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Water Res. 2015 Jun 15;77:201-212. doi: 10.1016/j.watres.2015.03.025. Epub 2015 Apr 3.

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

Author information

1
Department of Aquaculture, Institute of Aquaculture and Environmental Safety, Faculty of Agricultural and Environmental Sciences, Szent István University, 1. Pater Károly St., H-2100 Gödöllo, Hungary.
2
Mutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000 Zagreb, Croatia.
3
Water and Soil Quality Research Group, Department of Environmental Chemistry, Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona 18-26, E-08034 Barcelona, Spain.
4
Water and Soil Quality Research Group, Department of Environmental Chemistry, Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona 18-26, E-08034 Barcelona, Spain; Catalan Institute for Water Research (ICRA), H(2)O Building, Scientific and Technological Park of the University of Girona, Emili Grahit 101, 17003 Girona, Spain.
5
Institute Jožef Stefan, Jadranska 29, 1000 Ljubljana, Slovenia.
6
National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia.
7
National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia; Ecological Engineering Institute, Ljubljanska 9, 2000 Maribor, Slovenia; Jozef Stefan International Postgraduate School, Jamova cesta 39, 1000 Ljubljana, Slovenia.
8
National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia. Electronic address: metka.filipic@nib.si.

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.

KEYWORDS:

5-Fluorouracil; Anticancer drugs; Chronic exposure; Danio rerio; Genotoxic; Toxicogenomic

PMID:
25889180
DOI:
10.1016/j.watres.2015.03.025
[Indexed for MEDLINE]

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