Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring
Resumen:
Folate is an essential vitamin for vertebrate embryo development. Methotrexate (MTX) is a folate antagonist that is widely prescribed for autoimmune diseases, blood and solid organ malignancies, and dermatologic diseases. Although it is highly contraindicated for pregnant women, because it is associated with an increased risk of multiple birth defects, the effect of paternal MTX exposure on their offspring has been largely unexplored. Here, we found MTX treatment of adult medaka male fish (Oryzias latipes) causes cranial cartilage defects in their offspring. Small non-coding RNA (sncRNAs) sequencing in the sperm of MTX treated males identify differential expression of a subset of tRNAs, with higher abundance for specific 5′ tRNA halves. Sperm RNA methylation analysis on MTX treated males shows that m5C is the most abundant and differential modification found in RNAs ranging in size from 50 to 90 nucleotides, predominantly tRNAs, and that it correlates with greater testicular Dnmt2 methyltransferase expression. Injection of sperm small RNA fractions from MTX-treated males into normal fertilized eggs generated cranial cartilage defects in the offspring. Overall, our data suggest that paternal MTX exposure alters sperm sncRNAs expression and modifications that may contribute to developmental defects in their offspring.
| 2023 | |
| CSIC: I+D_2020_433 | |
|
Methotrexate Folate deficiency Sperm RNA Craniofacial defects |
|
| Inglés | |
| Universidad de la República | |
| COLIBRI | |
| https://hdl.handle.net/20.500.12008/42745 | |
| Acceso abierto | |
| Licencia Creative Commons Atribución (CC - By 4.0) |
| _version_ | 1807522806870573056 |
|---|---|
| author | Alata Jimenez, Nagif |
| author2 | Castellano, Mauricio Santillan, Emilio M. Boulias, Konstantinos Boan, Agustín Arias Padilla, Luisa F. Fernandino, Juan I. Greer, Eric L. Tosar Rovira, Juan Pablo Cochella, Luisa Strobl-Mazzulla, Pablo H. |
| author2_role | author author author author author author author author author author |
| author_facet | Alata Jimenez, Nagif Castellano, Mauricio Santillan, Emilio M. Boulias, Konstantinos Boan, Agustín Arias Padilla, Luisa F. Fernandino, Juan I. Greer, Eric L. Tosar Rovira, Juan Pablo Cochella, Luisa Strobl-Mazzulla, Pablo H. |
| author_role | author |
| bitstream.checksum.fl_str_mv | 6429389a7df7277b72b7924fdc7d47a9 a0ebbeafb9d2ec7cbb19d7137ebc392c 8010f418ede1186e294ac5448996bd7e 71ed42ef0a0b648670f707320be37b90 9668cb8aef58f96e97a01a168e325e1b |
| bitstream.checksumAlgorithm.fl_str_mv | MD5 MD5 MD5 MD5 MD5 |
| bitstream.url.fl_str_mv | http://localhost:8080/xmlui/bitstream/20.500.12008/42745/5/license.txt http://localhost:8080/xmlui/bitstream/20.500.12008/42745/2/license_url http://localhost:8080/xmlui/bitstream/20.500.12008/42745/3/license_text http://localhost:8080/xmlui/bitstream/20.500.12008/42745/4/license_rdf http://localhost:8080/xmlui/bitstream/20.500.12008/42745/1/10.1038.s41467-023-37427-7.pdf |
| collection | COLIBRI |
| dc.contributor.filiacion.none.fl_str_mv | Alata Jimenez Nagif Castellano Mauricio, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Investigaciones Nucleares. Santillan Emilio M. Boulias Konstantinos Boan Agustín Arias Padilla Luisa F. Fernandino Juan I. Greer Eric L. Tosar Rovira Juan Pablo, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Investigaciones Nucleares. Cochella Luisa Strobl-Mazzulla Pablo H. |
| dc.creator.none.fl_str_mv | Alata Jimenez, Nagif Castellano, Mauricio Santillan, Emilio M. Boulias, Konstantinos Boan, Agustín Arias Padilla, Luisa F. Fernandino, Juan I. Greer, Eric L. Tosar Rovira, Juan Pablo Cochella, Luisa Strobl-Mazzulla, Pablo H. |
| dc.date.accessioned.none.fl_str_mv | 2024-02-27T14:33:14Z |
| dc.date.available.none.fl_str_mv | 2024-02-27T14:33:14Z |
| dc.date.issued.none.fl_str_mv | 2023 |
| dc.description.abstract.none.fl_txt_mv | Folate is an essential vitamin for vertebrate embryo development. Methotrexate (MTX) is a folate antagonist that is widely prescribed for autoimmune diseases, blood and solid organ malignancies, and dermatologic diseases. Although it is highly contraindicated for pregnant women, because it is associated with an increased risk of multiple birth defects, the effect of paternal MTX exposure on their offspring has been largely unexplored. Here, we found MTX treatment of adult medaka male fish (Oryzias latipes) causes cranial cartilage defects in their offspring. Small non-coding RNA (sncRNAs) sequencing in the sperm of MTX treated males identify differential expression of a subset of tRNAs, with higher abundance for specific 5′ tRNA halves. Sperm RNA methylation analysis on MTX treated males shows that m5C is the most abundant and differential modification found in RNAs ranging in size from 50 to 90 nucleotides, predominantly tRNAs, and that it correlates with greater testicular Dnmt2 methyltransferase expression. Injection of sperm small RNA fractions from MTX-treated males into normal fertilized eggs generated cranial cartilage defects in the offspring. Overall, our data suggest that paternal MTX exposure alters sperm sncRNAs expression and modifications that may contribute to developmental defects in their offspring. |
| dc.description.sponsorship.none.fl_txt_mv | CSIC: I+D_2020_433 |
| dc.format.extent.es.fl_str_mv | 12 h. |
| dc.format.mimetype.es.fl_str_mv | application/pdf |
| dc.identifier.citation.es.fl_str_mv | Alata Jimenez, N, Castellano, M, Santillan, E [y otros autores]. "Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring". Nature communications. [en línea] 2023, 14: 1617. 12 h. DOI: 10.1038/s41467-023-37427-7. |
| dc.identifier.doi.none.fl_str_mv | 10.1038/s41467-023-37427-7 |
| dc.identifier.issn.none.fl_str_mv | 2041-1723 |
| dc.identifier.uri.none.fl_str_mv | https://hdl.handle.net/20.500.12008/42745 |
| dc.language.iso.none.fl_str_mv | en eng |
| dc.publisher.es.fl_str_mv | Springer Nature |
| dc.relation.ispartof.es.fl_str_mv | Nature communications, 2023, 14: 1617. |
| dc.rights.license.none.fl_str_mv | Licencia Creative Commons Atribución (CC - By 4.0) |
| dc.rights.none.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.source.none.fl_str_mv | reponame:COLIBRI instname:Universidad de la República instacron:Universidad de la República |
| dc.subject.es.fl_str_mv | Methotrexate Folate deficiency Sperm RNA Craniofacial defects |
| dc.title.none.fl_str_mv | Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring |
| dc.type.es.fl_str_mv | Artículo |
| dc.type.none.fl_str_mv | info:eu-repo/semantics/article |
| dc.type.version.none.fl_str_mv | info:eu-repo/semantics/publishedVersion |
| description | Folate is an essential vitamin for vertebrate embryo development. Methotrexate (MTX) is a folate antagonist that is widely prescribed for autoimmune diseases, blood and solid organ malignancies, and dermatologic diseases. Although it is highly contraindicated for pregnant women, because it is associated with an increased risk of multiple birth defects, the effect of paternal MTX exposure on their offspring has been largely unexplored. Here, we found MTX treatment of adult medaka male fish (Oryzias latipes) causes cranial cartilage defects in their offspring. Small non-coding RNA (sncRNAs) sequencing in the sperm of MTX treated males identify differential expression of a subset of tRNAs, with higher abundance for specific 5′ tRNA halves. Sperm RNA methylation analysis on MTX treated males shows that m5C is the most abundant and differential modification found in RNAs ranging in size from 50 to 90 nucleotides, predominantly tRNAs, and that it correlates with greater testicular Dnmt2 methyltransferase expression. Injection of sperm small RNA fractions from MTX-treated males into normal fertilized eggs generated cranial cartilage defects in the offspring. Overall, our data suggest that paternal MTX exposure alters sperm sncRNAs expression and modifications that may contribute to developmental defects in their offspring. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | COLIBRI_784adb3eef2b5915a4a44c0692a6c70b |
| identifier_str_mv | Alata Jimenez, N, Castellano, M, Santillan, E [y otros autores]. "Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring". Nature communications. [en línea] 2023, 14: 1617. 12 h. DOI: 10.1038/s41467-023-37427-7. 2041-1723 10.1038/s41467-023-37427-7 |
| instacron_str | Universidad de la República |
| institution | Universidad de la República |
| instname_str | Universidad de la República |
| language | eng |
| language_invalid_str_mv | en |
| network_acronym_str | COLIBRI |
| network_name_str | COLIBRI |
| oai_identifier_str | oai:colibri.udelar.edu.uy:20.500.12008/42745 |
| publishDate | 2023 |
| reponame_str | COLIBRI |
| repository.mail.fl_str_mv | mabel.seroubian@seciu.edu.uy |
| repository.name.fl_str_mv | COLIBRI - Universidad de la República |
| repository_id_str | 4771 |
| rights_invalid_str_mv | Licencia Creative Commons Atribución (CC - By 4.0) |
| spelling | Alata Jimenez NagifCastellano Mauricio, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Investigaciones Nucleares.Santillan Emilio M.Boulias KonstantinosBoan AgustínArias Padilla Luisa F.Fernandino Juan I.Greer Eric L.Tosar Rovira Juan Pablo, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Investigaciones Nucleares.Cochella LuisaStrobl-Mazzulla Pablo H.2024-02-27T14:33:14Z2024-02-27T14:33:14Z2023Alata Jimenez, N, Castellano, M, Santillan, E [y otros autores]. "Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring". Nature communications. [en línea] 2023, 14: 1617. 12 h. DOI: 10.1038/s41467-023-37427-7.2041-1723https://hdl.handle.net/20.500.12008/4274510.1038/s41467-023-37427-7Folate is an essential vitamin for vertebrate embryo development. Methotrexate (MTX) is a folate antagonist that is widely prescribed for autoimmune diseases, blood and solid organ malignancies, and dermatologic diseases. Although it is highly contraindicated for pregnant women, because it is associated with an increased risk of multiple birth defects, the effect of paternal MTX exposure on their offspring has been largely unexplored. Here, we found MTX treatment of adult medaka male fish (Oryzias latipes) causes cranial cartilage defects in their offspring. Small non-coding RNA (sncRNAs) sequencing in the sperm of MTX treated males identify differential expression of a subset of tRNAs, with higher abundance for specific 5′ tRNA halves. Sperm RNA methylation analysis on MTX treated males shows that m5C is the most abundant and differential modification found in RNAs ranging in size from 50 to 90 nucleotides, predominantly tRNAs, and that it correlates with greater testicular Dnmt2 methyltransferase expression. Injection of sperm small RNA fractions from MTX-treated males into normal fertilized eggs generated cranial cartilage defects in the offspring. Overall, our data suggest that paternal MTX exposure alters sperm sncRNAs expression and modifications that may contribute to developmental defects in their offspring.Submitted by Pintos Natalia (nataliapintosmvd@gmail.com) on 2024-02-26T15:22:15Z No. of bitstreams: 2 license_rdf: 24251 bytes, checksum: 71ed42ef0a0b648670f707320be37b90 (MD5) 10.1038.s41467-023-37427-7.pdf: 2647824 bytes, checksum: 9668cb8aef58f96e97a01a168e325e1b (MD5)Approved for entry into archive by Faget Cecilia (lfaget@fcien.edu.uy) on 2024-02-27T12:35:01Z (GMT) No. of bitstreams: 2 license_rdf: 24251 bytes, checksum: 71ed42ef0a0b648670f707320be37b90 (MD5) 10.1038.s41467-023-37427-7.pdf: 2647824 bytes, checksum: 9668cb8aef58f96e97a01a168e325e1b (MD5)Made available in DSpace by Luna Fabiana (fabiana.luna@seciu.edu.uy) on 2024-02-27T14:33:14Z (GMT). No. of bitstreams: 2 license_rdf: 24251 bytes, checksum: 71ed42ef0a0b648670f707320be37b90 (MD5) 10.1038.s41467-023-37427-7.pdf: 2647824 bytes, checksum: 9668cb8aef58f96e97a01a168e325e1b (MD5) Previous issue date: 2023CSIC: I+D_2020_43312 h.application/pdfenengSpringer NatureNature communications, 2023, 14: 1617.Las obras depositadas en el Repositorio se rigen por la Ordenanza de los Derechos de la Propiedad Intelectual de la Universidad de la República.(Res. Nº 91 de C.D.C. de 8/III/1994 – D.O. 7/IV/1994) y por la Ordenanza del Repositorio Abierto de la Universidad de la República (Res. Nº 16 de C.D.C. de 07/10/2014)info:eu-repo/semantics/openAccessLicencia Creative Commons Atribución (CC - By 4.0)MethotrexateFolate deficiencySperm RNACraniofacial defectsPaternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspringArtículoinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionreponame:COLIBRIinstname:Universidad de la Repúblicainstacron:Universidad de la RepúblicaAlata Jimenez, NagifCastellano, MauricioSantillan, Emilio M.Boulias, KonstantinosBoan, AgustínArias Padilla, Luisa F.Fernandino, Juan I.Greer, Eric L.Tosar Rovira, Juan PabloCochella, LuisaStrobl-Mazzulla, Pablo H.LICENSElicense.txtlicense.txttext/plain; charset=utf-84267http://localhost:8080/xmlui/bitstream/20.500.12008/42745/5/license.txt6429389a7df7277b72b7924fdc7d47a9MD55CC-LICENSElicense_urllicense_urltext/plain; charset=utf-844http://localhost:8080/xmlui/bitstream/20.500.12008/42745/2/license_urla0ebbeafb9d2ec7cbb19d7137ebc392cMD52license_textlicense_texttext/html; charset=utf-820277http://localhost:8080/xmlui/bitstream/20.500.12008/42745/3/license_text8010f418ede1186e294ac5448996bd7eMD53license_rdflicense_rdfapplication/rdf+xml; charset=utf-824251http://localhost:8080/xmlui/bitstream/20.500.12008/42745/4/license_rdf71ed42ef0a0b648670f707320be37b90MD54ORIGINAL10.1038.s41467-023-37427-7.pdf10.1038.s41467-023-37427-7.pdfapplication/pdf2647824http://localhost:8080/xmlui/bitstream/20.500.12008/42745/1/10.1038.s41467-023-37427-7.pdf9668cb8aef58f96e97a01a168e325e1bMD5120.500.12008/427452024-02-27 11:33:14.216oai:colibri.udelar.edu.uy:20.500.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Universidadhttps://udelar.edu.uy/https://www.colibri.udelar.edu.uy/oai/requestmabel.seroubian@seciu.edu.uyUruguayopendoar:47712024-07-25T14:29:21.652589COLIBRI - Universidad de la Repúblicafalse |
| spellingShingle | Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring Alata Jimenez, Nagif Methotrexate Folate deficiency Sperm RNA Craniofacial defects |
| status_str | publishedVersion |
| title | Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring |
| title_full | Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring |
| title_fullStr | Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring |
| title_full_unstemmed | Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring |
| title_short | Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring |
| title_sort | Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring |
| topic | Methotrexate Folate deficiency Sperm RNA Craniofacial defects |
| url | https://hdl.handle.net/20.500.12008/42745 |
