title: In vivo interactions between ionizing radiation, inflammation and chemical carcinogens identified by increased DNA damage responses.
abstract: Exposure to ionizing radiation or a variety of chemical agents is known to increase the risk of developing malignancy and many tumors have been linked to inflammatory processes. In most studies, the potentially harmful effects of ionizing radiation or other agents are considered in isolation, mainly due to the large number of experiments required to assess the effects of mixed exposures with different doses and different schedules, and the length of time and expense of studies using disease as the measure of outcome. Here, we have used short-term DNA damage responses to identify interactive effects of mixed exposures. The data demonstrate that exposure to ionizing radiation on two separate occasions ten days apart leads to an increase in the percentage of cells with a sub-G(0) DNA content compared to cells exposed only once, and this is a greater than additive effect. Short-term measurements of p53 stabilization, induction of p21/Cdkn1a and of apoptosis also identify these interactive effects. We also demonstrate similar interactive effects of radiation with the mutagenic chemical methyl-nitrosourea and with a nonspecific pro-inflammatory agent, lipopolysaccharide. The magnitude of the interactive effects is greater in cells taken from mice first exposed as juveniles compared to adults. These data indicate that short-term measurements of DNA damage and response to damage are useful for the identification of interactions between ionizing radiation and other agents.
authors.affiliation: Centre for Oncology and Molecular Medicine, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom.
authors.forename: K A
authors.initials: KA
authors.lastname: McAllister
authors.forename: S A
authors.initials: SA
authors.lastname: Lorimore
authors.forename: E G
authors.initials: EG
authors.lastname: Wright
authors.forename: P J
authors.initials: PJ
authors.lastname: Coates
mesh_terms: D000367:Age Factors; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000528:radiation effects*; D024201:Bystander Effect; D002273:Carcinogens / Q000633:toxicity*; D003043:Cocarcinogenesis; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004347:Drug Interactions; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000528:radiation effects; D007249:Inflammation / Q000235:genetics*; D008070:Lipopolysaccharides / Q000633:toxicity; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D008808:Mice, Inbred CBA; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013997:Time Factors; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D002273:Carcinogens; D008070:Lipopolysaccharides; D008770:Methylnitrosourea; D004247:DNA