Assessment of toxicity and genotoxicity of low doses of 5-fluorouracil in zebrafish (Danio rerio) two-generation study. (15th June 2015)

• Record Type: Journal Article
• Authors: Kovács, Róbert; Csenki, Zsolt; Bakos, Katalin; Urbányi, Béla; Horváth, Ákos; Garaj-Vrhovac, Vera; Gajski, Goran; Gerić, Marko; Negreira, Noelia; López de Alda, Miren; Barceló, Damià; Heath, Ester; Kosjek, Tina; Žegura, Bojana; Novak, Matjaž; Zajc, Irena; Baebler, Špela; Rotter, Ana; Ramšak, Živa; Filipič, Metka
• Is Part Of: Water research. Volume 77(2015)
• Page Start: 201
• Page End: 212
• Publication Date: 2015-06-15
• Subjects: Anticancer drugs -- 5-Fluorouracil -- Chronic exposure -- Danio rerio -- Genotoxic -- Toxicogenomic; Water -- Pollution -- Research -- Periodicals; 363.7394
• DOI: 10.1016/j.watres.2015.03.025
• Languages: English
• ISSNs: 0043-1354

Abstract

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. Graphical abstract: Highlights: Residues of anti-neoplastic drugs are emerging pollutants in aquatic environments. Missing chronic ecotoxicity data constitute a critical knowledge gap. Zebrafish two-generation chronic toxicity study of 5-FU was performed. Genotoxic effects were detected at environmental concentrations. Gene expression analysis revealed up-regulation of oncogenes.