Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring

Autores
Alata Jimenez, Nagif; Castellano, Mauricio; Santillan, Emilio M.; Boulias, Konstantinos; Boan, Agustín Fernando; Arias Padilla, Luisa Fernanda; Fernandino, Juan Ignacio; Greer, Eric L.; Tosar, Juan P.; Cochella, Luisa; Strobl Mazzulla, Pablo H.
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Alata Jimenez, Nagif. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Castellano, Mauricio. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica; Uruguay
Fil: Santillan, Emilio M.. University Johns Hopkins; Estados Unidos
Fil: Boulias, Konstantinos. Harvard Medical School; Estados Unidos. Boston Children’s Hospital; Estados Unidos
Fil: Boan, Agustín Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Arias Padilla, Luisa Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Fernandino, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Greer, Eric L.. Harvard Medical School; Estados Unidos. Boston Children’s Hospital; Estados Unidos
Fil: Tosar, Juan P.. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica; Uruguay
Fil: Cochella, Luisa. University Johns Hopkins; Estados Unidos
Fil: Strobl Mazzulla, Pablo H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Materia
Methotrexate
Paternal exposure
Offspring craniofacial defects
tsRNAs
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/224436
Acceder
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network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspringAlata Jimenez, NagifCastellano, MauricioSantillan, Emilio M.Boulias, KonstantinosBoan, Agustín FernandoArias Padilla, Luisa FernandaFernandino, Juan IgnacioGreer, Eric L.Tosar, Juan P.Cochella, LuisaStrobl Mazzulla, Pablo H.MethotrexatePaternal exposureOffspring craniofacial defectstsRNAshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Folate 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.Fil: Alata Jimenez, Nagif. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Castellano, Mauricio. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica; UruguayFil: Santillan, Emilio M.. University Johns Hopkins; Estados UnidosFil: Boulias, Konstantinos. Harvard Medical School; Estados Unidos. Boston Children’s Hospital; Estados UnidosFil: Boan, Agustín Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Arias Padilla, Luisa Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Fernandino, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Greer, Eric L.. Harvard Medical School; Estados Unidos. Boston Children’s Hospital; Estados UnidosFil: Tosar, Juan P.. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica; UruguayFil: Cochella, Luisa. University Johns Hopkins; Estados UnidosFil: Strobl Mazzulla, Pablo H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaNature2023-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/224436Alata Jimenez, Nagif; Castellano, Mauricio; Santillan, Emilio M.; Boulias, Konstantinos; Boan, Agustín Fernando; et al.; Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring; Nature; Nature Communications; 14; 1; 12-2023; 1-122041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-023-37427-7info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41467-023-37427-7info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:58:59Zoai:ri.conicet.gov.ar:11336/224436instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:58:59.725CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring
title Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring
spellingShingle Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring
Alata Jimenez, Nagif
Methotrexate
Paternal exposure
Offspring craniofacial defects
tsRNAs
title_short 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_sort Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring
dc.creator.none.fl_str_mv Alata Jimenez, Nagif
Castellano, Mauricio
Santillan, Emilio M.
Boulias, Konstantinos
Boan, Agustín Fernando
Arias Padilla, Luisa Fernanda
Fernandino, Juan Ignacio
Greer, Eric L.
Tosar, Juan P.
Cochella, Luisa
Strobl Mazzulla, Pablo H.
author Alata Jimenez, Nagif
author_facet Alata Jimenez, Nagif
Castellano, Mauricio
Santillan, Emilio M.
Boulias, Konstantinos
Boan, Agustín Fernando
Arias Padilla, Luisa Fernanda
Fernandino, Juan Ignacio
Greer, Eric L.
Tosar, Juan P.
Cochella, Luisa
Strobl Mazzulla, Pablo H.
author_role author
author2 Castellano, Mauricio
Santillan, Emilio M.
Boulias, Konstantinos
Boan, Agustín Fernando
Arias Padilla, Luisa Fernanda
Fernandino, Juan Ignacio
Greer, Eric L.
Tosar, Juan P.
Cochella, Luisa
Strobl Mazzulla, Pablo H.
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Methotrexate
Paternal exposure
Offspring craniofacial defects
tsRNAs
topic Methotrexate
Paternal exposure
Offspring craniofacial defects
tsRNAs
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.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.
Fil: Alata Jimenez, Nagif. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Castellano, Mauricio. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica; Uruguay
Fil: Santillan, Emilio M.. University Johns Hopkins; Estados Unidos
Fil: Boulias, Konstantinos. Harvard Medical School; Estados Unidos. Boston Children’s Hospital; Estados Unidos
Fil: Boan, Agustín Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Arias Padilla, Luisa Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Fernandino, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Greer, Eric L.. Harvard Medical School; Estados Unidos. Boston Children’s Hospital; Estados Unidos
Fil: Tosar, Juan P.. Instituto Pasteur de Montevideo; Uruguay. Universidad de la Republica; Uruguay
Fil: Cochella, Luisa. University Johns Hopkins; Estados Unidos
Fil: Strobl Mazzulla, Pablo H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina
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.
publishDate 2023
dc.date.none.fl_str_mv 2023-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/224436
Alata Jimenez, Nagif; Castellano, Mauricio; Santillan, Emilio M.; Boulias, Konstantinos; Boan, Agustín Fernando; et al.; Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring; Nature; Nature Communications; 14; 1; 12-2023; 1-12
2041-1723
CONICET Digital
CONICET
url http://hdl.handle.net/11336/224436
identifier_str_mv Alata Jimenez, Nagif; Castellano, Mauricio; Santillan, Emilio M.; Boulias, Konstantinos; Boan, Agustín Fernando; et al.; Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring; Nature; Nature Communications; 14; 1; 12-2023; 1-12
2041-1723
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-023-37427-7
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41467-023-37427-7
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature
publisher.none.fl_str_mv Nature
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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