Treatment with a DNA methyltransferase inhibitor feminizes zebrafish and induces long-term expression changes in the gonads

[Background] The 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).

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PID https://www.doi.org/10.1186/s13072-017-0168-7
PID handle:10261/158021
PID pmc:PMC5721477
PID pmid:29216900
URL http://link.springer.com/content/pdf/10.1186/s13072-017-0168-7.pdf
URL https://digital.csic.es/handle/10261/158021
URL http://europepmc.org/articles/PMC5721477
URL http://link.springer.com/article/10.1186/s13072-017-0168-7
URL http://hdl.handle.net/10044/1/72972
URL https://epigeneticsandchromatin.biomedcentral.com/track/pdf/10.1186/s13072-017-0168-7
URL https://doaj.org/toc/1756-8935
URL http://dx.doi.org/10.1186/s13072-017-0168-7
URL https://academic.microsoft.com/#/detail/2772285587
URL https://core.ac.uk/display/145228681
URL https://epigeneticsandchromatin.biomedcentral.com/articles/10.1186/s13072-017-0168-7
URL https://dx.doi.org/10.1186/s13072-017-0168-7
URL http://hdl.handle.net/10261/158021
URL https://digital.csic.es/bitstream/10261/158021/1/Ribas_et_al_2017pdf
URL https://www.ncbi.nlm.nih.gov/pubmed/29216900
URL http://europepmc.org/abstract/MED/29216900
URL https://link.springer.com/article/10.1186/s13072-017-0168-7
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Author Francesc Piferrer, 0000-0003-0903-4736
Author Marco Antonio Imués-Figueroa, 0000-0002-7607-540X
Author Laia Ribas, 0000-0001-5538-6236
Contributor Ministerio de Economía y Competitividad (España)
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Collected From Europe PubMed Central; PubMed Central; Digital.CSIC; ORCID; UnpayWall; Datacite; DOAJ-Articles; Crossref; Spiral - Imperial College Digital Repository; Microsoft Academic Graph
Hosted By Europe PubMed Central; Digital.CSIC; Epigenetics & Chromatin; Spiral - Imperial College Digital Repository
Publication Date 2017-12-01
Publisher BioMed Central
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Country United Kingdom; Spain
Description [Results] Early treatment with 5-aza-dC 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-dC-exposed females included significant changes in the expression of key reproduction-related genes (e.g. cyp11a1, esr2b and figla), and that several pro-female-related pathways such as the Fanconi anaemia 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.
Description [Conclusions] 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 cancer
Description Work supported by Ministry of Economy and Competitiveness (MEC) grants from Spanish government (“EpiFarm”: AGL2013-41047-R) and Aquagenomics (CDS2007-0002) to FP LR was supported by an Epifarm contract
Description Peer reviewed
Language English
Resource Type Article; UNKNOWN
system:type publication
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Source https://science-innovation-policy.openaire.eu/search/publication?articleId=dedup_wf_001::944626644d36d9a7d92ece0c13b9a47e
Author jsonws_user
Last Updated 25 December 2020, 05:36 (CET)
Created 25 December 2020, 05:36 (CET)