TY - JOUR

T1 - Whole-genome gene expression modifications associated with nitrosamine exposure and micronucleus frequency in human blood cells

AU - Hebels, Dennie G A J

AU - Jennen, Danyel G J

AU - van Herwijnen, Marcel H M

AU - Moonen, Edwin J C

AU - Pedersen, Marie

AU - Knudsen, Lisbeth E

AU - Kleinjans, Jos C S

AU - de Kok, Theo M C M

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

U2 - 10.1093/mutage/ger043

DO - 10.1093/mutage/ger043

M3 - Journal article

C2 - 21724973

VL - 26

SP - 753

EP - 761

JO - Mutagenesis

JF - Mutagenesis

SN - 0267-8357

IS - 6

ER -