Naslov
Assessment of toxicity and genotoxicity of low doses of 5-fluorouracil in zebrafish (Danio rerio) two-generation study

Autori
Kovacs, Robert ; Csenki, Zsolt ; Bakos, Katalin ; Urbanyi, Bela ; Horvath, Akos ; Garaj- Vrhovac, Vera ; Gajski, Goran ; Gerić, Marko ; Negreira, Noelia ; Lopez de Alda, Miren ; Barcelo, Damia ; Heath, Ester ; Kosjek, Tina ; Žegura, Bojana ; Novak, Matjaž ; Zajc, Irena ; Baebler, Špela ; Rotter, Ana ; Ramšak, Živa ; Filipič, Metka

Izvornik
Water research (0043-1354) 77 (2015); 201-212

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Anticancer drugs ; 5-Fluorouracil ; Chronic exposure ; Danio rerio ; Genotoxic ; Toxicogenomics

Sažetak
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 mg/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 mg/L and 1 mg/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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija

POVEZANOST RADA