Oncotarget

Research Papers:

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 and Francesca Pacchierotti

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Oncotarget. 2015; 6:36098-36112. https://doi.org/10.18632/oncotarget.5553

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Abstract

Lorena Paris1,2,*, Paola Giardullo3,4,*, Simona Leonardi1,*, Barbara Tanno1, Roberta Meschini2, Eugenia Cordelli1, Barbara Benassi1, Maria Grazia Longobardi5, Alberto Izzotti5,6, Alessandra Pulliero5, Mariateresa Mancuso1, Francesca Pacchierotti1

1Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy

2Department of Ecological and Biological Sciences, Tuscia University, Viterbo, Italy

3Department of Radiation Physics, Guglielmo Marconi University, Rome, Italy

4Department of Sciences, University of Roma Tre, Rome, Italy

5Department of Health Sciences, University of Genoa, Genoa, Italy

6IRCCS AOU San Martino IST Genoa, Italy

*These authors have contributed equally to this work

Correspondence to:

Mariateresa Mancuso, e-mail: mariateresa.mancuso@enea.it

Francesca Pacchierotti, e-mail: francesca.pacchierotti@enea.it

Keywords: transgenerational carcinogenesis, epigenetic inheritance, medulloblastoma, patched1 knockout mice, microRNA

Received: July 30, 2015     Accepted: September 21, 2015     Published: October 03, 2015

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.


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