title: Dose- and time-dependent changes of micronucleus frequency and gene expression in the progeny of irradiated cells: two components in radiation-induced genomic instability?
abstract: Murine embryonic C3H/10T½ fibroblasts were exposed to X-rays at doses of 0.2, 0.5, 1, 2 or 5 Gy. To follow the development of radiation-induced genomic instability (RIGI), the frequency of micronuclei was measured with flow cytometry at 2 days after exposure and in the progeny of the irradiated cells at 8 and 15 days after exposure. Gene expression was measured at the same points in time by PCR arrays profiling the expression of 84 cancer-relevant genes. The micronucleus results showed a gradual decrease in the slope of the dose-response curve between days 2 and 15. The data were consistent with a model assuming two components in RIGI. The first component is characterized by dose-dependent increase in micronuclei. It may persist more than ten cell generations depending on dose, but eventually disappears. The second component is more persistent and independent of dose above a threshold higher than 0.2 Gy. Gene expression analysis 2 days after irradiation at 5 Gy showed consistent changes in genes that typically respond to DNA damage. However, the consistency of changes decreased with time, suggesting that non-specificity and increased heterogeneity of gene expression are characteristic to the second, more persistent component of RIGI.
authors.affiliation: University of Eastern Finland, Department of Environmental Science, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Katriina
authors.initials: K
authors.lastname: Huumonen
authors.affiliation: National Institute for Health and Welfare, Department of Environmental Health, P.O. Box 95, 70701 Kuopio, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Korkalainen
authors.affiliation: Kuopio University Hospital, Cancer Center, P.O. Box 1777, 70211 Kuopio, Finland.
authors.forename: Eeva
authors.initials: E
authors.lastname: Boman
authors.affiliation: Kuopio University Hospital, Cancer Center, P.O. Box 1777, 70211 Kuopio, Finland.
authors.forename: Janne
authors.initials: J
authors.lastname: Heikkilä
authors.affiliation: University of Eastern Finland, Department of Environmental Science, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Höytö
authors.affiliation: Kuopio University Hospital, Cancer Center, P.O. Box 1777, 70211 Kuopio, Finland.
authors.forename: Tapani
authors.initials: T
authors.lastname: Lahtinen
authors.affiliation: University of Eastern Finland, Department of Environmental Science, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Luukkonen
authors.affiliation: National Institute for Health and Welfare, Department of Environmental Health, P.O. Box 95, 70701 Kuopio, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Viluksela
authors.affiliation: University of Eastern Finland, Department of Environmental Science, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Jonne
authors.initials: J
authors.lastname: Naarala
authors.affiliation: University of Eastern Finland, Department of Environmental Science, P.O. Box 1627, 70211 Kuopio, Finland. Electronic address: jukka.juutilainen@uef.fi.
authors.forename: Jukka
authors.initials: J
authors.lastname: Juutilainen
mesh_terms: D000818:Animals; D002460:Cell Line; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000528:radiation effects*; D042822:Genomic Instability / Q000187:drug effects*; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000528:radiation effects*; D013997:Time Factors; D014965:X-Rays / Q000009:adverse effects
keywords: Delayed effects; Dose–response; Radiation-induced genomic instability; X-rays