Speaker
Dr
Lorena Paris
(Unit of Radiation Biology and Human Health, ENEA, Rome, Italy; Department of Ecology and Biology, University of Tuscia, Viterbo, Italy)
Description
The inheritance of an increased susceptibility to spontaneous or induced carcinogenesis after paternal irradiation has been suggested, but it remains a controversial issue, also because its mechanisms are still unknown. To further test this hypothesis, we set up experiments employing Ptch1+/- mice that are prone to developing spontaneous and radiation-induced cancer and, as such, could enhance an inherited tumour susceptibility phenotype.
Wild-type male CD-1 mice were irradiated with 1 Gy X-rays and mated 42 days later with untreated Ptch1+/- females to test transgenerational effects transmitted by spermatogonial irradiation. After mating, sperm of irradiated fathers were collected for the analysis of genetic and epigenetic alterations. Half of the progeny was enrolled in a lifetime carcinogenicity study to test the transmission of increased spontaneous cancer incidence; the other half was irradiated on postnatal day 2 (P2) with 1 Gy X-rays, according to previous results showing the sensitivity of cerebellum cells at this stage for the development of radiation-induced medulloblastoma. Tumour incidence of both groups was compared with historical laboratory data obtained on the progeny of non-irradiated fathers. In parallel, the level of spontaneous and radiation-induced DNA damage and repair in P2 cerebellum cells was analyzed by comet assay in the progeny of irradiated and unirradiated fathers. In addition, the possible transmission of genomic instability was investigated in bone marrow and spleen cells by comet and micronucleus assays.
Data collected so far show a nearly significant increase of the incidence of radiation-induced medulloblastoma in the progeny of irradiated fathers, whereas no difference is observed in the spontaneous tumour incidence between the progeny of irradiated and unirradiated fathers. The dose-effect relationships for DNA damage induction in P2 cerebellum cells obtained in the progeny of irradiated and unirradiated fathers did not differ. The study of DNA repair in these cells and of genomic instability in bone marrow and spleen cells is in progress. Overall, although preliminary, these data suggest that Ptch1+/- mice could represent a promising tool to investigate transgenerational genomic instability and carcinogenesis. To elucidate the molecular mechanisms of possible transgenerational carcinogenesis, tumours will be characterized for Ptch1 Loss of Heterozygosity/epigenetic silencing and gene expression profiling.
Primary author
Dr
Lorena Paris
(Unit of Radiation Biology and Human Health, ENEA, Rome, Italy; Department of Ecology and Biology, University of Tuscia, Viterbo, Italy)
Co-authors
Dr
Anna Saran
(Unit of Radiation Biology and Human Health, ENEA, Rome, Italy)
Dr
Eugenia Cordelli
(Unit of Radiation Biology and Human Health, ENEA, Rome, Italy)
Dr
Francesca Pacchierotti
(Unit of Radiation Biology and Human Health, ENEA, Rome, Italy)
Dr
Mariateresa Mancuso
(Unit of Radiation Biology and Human Health, ENEA, Rome, Italy)
Dr
Paola Giardullo
(Guglielmo Marconi University, Rome, Italy)
Dr
Roberta Meschini
(Department of Ecology and Biology, University of Tuscia, Viterbo, Italy)
Dr
Simona Leonardi
(Unit of Radiation Biology and Human Health, ENEA, Rome, Italy)
