title: Transgenerational inheritance of enhanced susceptibility to radiation-induced medulloblastoma in newborn Ptch1⁺/⁻ mice after paternal 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.
authors.affiliation: Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.|Department of Ecological and Biological Sciences, Tuscia University, Viterbo, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Paris
authors.affiliation: Department of Radiation Physics, Guglielmo Marconi University, Rome, Italy.|Department of Sciences, University of Roma Tre, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Giardullo
authors.affiliation: Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Leonardi
authors.affiliation: Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tanno
authors.affiliation: Department of Ecological and Biological Sciences, Tuscia University, Viterbo, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Meschini
authors.affiliation: Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Cordelli
authors.affiliation: Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Benassi
authors.affiliation: Department of Health Sciences, University of Genoa, Genoa, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Longobardi
authors.affiliation: Department of Health Sciences, University of Genoa, Genoa, Italy.|IRCCS AOU San Martino IST, Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Izzotti
authors.affiliation: Department of Health Sciences, University of Genoa, Genoa, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pulliero
authors.affiliation: Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Mancuso
authors.affiliation: Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pacchierotti
mesh_terms: D000818:Animals; D002528:Cerebellar Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D020552:Comet Assay; D005260:Female; D008297:Male; D008527:Medulloblastoma / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface
keywords: epigenetic inheritance; medulloblastoma; microRNA; patched1 knockout mice; transgenerational carcinogenesis