title: Whole-genome gene expression modifications associated with nitrosamine exposure and micronucleus frequency in human blood cells.
abstract: N-nitroso compounds (NOCs) are suspected human carcinogens and relevant in human exposure. NOCs also induce micronuclei (MN) formation in vivo. Since lymphocytic MN represent a validated biomarker of human cancer risk, establishing a link between NOC exposure and MN frequency in humans and concurrently investigating associated transcriptomic responses may provide crucial information on underlying molecular mechanisms that predispose to carcinogenicity. We used lymphocytes, from adult females participating in the pan-European biomarker research project NewGeneris, as a surrogate tissue for analysing such potentially carcinogenic gene expression and MN formation events in target organs. To assess NOC exposure, urine samples were analysed for marker nitrosamines. NOC excretion levels and MN frequency were subsequently linked to peripheral blood transcriptomics. We demonstrated a significant association between MN frequency and urinary NOCs (r = 0.41, P = 0.025) and identified modifications in among others cytoskeleton remodeling, cell cycle, apoptosis and survival, signal transduction, immune response, G-protein signaling and development pathways, which indicate a response to NOC-induced genotoxicity. Moreover, we established a network of genes, the most important ones of which include FBXW7, BUB3, Caspase 2, Caspase 8, SMAD3, Huntingtin and MGMT, which are involved in processes relevant in carcinogenesis. The modified genetic processes and genes found in this study may be of interest for future investigations into the potential carcinogenic risk associated with NOC exposure in humans.
authors: Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, PO Box 616, 6200 MD Maastricht, The Netherlands. d.hebels@maastrichtuniversity.nl
authors: Dennie G A J
authors: DG
authors: Hebels
authors: Danyel G J
authors: DG
authors: Jennen
authors: Marcel H M
authors: MH
authors: van Herwijnen
authors: Edwin J C
authors: EJ
authors: Moonen
authors: Marie
authors: M
authors: Pedersen
authors: Lisbeth E
authors: LE
authors: Knudsen
authors: Jos C S
authors: JC
authors: Kleinjans
authors: Theo M C M
authors: TM
authors: de Kok
mesh_terms: D000328:Adult; D001773:Blood Cells / Q000378:metabolism*; D004781:Environmental Exposure / Q000032:analysis*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D015162:Micronucleus Tests; D009602:Nitrosamines / Q000009:adverse effects* / Q000652:urine; D015398:Signal Transduction / Q000235:genetics
chemical_list: D009602:Nitrosamines