title: Global gene expression analysis in cord blood reveals gender-specific differences in response to carcinogenic exposure in utero.
abstract: BACKGROUND
  It has been suggested that fetal carcinogenic exposure might lead to predisposition to develop cancer during childhood or in later life possibly through modulation of the fetal transcriptome. Because gender effects in the incidence of childhood cancers have been described, we hypothesized differences at the transcriptomic level in cord blood between male and female newborns as a consequence of fetal carcinogenic exposure. The objective was to investigate whether transcriptomic responses to dietary genotoxic and nongenotoxic carcinogens show gender-specific mechanisms-of-action relevant for chemical carcinogenesis.
  
  
  METHODS
  Global gene expression was applied in umbilical cord blood samples, the CALUX-assay was used for measuring dioxin(-like), androgen(-like), and estrogen(-like) internal exposure, and acrylamide-hemoglobin adduct levels were determined by mass spectrometry adduct-FIRE-procedure(TM). To link gene expression to an established phenotypic biomarker of cancer risk, micronuclei frequencies were investigated.
  
  
  RESULTS
  While exposure levels did not differ between sexes at birth, important gender-specific differences were observed in gene expressions associated with these exposures linked with cell cycle, the immune system and more general cellular processes such as posttranslation. Moreover, oppositely correlating leukemia/lymphoma genes between male and female newborns were identified in relation to the different biomarkers of exposure that might be relevant to male-specific predisposition to develop these cancers in childhood. CONCLUSIONS/IMPACT: This study reveals different transcriptomic responses to environmental carcinogens between the sexes. In particular, male-specific TNF-alpha-NF-kB signaling upon dioxin exposure and activation of the Wnt-pathway in boys upon acrylamide exposure might represent possible mechanistic explanations for gender specificity in the incidence of childhood leukemia.
authors.affiliation: Department of Toxicogenomics, Maastricht University, 6200 MD, Maastricht, The Netherlands.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hochstenbach
authors.forename: Danitsja M
authors.initials: DM
authors.lastname: van Leeuwen
authors.forename: Hans
authors.initials: H
authors.lastname: Gmuender
authors.forename: Ralf W
authors.initials: RW
authors.lastname: Gottschalk
authors.forename: Martinus
authors.initials: M
authors.lastname: Løvik
authors.forename: Berit
authors.initials: B
authors.lastname: Granum
authors.forename: Unni
authors.initials: U
authors.lastname: Nygaard
authors.forename: Ellen
authors.initials: E
authors.lastname: Namork
authors.forename: Micheline
authors.initials: M
authors.lastname: Kirsch-Volders
authors.forename: Ilse
authors.initials: I
authors.lastname: Decordier
authors.forename: Kim
authors.initials: K
authors.lastname: Vande Loock
authors.forename: Harrie
authors.initials: H
authors.lastname: Besselink
authors.forename: Margareta
authors.initials: M
authors.lastname: Törnqvist
authors.forename: Hans
authors.initials: H
authors.lastname: von Stedingk
authors.forename: Per
authors.initials: P
authors.lastname: Rydberg
authors.forename: Jos C S
authors.initials: JC
authors.lastname: Kleinjans
authors.forename: Henk
authors.initials: H
authors.lastname: van Loveren
authors.forename: Joost H M
authors.initials: JH
authors.lastname: van Delft
mesh_terms: D020106:Acrylamide / Q000378:metabolism; D000328:Adult; D015415:Biomarkers; D002273:Carcinogens / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D005333:Fetus / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000706:statistics & numerical data; D011247:Pregnancy; D011944:Receptors, Androgen / Q000235:genetics; D012727:Sex Characteristics; D015398:Signal Transduction
chemical_list: C410798:AR protein, human; D015415:Biomarkers; D002273:Carcinogens; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D011944:Receptors, Androgen; D020106:Acrylamide