Micronuclei in Cord Blood Lymphocytes and Associations with Biomarkers of Exposure to Carcinogens and Hormonally Active Factors, Gene Polymorphisms, and Gene Expression: The NewGeneris Cohort
Background: Leukemia incidence has increased in recent decades among European children, suggesting that early-life environmental exposures play an important role in disease development.
Objectives: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
1Epidemiology, 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; 2Hospital del Mar Medical Research Institute, Barcelona, Spain; 3Molecular and Environmental Epidemiology, National Institute of Environmental Health, Budapest, Hungary; 4BioDetection Systems b.v., Amsterdam, the Netherlands; 5National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece; 6Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom; 7Department of Social Medicine, University of Crete, Heraklion, Crete, Greece; 8Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany; 9Laboratory of Cell Genetics, Faculty of Science and Bio-engineering, Vrije Universiteit Brussel, Brussels, Belgium; 10Division of Biostatistics, Leeds Institute for Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom; 11Center for Primary Health Care Research, Lund University, Malmö, Sweden; 12Genedata AG, Basel, Switzerland; 13Department of Toxicology and Toxicogenomics, Maastricht University, Maastricht, the Netherlands; 14Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway; 15Department of Public Health, University of Copenhagen, Copenhagen, Denmark; 16Centre for Research in Environmental Epidemiology, Barcelona, Spain; 17CIBER Epidemiología y Salud Pública, Barcelona, Spain; 18National School of Public Health, Athens, Greece; 19Environmental Chemistry Unit, Department of Materials and Environmental Chemistry, Stockholm University, Stockholm, Sweden; 20Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden; 21Laboratory for Health Protection Research, National Institute of Public Health and the Environment, Bilthoven, the Netherlands
Recommended Citation:
Domenico Franco Merlo,1 Silvia Agramunt,2 Lívia Anna,et al. Micronuclei in Cord Blood Lymphocytes and Associations with Biomarkers of Exposure to Carcinogens and Hormonally Active Factors, Gene Polymorphisms, and Gene Expression: The NewGeneris Cohort[J]. Environmental Health Perspectives,2014-01-01,Volume 122(Issue 2):193