotoxicity, apoptotic events, calpain and caspase-12 activity, and ER stress-related molecules in MCA-exposed cells. Taken together, these results suggest that the higher concentration of MCA exerts its cytotoxic effects in
neuronal cells by triggering apoptosis via a ROS-induced ER stress signaling pathway.

Applicant's summary and conclusion

MCA increased the release of lactate dehydrogenase at 0.5 to 2 mM, was cytotoxic, induced apoptotic events and ER stress. Pre-preparation with acetylcysteine reduced the magnitude of these effects. From this it was concluded that apoptosis in the cells was induced by the induction of an ER stress signal via reactive oxygen species.