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Lethal and Sub-Lethal Effects and Modulation of Gene Expression Induced by T Kinase Inhibitors in Zebrafish (Danio
Tina Elersek1, Matjaž Novak1, Mateja Mlinar1
1Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia.
Abstract:
Tyrosine kinase inhibitors (TKIs) are designed for targeted cancer therapy. The consumption of these drugs during the last 20 years has been constantly rising. In the zebrafish (Danio rerio) embryo toxicity test, we assessed the toxicity of six TKIs: imatinib mesylate, erlotinib, nilotinib, dasatinib, sorafenib and regorafenib. Imatinib mesylate and dasatinib induced lethal effects, while regorafenib, sorfenib and dasatinib caused a significant increase of sub-lethal effects, predominantly oedema, no blood circulation and formation of blood aggregates. The analyses of the changes in the expression of selected genes associated with the hormone system after the exposure to imatinib mesylate, dasatinib and regorafenib demonstrated that all three tested TKIs deregulated the expression of oestrogen receptor esr1, cytochrome P450 aromatase (cypa19b) and hydroxysteroid-dehydrogenase (hsd3b), regorafenib, and also thyroglobulin (tg). The expression of genes involved in the DNA damage response (gadd45 and mcm6) and apoptosis (bcl2) was deregulated only by exposure to regorafenib. The data indicate that common mechanisms, namely antiangiogenic activity and interference with steroidogenesis are involved in the TKI induced sub-lethal effects and potential hormone disrupting activity, respectively. The residues of TKIs may represent an environmental hazard; therefore, further ecotoxicological studies focusing also on the effects of their mixtures are warranted.
Insights
Tyrosine kinase inhibitors (TKIs) cause lethal and sub-lethal effects in zebrafish embryos. These cancer drugs disrupt hormone systems and DNA repair, posing potential environmental hazards.
Area of Science:
- Environmental toxicology
- Pharmacology
- Developmental biology
Background:
- Tyrosine kinase inhibitors (TKIs) are crucial targeted cancer therapies with increasing global consumption.
- Understanding the environmental impact of TKIs is vital due to their widespread use.
Purpose of the Study:
- To assess the ecotoxicity of six common TKIs using the zebrafish embryo model.
- To investigate the molecular mechanisms underlying TKI-induced toxicity, including effects on gene expression related to hormone systems and DNA damage.
Main Methods:
- Zebrafish (Danio rerio) embryo toxicity test was employed.
- Six TKIs (imatinib mesylate, erlotinib, nilotinib, dasatinib, sorafenib, regorafenib) were tested.
- Gene expression analysis was performed for hormone system and DNA damage response pathways.
Main Results:
- Imatinib mesylate and dasatinib induced lethal effects.
- Sub-lethal effects like edema and circulatory issues were observed with regorafenib, sorafenib, and dasatinib.
- TKIs deregulated genes involved in hormone systems (esr1, cypa19b, hsd3b, tg) and DNA damage response (gadd45, mcm6) and apoptosis (bcl2).
Conclusions:
- TKIs exhibit antiangiogenic activity and interfere with steroidogenesis, explaining observed sub-lethal and hormone-disrupting effects.
- TKI residues in the environment may pose a hazard, necessitating further ecotoxicological research, including mixture effects.
