Oncogenic bystander radiation effects in Patched heterozygous mouse cerebellum.
The central dogma of radiation biology, that biological effects of ionizing radiation are a direct consequence of DNA damage occurring in irradiated cells, has been challenged by observations that genetic/epigenetic changes occur in unexposed "bystander cells" neighboring directly-hit cells, due to cell-to-cell communication or soluble factors released by irradiated cells. To date, the vast majority of these effects are described in cell-culture systems, while in vivo validation and assessment of biological consequences within an organism remain uncertain. Here, we describe the neonatal mouse cerebellum as an accurate in vivo model to detect, quantify, and mechanistically dissect radiation-bystander responses. DNA double-strand breaks and apoptotic cell death were induced in bystander cerebellum in vivo. Accompanying these genetic events, we report bystander-related tumor induction in cerebellum of radiosensitive Patched-1 (Ptch1) heterozygous mice after x-ray exposure of the remainder of the body. We further show that genetic damage is a critical component of in vivo oncogenic bystander responses, and provide evidence supporting the role of gap-junctional intercellular communication (GJIC) in transmission of bystander signals in the central nervous system (CNS). These results represent the first proof-of-principle that bystander effects are factual in vivo events with carcinogenic potential, and implicate the need for re-evaluation of approaches currently used to estimate radiation-associated health risks.
Mancuso
Mariateresa
M
Section of Toxicology and Biomedical Sciences and Italian National Metrological Institute, Biotechnologies, Agro-Industry and Health Protection, Ente per le Nuove Technologie, l'Energia e l'Ambiente Centro Ricerche Casaccia, 00123 Rome, Italy.
Pasquali
Emanuela
E
Leonardi
Simona
S
Tanori
Mirella
M
Rebessi
Simonetta
S
Di Majo
Vincenzo
V
Pazzaglia
Simonetta
S
Toni
Maria Pia
MP
Pimpinella
Maria
M
Covelli
Vincenzo
V
Saran
Anna
A
D000818:Animals; D000831:Animals, Newborn; D024201:Bystander Effect / Q000528:radiation effects*; D002450:Cell Communication; D002531:Cerebellum / Q000473:pathology / Q000528:radiation effects*; D004249:DNA Damage; D017629:Gap Junctions; D016147:Genes, Tumor Suppressor; D006579:Heterozygote; D051379:Mice; D009369:Neoplasms / Q000209:etiology* / Q000473:pathology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011839:Radiation, Ionizing; D011956:Receptors, Cell Surface / Q000235:genetics*
D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface