PUBLICATION
Assessment of toxicity and genotoxicity of low doses of 5-fluorouracil in zebrafish (Danio rerio) two-generation study
- Authors
- Kovács, R., Csenki, Z., Bakos, K., Urbányi, B., Horváth, Á., Garaj-Vrhovac, V., Gajski, G., Gerić, M., Negreira, N., López de Alda, M., Barceló, D., Heath, E., Kosjek, T., Žegura, B., Novak, M., Zajc, I., Baebler, Š., Rotter, A., Ramšak, Ž., Filipič, M.
- ID
- ZDB-PUB-150419-2
- Date
- 2015
- Source
- Water research 77: 201-212 (Journal)
- Registered Authors
- Keywords
- 5-Fluorouracil, Anticancer drugs, Chronic exposure, Danio rerio, Genotoxic, Toxicogenomic
- Datasets
- GEO:GSE63039
- MeSH Terms
-
- Animals
- Antimetabolites, Antineoplastic/toxicity*
- Blood Cells/drug effects
- Comet Assay
- DNA Damage/drug effects
- Fluorouracil/toxicity*
- Gene Expression Profiling
- Gills/drug effects
- Gonads/drug effects
- Kidney/drug effects
- Kidney/pathology
- Liver/drug effects
- Liver/pathology
- Reproduction/drug effects
- Toxicity Tests, Chronic
- Water Pollutants, Chemical/toxicity*
- Zebrafish/genetics
- Zebrafish/growth & development*
- PubMed
- 25889180 Full text @ Water Res.
Citation
Kovács, R., Csenki, Z., Bakos, K., Urbányi, B., Horváth, Á., Garaj-Vrhovac, V., Gajski, G., Gerić, M., Negreira, N., López de Alda, M., Barceló, D., Heath, E., Kosjek, T., Žegura, B., Novak, M., Zajc, I., Baebler, Š., Rotter, A., Ramšak, Ž., Filipič, M. (2015) Assessment of toxicity and genotoxicity of low doses of 5-fluorouracil in zebrafish (Danio rerio) two-generation study. Water research. 77:201-212.
Abstract
Residues of anti-neoplastic drugs represent new and emerging pollutants in aquatic environments. Many of these drugs are genotoxic, and it has been postulated that they can cause adverse effects in aquatic ecosystems. 5-Fluorouracil (5-FU) is one of the most extensively used anti-neoplastic drugs in cancer therapy, and this article describes the results of the first investigation using a two-generation toxicity study design with zebrafish (Danio rerio). Exposure of zebrafish to 5-FU (0.01, 1.0 and 100 μg/L) was initiated with adult zebrafish (F0 generation) and continued through the hatchings and adults of the F1 generation, and the hatchings of the F2 generation, to day 33 post-fertilisation. The exposure did not affect survival, growth and reproduction of the zebrafish; however, histopathological changes were observed in the liver and kidney, along with genotoxic effects, at all 5-FU concentrations. Increases in DNA damage determined using the comet assay were significant in the liver and blood cells, but not in the gills and gonads. In erythrocytes, a significant, dose-dependent increase in frequency of micronuclei was observed at all 5-FU concentrations. Whole genome transcriptomic analysis of liver samples of F1 generation zebrafish exposed to 0.01 μg/L and 1 μg/L 5-FU revealed dose-dependent increases in the number of differentially expressed genes, including up-regulation of several DNA-damage-responsive genes and oncogenes (i.e., jun, myca). Although this chronic exposure to environmentally relevant concentrations of 5-FU did not affect the reproduction of the exposed zebrafish, it cannot be excluded that 5-FU can lead to degenerative changes, including cancers, which over long-term exposure of several generations might affect fish populations. The data from this study contribute to a better understanding of the potential consequences of chronic exposure of fish to low concentrations of anti-neoplastic drugs, and they demonstrate that further studies into multi-generation toxicity are needed.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping