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

Lorena Paris, Paola Giardullo, Simona Leonardi, Barbara Tanno, Roberta Meschini, Eugenia Cordelli, Barbara Benassi, Maria Grazia Longobardi, Alberto Izzotti, Alessandra Pulliero, Mariateresa Mancuso, Francesca Pacchierotti

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)36098-36112
Number of pages15
Issue number34
Publication statusPublished - 2015


  • Epigenetic inheritance
  • Medulloblastoma
  • microRNA
  • Patched1 knockout mice
  • Transgenerational carcinogenesis

ASJC Scopus subject areas

  • Oncology


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