title: 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.
abstract: BACKGROUND
  Leukemia incidence has increased in recent decades among European children, suggesting that early-life environmental exposures play an important role in disease development.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Domenico Franco
authors.initials: DF
authors.lastname: Merlo
authors.forename: Silvia
authors.initials: S
authors.lastname: Agramunt
authors.forename: Lívia
authors.initials: L
authors.lastname: Anna
authors.forename: Harrie
authors.initials: H
authors.lastname: Besselink
authors.forename: Maria
authors.initials: M
authors.lastname: Botsivali
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Brady
authors.forename: Marcello
authors.initials: M
authors.lastname: Ceppi
authors.forename: Leda
authors.initials: L
authors.lastname: Chatzi
authors.forename: Bowang
authors.initials: B
authors.lastname: Chen
authors.forename: Ilse
authors.initials: I
authors.lastname: Decordier
authors.forename: Peter B
authors.initials: PB
authors.lastname: Farmer
authors.forename: Sarah
authors.initials: S
authors.lastname: Fleming
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Fontana
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.forename: Eleni
authors.initials: E
authors.lastname: Fthenou
authors.forename: Fabio
authors.initials: F
authors.lastname: Gallo
authors.forename: Panagiotis
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authors.lastname: Georgiadis
authors.forename: Hans
authors.initials: H
authors.lastname: Gmuender
authors.forename: Roger W
authors.initials: RW
authors.lastname: Godschalk
authors.forename: Berit
authors.initials: B
authors.lastname: Granum
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Hardie
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Kevin
authors.initials: K
authors.lastname: Hochstenbach
authors.forename: Lisbeth E
authors.initials: LE
authors.lastname: Knudsen
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Katalin
authors.initials: K
authors.lastname: Kovács
authors.forename: Soterios A
authors.initials: SA
authors.lastname: Kyrtopoulos
authors.forename: Martinus
authors.initials: M
authors.lastname: Løvik
authors.forename: Jeanette K
authors.initials: JK
authors.lastname: Nielsen
authors.forename: Unni Cecilie
authors.initials: UC
authors.lastname: Nygaard
authors.forename: Marie
authors.initials: M
authors.lastname: Pedersen
authors.forename: Per
authors.initials: P
authors.lastname: Rydberg
authors.forename: Bernadette
authors.initials: B
authors.lastname: Schoket
authors.forename: Dan
authors.initials: D
authors.lastname: Segerbäck
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.forename: Jordi
authors.initials: J
authors.lastname: Sunyer
authors.forename: Margareta
authors.initials: M
authors.lastname: Törnqvist
authors.forename: Henk
authors.initials: H
authors.lastname: van Loveren
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: van Schooten
authors.forename: Kim
authors.initials: K
authors.lastname: Vande Loock
authors.forename: Hans
authors.initials: H
authors.lastname: von Stedingk
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: Jos C
authors.initials: JC
authors.lastname: Kleinjans
authors.forename: Micheline
authors.initials: M
authors.lastname: Kirsch-Volders
authors.forename: Joost H M
authors.initials: JH
authors.lastname: van Delft
mesh_terms: D015415:Biomarkers / Q000032:analysis*; D002273:Carcinogens / Q000032:analysis* / Q000633:toxicity; D002648:Child; D015331:Cohort Studies; D018736:DNA Adducts / Q000009:adverse effects / Q000032:analysis; D005060:Europe / Q000453:epidemiology; D005260:Female; D005312:Fetal Blood / Q000737:chemistry / Q000166:cytology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D006728:Hormones / Q000009:adverse effects / Q000032:analysis*; D006801:Humans; D007938:Leukemia / Q000139:chemically induced / Q000453:epidemiology*; D008315:Malondialdehyde / Q000009:adverse effects / Q000032:analysis; D015162:Micronucleus Tests; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000453:epidemiology*; D013601:T-Lymphocytes / Q000737:chemistry* / Q000187:drug effects
chemical_list: D015415:Biomarkers; D002273:Carcinogens; D018736:DNA Adducts; D006728:Hormones; D008315:Malondialdehyde