Merlo Domenico Franco, Agramunt Silvia, Anna Lívia, Besselink Harrie, Botsivali Maria, Brady Nigel J, Ceppi Marcello, Chatzi Leda, Chen Bowang, Decordier Ilse, Farmer Peter B, Fleming Sarah, Fontana Vincenzo, Försti Asta, Fthenou Eleni, Gallo Fabio, Georgiadis Panagiotis, Gmuender Hans, Godschalk Roger W, Granum Berit, Hardie Laura J, Hemminki Kari, Hochstenbach Kevin, Knudsen Lisbeth E, Kogevinas Manolis, Kovács Katalin, Kyrtopoulos Soterios A, Løvik Martinus, Nielsen Jeanette K, Nygaard Unni Cecilie, Pedersen Marie, Rydberg Per, Schoket Bernadette, Segerbäck Dan, Singh Rajinder, Sunyer Jordi, Törnqvist Margareta, van Loveren Henk, van Schooten Frederik J, Vande Loock Kim, von Stedingk Hans, Wright John, Kleinjans Jos C, Kirsch-Volders Micheline, van Delft Joost H M
Epidemiology, Biostatistics, and Clinical Trials, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera Universitaria (AOU) San Martino-Istituto Nazionale per la Ricerca sul Cancro (IST), Genoa, Italy.
Environ Health Perspect. 2014 Feb;122(2):193-200. doi: 10.1289/ehp.1206324. Epub 2013 Nov 19.
Leukemia incidence has increased in recent decades among European children, suggesting that early-life environmental exposures play an important role in disease development.
We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored.
DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe.
Malondialdehyde DNA adducts (M1dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure-outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M1dG-DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX® (chemically activated luciferase expression for androgens) (8 genes), ERα CALUX® (for estrogens) (2 genes), and DR CALUX® (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity and MNBN frequency. Polymorphisms in EPHX1/2 and CYP2E1 were associated with MNBN.
We measured in utero exposure to selected environmental carcinogens and circulating hormonally acting factors and detected associations with MN frequency in newborns circulating T lymphocytes. The results highlight mechanisms that may contribute to carcinogen-induced leukemia and require further research.
近几十年来，欧洲儿童白血病发病率有所上升，这表明早期环境暴露在疾病发展中起着重要作用。
我们研究了一种假说，即子宫内接触致癌物和激素作用因子可能会增加儿童易感性。利用来自NewGeneris队列的脐带血样本，我们检测了一系列致癌物暴露生物标志物和激素作用因子与微核（MN）频率之间的关联，以此作为癌症风险的替代指标。同时还探讨了与基因表达和基因型的关联。
对2006年至2010年期间在欧洲招募的623名新生儿淋巴细胞中通过MN频率测量的基因组损伤，研究了DNA和蛋白质加合物、基因表达谱、循环激素作用因子以及全基因组关联研究（GWAS）数据。
丙二醛DNA加合物（M1dG）与双核淋巴细胞（MNBN）中MN频率增加有关，而接触雄激素、雌激素和二噁英类化合物与单核淋巴细胞（MNMONO）中MN频率有关，尽管未观察到暴露与结果之间的单调关系。MNBN频率较低与PDCD11、LATS2、TRIM13、CD28、SMC1A、IL7R和NIPBL基因表达增加1个单位有关。分别有5个和6个基因的基因表达与最高和最低类别大体积和M1dG-DNA加合物相比显著更高。与血浆雄激素AR CALUX®（雄激素化学激活荧光素酶表达）最高和最低类别相比，11个基因的基因表达水平显著更低（8个基因），雌激素ERα CALUX®（2个基因）和二噁英DR CALUX®（2个基因）。11号染色体上靠近FOLH1的几个单核苷酸多态性（SNP）显著改变了雄激素活性与MNBN频率之间的关联。EPHX1/2和CYP2E1中的多态性与MNBN有关。
我们测量了子宫内对选定环境致癌物和循环激素作用因子的暴露，并检测到与新生儿循环T淋巴细胞中MN频率的关联。结果突出了可能导致致癌物诱发白血病的机制，需要进一步研究。
