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A DNA-demethylating agent (the decitabine) used for cancer treatment is able to modulate sex in the zebrafish model

AuthorsRibas, Laia ; Piferrer, Francesc
Issue Date16-Mar-2018
PublisherSocietat Catalana de Biologia
CitationVIII Jornada de Cromatina i Epigenètica (2018)
AbstractThe role of epigenetic modifications such as DNA methylation during vertebrate sexual development is far from being clear. Using the zebrafish model, we tested the effects of one of the most common DNA methyltransferase (dnmt) inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC), which is approved for the treatment of acute myeloid leukaemia and is under active investigation for the treatment of solid tumours. Several dose-response experiments were carried out during two periods, including not only the very first days of development (0-6 days post fertilization, dpf), as done in previous studies, but also, and as a novelty, the period of gonadal development (10-30 dpf) in zebrafish. Early treatment with 5-azadC altered embryonic development, delayed hatching and increased teratology and mortality, as expected. The most striking result, however, was an increase in the number of females, suggesting that alterations induced by 5-aza-dC treatment can affect sexual development as well. Results were confirmed when treatment coincided with gonadal development. In addition, we also found that the adult gonadal transcriptome of 5-aza-dCexposed females included significant changes in the expression of key reproductionrelated genes (e.g., cyp11a1, esr2b and figla), and that several pro-female related pathways such as the Fanconi anemia or the Wnt signalling pathways were downregulated. Furthermore, an overall inhibition of genes implicated in epigenetic regulatory mechanisms (e.g., dnmt1, dicer, cbx4) was also observed. Taken together, our results indicate that treatment with a DNA methylation inhibitor can also alter the sexual development in zebrafish, with permanent alterations of the adult gonadal transcriptome, at least in females. Our results show the importance of DNA methylation for proper control of sexual development, open new avenues for the potential control of sex ratios in fish (aquaculture, population control), and call attention to possibly hidden long-term effects of dnmt therapy when used, for example, in the treatment of prepuberal children affected by some types of cáncer
DescriptionVIII Jornada de Cromatina i Epigenètica organizada por la Secció de Cromatina i Epigenètica de la Societat Catalana de Biologia (SCB) con el Barcelona Chromatin Club (BCC), 16 March 2018, Barcelona.-- 1 page
Appears in Collections:(ICM) Comunicaciones congresos
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