Sorry, you need to enable JavaScript to visit this website.

Transgenerational inheritance of enhanced susceptibility to radiation-induced medulloblastoma in newborn Ptch1+/- mice after paternal irradiation

TitleTransgenerational inheritance of enhanced susceptibility to radiation-induced medulloblastoma in newborn Ptch1+/- mice after paternal irradiation
Publication TypeArticolo su Rivista peer-reviewed
Year of Publication2015
AuthorsParis, L., Giardullo Paola, Leonardi Simona, Tanno Barbara, Meschini R., Cordelli Eugenia, Benassi Barbara, Longobardi M.G., Izzotti A., Pulliero A., Mancuso Mariateresa, and Pacchierotti Francesca
JournalOncotarget
Volume6
Pagination36098-36112
ISSN19492553
Keywordsanimal cell, animal experiment, animal model, animal tissue, article, cancer risk, cancer susceptibility, cell proliferation, controlled study, DNA, DNA damage, DNA repair, epigenetics, Female, gene loss, germ cell, granule cell, heterozygosity loss, inheritance, interstitial chromosome deletion, male, medulloblastoma, microRNA, mouse, nerve cell differentiation, neural stem cell, newborn, nonhuman, protein Patched 1, radiation carcinogenesis, Radiation exposure, radiation induced neoplasm, spermatogonium, transgenerational inheritance, X irradiation
Abstract

The hypothesis of transgenerational induction of increased cancer susceptibility after paternal radiation exposure has long been controversial because of inconsistent results and the lack of a mechanistic interpretation. Here, exploiting Ptch1 heterozygous knockout mice, susceptible to spontaneous and radiation-induced medulloblastoma, we show that exposure of paternal germ cells to 1 Gy X-rays, at the spermatogonial stage, increased by a considerable 1.4-fold the offspring susceptibility to medulloblastoma induced by neonatal irradiation. This effect gained further biological significance thanks to a number of supporting data on the immunohistochemical characterization of the target tissue and preneoplastic lesions (PNLs). These results altogether pointed to increased proliferation of cerebellar granule cell precursors and PNLs cells, which favoured the development of frank tumours. The LOH analysis of tumor DNA showed Ptch1 biallelic loss in all tumor samples, suggesting that mechanisms other than interstitial deletions, typical of radiation-induced medulloblastoma, did not account for the observed increased cancer risk. This data was supported by comet analysis showing no differences in DNA damage induction and repair in cerebellar cells as a function of paternal irradiation. Finally, we provide biological plausibility to our results offering evidence of a possible epigenetic mechanism of inheritance based on radiation-induced changes of the microRNA profile of paternal sperm.

Notes

cited By 1

URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84946854572&doi=10.18632%2foncotarget.5553&partnerID=40&md5=144519e48bf5e930b545dd5f1229ab76
DOI10.18632/oncotarget.5553
Citation KeyParis201536098