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Published on: June 5, 2020
Effects of microcystins-LR on genotoxic responses in human intestinal epithelial cells (NCM460)
Cong Wen1, Shuilin Zheng1, Yue Yang1
1Department of Occupational and Environmental, Xiangya School of Public Health, Central South University, Changsha, China.
Abstract:
Microcystin-LR (MC-LR), a cyclic heptapeptide toxin produced by cyanobacteria, was found to induce genotoxic actions in various types of cells. Some investigators reported that microcystin-LR acted as tumor initiator in the observed genotoxic action mediated by this cyanotoxin. However, the underlying mechanisms underlying MC-induced DNA damage in the human intestine epithelium cell line (NCM460) are not known. The purpose of this study was to examine the influence of 24 hr exposure to 5 or 10 µM MC-LR on intestinal DNA damage using NCM460 intestine cell line as a model. Data showed that MC-LR increased Olive tail moment (OTM) as evidenced by the comet assay, inhibited protein phosphatase 2A (PP2A) activity, elevated reactive oxygen species levels (ROS) and enhanced γ-H2AX and p-p53 protein expression levels. Results indicated that MC-LR produced intestinal DNA damage by inhibiting PP2A activity, activating p53 protein and subsequently initiating excess generation of ROS. These observations suggest that MC-LR-induced intestinal DNA damage involves a complex series of events that include oxidant stress, PP2A enzymic inhibition and activation of p53 protein.
Insights
Microcystin-LR (MC-LR) causes intestinal DNA damage by inhibiting protein phosphatase 2A (PP2A) and increasing reactive oxygen species (ROS). This cyanotoxin exposure activates p53, leading to DNA damage in human intestinal cells.
Area of Science:
- Environmental toxicology
- Cellular mechanisms of toxicity
- Genotoxicity studies
Background:
- Cyanobacteria produce microcystin-LR (MC-LR), a toxin linked to genotoxic effects.
- MC-LR's role as a tumor initiator is suggested, but its DNA damage mechanisms in intestinal cells are unclear.
Purpose of the Study:
- To investigate the impact of MC-LR on intestinal DNA damage.
- To elucidate the molecular pathways of MC-LR-induced genotoxicity in NCM460 cells.
Main Methods:
- Exposure of NCM460 human intestinal cells to 5 or 10 µM MC-LR for 24 hours.
- Comet assay to measure DNA damage (Olive tail moment).
- Assays for protein phosphatase 2A (PP2A) activity, reactive oxygen species (ROS) levels, and expression of γ-H2AX and p-p53 proteins.
Main Results:
- MC-LR exposure significantly increased DNA damage (Olive tail moment).
- MC-LR inhibited PP2A activity, elevated ROS levels, and increased γ-H2AX and p-p53 expression.
- Evidence suggests MC-LR induces DNA damage via PP2A inhibition, p53 activation, and subsequent ROS generation.
Conclusions:
- MC-LR induces intestinal DNA damage through a mechanism involving oxidant stress, PP2A inhibition, and p53 activation.
- These findings highlight a complex pathway for MC-LR genotoxicity in the human intestine.
