Deregulation of whole-transcriptome gene expression in zebrafish (Danio rerio) after chronic exposure to low doses of imatinib mesylate in a complete life cycle study

Lethal and Sub-Lethal Effects and Modulation of Gene Expression Induced by T Kinase Inhibitors in Zebrafish (Danio Rerio) Embryos

“…However, no data is available for environmental occurrence of other TKIs. Published ecotoxicological studies showed high toxicity of IMAT to daphnids upon chronic exposure, while algae, higher plants and fish were less sensitive [4,6,[20][21][22]. The studies on daphnids [6] and higher plants [20] showed that IMAT has genotoxic potential, which was also confirmed in the in vitro studies with fish and human cell lines [23][24][25].…”

“…IMAT has been shown to exhibit endocrine disrupting activity (estrogenic activity) in vitro [26]. In a recent study of toxicity from chronic exposure across the generation using zebrafish, we demonstrated that IMAT deregulates the expression of a number of genes associated with steroidogenesis and hormone metabolism and function, as well as certain genes involved in the DNA damage response in adult fish [22]. In addition, IMAT has been shown to cause DNA damage in non-target environmental organisms in plants [20,41] and daphnids [6], and mammalian and fish cells in vitro [23,24], but not in vivo in adult zebrafish [22].…”

“…In a recent study of toxicity from chronic exposure across the generation using zebrafish, we demonstrated that IMAT deregulates the expression of a number of genes associated with steroidogenesis and hormone metabolism and function, as well as certain genes involved in the DNA damage response in adult fish [22]. In addition, IMAT has been shown to cause DNA damage in non-target environmental organisms in plants [20,41] and daphnids [6], and mammalian and fish cells in vitro [23,24], but not in vivo in adult zebrafish [22]. To gain insight into the potential endocrine disrupting activity and genotoxicity of TKIs, we investigated the influence of REGO, DASA and IMAT on the expression of selected genes related to the hypothalamic-pituitary-thyroid (HPT) axis, steroidogenesis, oestrogen signaling and DNA damage response pathways during early embryonic development.…”

“…The oestrogen receptor (esr1) plays a fundamental role in ovarian maintenance [42] and its deregulation may have consequences for the reproduction. In the zebrafish whole-generation study, IMAT downregulated esr2 in females [22]. Cytochrome P450 aromatase (cyp19) is responsible for the conversion of androgens to estrogens, which play a critical role in developmental sex differentiation in vertebrates [43].…”

“…Moreover, IMAT has estrogenic activity in the E-screen assay system using MDA-MB-231 cells [26]. In a recent study, Novak et al [22] demonstrated that lifelong chronic exposure of zebrafish to IMAT deregulated the expression of genes associated with steroidogenesis and hormone metabolism and function, suggesting hormone-disrupting activity. Ecotoxicological data are scarce for other TKIs currently in use.…”