Academic journal article Environmental Health Perspectives

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

Academic journal article Environmental Health Perspectives

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

Article excerpt

Introduction

Cancer incidence among European children, specifically leukemia, has steadily increased over the last three decades (Kaatsch 2010). In view of the relatively short latent period for leukemia and its very early onset in childhood, it has been suggested that fetal exposure to environmental carcinogens may increase susceptibility to this cancer (Wild and Kleinjans 2003).

The European Union (EU)-funded project Newborns and Genotoxic exposure risks (NewGeneris) was designed to evaluate the hypothesis that maternal intake of dietary and other environmental carcinogens results in in utero exposure and early biological effects in the unborn child, possibly leading to increased risk of cancer in later childhood (Merlo et al. 2009). The primary aim of the present study was to investigate the relationship between biomarkers of exposure to carcinogenic compounds and micronuclei (MN) frequency in umbilical cord blood lymphocytes from the NewGeneris mother-child birth cohort. The secondary aim was to ascertain whether i ndividual genotypes modify these relationships.

An array of exposure biomarkers quantifying a range of potentially carcinogenic exposures, many of dietary origin, were measured in fetal cord blood samples. DNA and hemoglobin (Hb) adducts reflect biologically effective doses of exposure to genotoxic agents (Phillips 2008). The DNA adducts selected for study were 3-(2'-deoxy-[beta]-D-erythro-pentofuranosyl)pyrimido[1,2-[alpha]]purine-10(3H)-one ([M.sub.1]dG), O6-methyldeoxyguanosine ([O.sup.6]-MedG), and bulky DNA adducts. Hb adducts from acrylamide (AA), glycidamide (GA), and ethylene oxide (EtO) [for which data in this cohort have been published before (Pedersen et al. 2012)] were also evaluated, and three versions of the chemically activated luciferase gene expression (CALUX[R]) bioassay were used to assess exposure to androgenic (AR), estrogenic (ER[alpha]), and dioxin-like (DR) compounds.

Facilitated by the development of micro-array technologies, gene expression--based biomarkers have been developed and applied for human biomonitoring purposes (McHale et al. 2011; Rager et al. 2011; Ren et al. 2011; van Leeuwen et al. 2008). Gene expression profiling has the potential to identify new biomarkers of exposure that may simultaneously reflect the earliest biological events in disease pathogenesis. Here, we evaluated the expression of 36 genes that were associated with biomarkers of carcinogen exposure by quantitative real-time polymerase chain reaction (qRT-PCR) (Hochstenbach et al. 2012).

MN frequency was assessed as the primary outcome. MN are a potential biomarker of cancer risk, because increased micronucleated binucleated (MNBN) frequencies in T lymphocytes have been shown to be associated with cancer risk in adults (Bonassi et al. 2007). MN are small extranuclear bodies arising in dividing cells that are caused by chromosomal breakage and/or whole chromosome loss (Fenech 2007; Kirsch-Volders et al. 2011). MNBN provide a measure of the lesions that have recently occurred in vivo, whereas micronucleated mononucleated lymphocytes (MNMONO) give an estimation of the genome damage accumulated over a long period in stem cells and circulating lymphocytes (Kirsch-Volders and Fenech 2001).

Furthermore, we performed a genomewide association study (GWAS) to investigate whether associations between exposure biomarkers and MN are modified by genetic variation.

Materials and Methods

Study population and sample collection. Pregnant women (n = 1,200) were enrolled between 2006 and 2010 in Heraklion, Crete, Greece; Barcelona and Sabadell, Spain; Bradford, England; Copenhagen, Denmark; and Oslo and Akerhus, Norway (Pedersen et al. 2012). The participation of mothers in the study was based on previously described eligibility criteria (Pedersen et al. 2012). Study protocols were approved by local ethics committees, and informed consent was obtained from all participating mothers before sample collection. …

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