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

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

doi:10.1038/s41467-023-37427-7

Cited by 15 publications

(2 citation statements)

References 92 publications

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“…Our studies demonstrate that male drinking is a plausible yet completely unexamined factor in the development of alcohol-related craniofacial abnormalities. Similarly, pharmacological inhibition of male folic acid metabolism using methotrexate alters the sperm epigenetic program, which correlates with craniofacial defects in offspring (Alata Jimenez et al, 2023). Collectively, these studies emphasize the potential relevance of paternal exposures to congenital malformations.…”

Section: Paternally Programmed Congenital Malformations Do They Exist?mentioning

confidence: 88%

Teratogenesis and the epigenetic programming of congenital defects: Why paternal exposures matter

Golding

2023

Birth Defects Research

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Until recently, clinicians and researchers did not realize paternal exposures could impact child developmental outcomes. Indeed, although there is growing recognition that sperm carry a large amount of non‐genomic information and that paternal stressors influence the health of the next generation, toxicologists are only now beginning to explore the role paternal exposures have in dysgenesis and the incidence of congenital malformations. In this commentary, I will briefly summarize the few studies describing congenital malformations resulting from preconception paternal stressors, argue for the theoretical expansion of teratogenic perspectives into the male preconception period, and discuss some of the challenges in this newly emerging branch of toxicology. I argue that we must consider gametes the same as any other malleable precursor cell type and recognize that environmentally‐induced epigenetic changes acquired during the formation of the sperm and oocyte hold equal teratogenic potential as exposures during early development. Here, I propose the term epiteratogen to reference agents acting outside of pregnancy that, through epigenetic mechanisms, induce congenital malformations. Understanding the interactions between the environment, the essential epigenetic processes intrinsic to spermatogenesis, and their cumulative influences on embryo patterning is essential to addressing a significant blind spot in the field of developmental toxicology.

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Section: Paternally Programmed Congenital Malformations Do They Exist?mentioning

confidence: 88%

Teratogenesis and the epigenetic programming of congenital defects: Why paternal exposures matter

Golding

2023

Birth Defects Research

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“…Because tsRNAs widely exist in blood and other body fluids, many clinical studies have recently harnessed tsRNAs as biomarkers for a range of clinical diseases and conditions ( 21 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ). In fact, tsRNAs have been found to play important roles in a wide and expanding range of biological and disease conditions including regulating viral infection ( 69 , 70 ), cancer progression ( 71 , 72 , 73 ), stem cell differentiation ( 12 , 47 , 74 , 75 ), epigenetic inheritance ( 46 , 52 , 53 , 76 , 77 , 78 , 79 ), and symbiosis ( 80 , 81 ).…”

Section: Tsrna Momentummentioning

confidence: 99%