Low Dose Radiation Causes Skin Cancer in Mice and Has a Differential Effect on Distinct Epidermal Stem Cells.

The carcinogenic effect of ionizing radiation has been evaluated based on limited populations accidently exposed to high dose radiation. In contrast, insufficient data are available on the effect of low dose radiation, such as radiation deriving from medical investigations and interventions, as well as occupational exposure that concern a large fraction of western populations. Using mouse skin epidermis as a model, we showed that low dose radiation results in DNA damage in sebaceous gland and bulge epidermal stem cells (SCs). While the first commit apoptosis upon low dose irradiation, the latter survive. Bulge SC survival coincides with higher HIF-1α expression and a metabolic switch upon low dose radiation. Knocking down HIF-1α sensitizes bulge SCs to low dose radiation-induced apoptosis, while upregulation of HIF-1α in the epidermis, including sebaceous gland SCs, rescues cell death. Most importantly, we show that low dose radiation results in cancer formation with full penetrance in the radiation-sensitive Patched1 heterozygous mice. Overall, our results demonstrate for the first time that low dose radiation can be a potent carcinogen in individuals predisposed to cancer. This article is protected by copyright. All rights reserved.