Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, PO Box 616, 6200 MD Maastricht, The Netherlands.
Mutagenesis. 2011 Nov;26(6):753-61. doi: 10.1093/mutage/ger043. Epub 2011 Jul 1.
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.
亚硝胺化合物（NOCs）被怀疑是人类致癌物，与人类暴露有关。NOCs 也会在体内诱导微核（MN）的形成。由于淋巴细胞 MN 代表了人类癌症风险的验证生物标志物，因此在人类中建立 NOC 暴露与 MN 频率之间的联系，并同时调查相关的转录组反应，可能为易患致癌性的潜在分子机制提供关键信息。我们使用来自参加泛欧生物标志物研究项目 NewGeneris 的成年女性的淋巴细胞作为替代组织，分析潜在致癌基因表达和 MN 形成事件在靶器官中的发生情况。为了评估 NOC 暴露情况，对尿液样本进行了亚硝胺标记物分析。随后，将 NOC 排泄水平和 MN 频率与外周血转录组学联系起来。我们证明了 MN 频率与尿 NOC 之间存在显著相关性（r = 0.41，P = 0.025），并确定了细胞骨架重塑、细胞周期、细胞凋亡和存活、信号转导、免疫反应、G 蛋白信号和发育途径等方面的修饰，这表明对 NOC 诱导的遗传毒性有反应。此外，我们建立了一个基因网络，其中最重要的基因包括 FBXW7、BUB3、Caspase 2、Caspase 8、SMAD3、Huntingtin 和 MGMT，它们涉及到致癌过程中的相关过程。本研究中发现的修饰遗传过程和基因可能是未来研究 NOC 暴露与人类潜在致癌风险相关的重要内容。
