title: Cell type-dependent gene transcription profile in a three-dimensional human skin tissue model exposed to low doses of ionizing radiation: implications for medical exposures.
abstract: The concern over possible health risks from exposures to low doses of ionizing radiation has been driven largely by the increase in medical exposures, the routine implementation of X-ray backscatter devices for airport security screening, and, most recently, the nuclear incident in Japan. Because of a paucity of direct epidemiological data at very low doses, cancer risk must be estimated from high dose exposure scenarios. However, there is increasing evidence that low and high dose exposures result in different signaling events and may have different response mechanisms than higher doses. We have examined the radiation-induced temporal response after exposure to 10 cGy of an in vitro three dimensional (3D) human skin tissue model using microarray-based transcriptional profiling. Cell type-specific analysis showed significant changes in gene expression with the levels of >1,400 genes altered in the dermis and >400 genes regulated in the epidermis. The two cell layers rarely exhibited overlapping responses at the mRNA level. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) measurements validated the microarray data in both regulation direction and value. Key pathways identified relate to cell cycle regulation, immune responses, hypoxia, reactive oxygen signaling, and DNA damage repair. The proliferation status as well as the expression of PCNA was examined in histological samples. We discuss in particular the role of proliferation, emphasizing how the disregulation of cellular signaling in normal tissue may impact progression toward radiation-induced secondary diseases.
authors.affiliation: Department of Systems Toxicology, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.
authors.forename: Claere
authors.initials: C
authors.lastname: von Neubeck
authors.forename: Harish
authors.initials: H
authors.lastname: Shankaran
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Karin
authors.forename: Paula M
authors.initials: PM
authors.lastname: Kauer
authors.forename: William B
authors.initials: WB
authors.lastname: Chrisler
authors.forename: Xihai
authors.initials: X
authors.lastname: Wang
authors.forename: R Joe
authors.initials: RJ
authors.lastname: Robinson
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
authors.forename: Susan C
authors.initials: SC
authors.lastname: Tilton
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Sowa
mesh_terms: D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D004781:Environmental Exposure; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000528:radiation effects*; D006801:Humans; D066298:In Vitro Techniques; D046228:Microarray Analysis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D018809:Proliferating Cell Nuclear Antigen