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

Nature Communications · 11 authors, 7 centres

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TL;DR

This study used a medaka fish model to show that paternal exposure to methotrexate alters sperm tRNA-derived small RNA content and increases tRNA methylation, which when injected into zygotes can partially recapitulate the craniofacial cartilage defects observed in offspring of exposed fathers.

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There was a higher abundance of specific 5'tsRNAs and increased methylation levels (m5C, m2G, m7G, m2’2G) in the tRNA fraction from MTX-treated males. Zygotic injection of small RNAs isolated from MTX-treated sperm partially reproduced craniofacial cartilage malformations (basihyal and ceratohyal defects) seen in offspring of treated males. The results suggest a mechanism where paternal MTX exposure alters sperm epitranscriptome, potentially influencing early embryonic development and offspring phenotype.

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other

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preclinical research

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ORIGINAL PAPER

PMC10036556

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

Nature Communications

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ABSTRACT

Abstract 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. Subject terms: Cartilage development, Epigenetic memory, Non-coding RNAs, Methylation

CITATION EXPORT

Nagif Alata Jimenez, Mauricio Castellano, Emilio M Santillan et al.. Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring. Nature Communications. (2023). https://doi.org/10.1038/s41467-023-37427-7

AUTHORS

11 · 7 CENTRES

Nagif Alata Jimenez, Mauricio Castellano, Emilio M Santillan, Konstantinos Boulias, Agustín Boan, Luisa F Arias Padilla, Juan I Fernandino, Eric L Greer, Juan P Tosar, Luisa Cochella, Pablo H Strobl-Mazzulla

1Laboratory of Developmental Biology, Instituto de Investigaciones Biotecnológicas- Instituto Tecnológico de Chascomús (CONICET-UNSAM), Chascomús, Argentina
2Escuela de Bio y Nanotecnologías (UNSAM), Chascomús, Argentina
3Functional Genomics Unit, Instituto Pasteur de Montevideo, Montevideo, Uruguay
4School of Science, Universidad de la República, Montevideo, Uruguay
5Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MA USA
6Department of Pediatrics, HMS Initiative for RNA Medicine, Harvard Medical School, Boston, MA USA
7Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA USA