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Global gene expression analysis in cord blood reveals gender-specific differences in response to carcinogenic exposure in utero

ABSTRACT: Gender effects in the incidence of childhood cancers have been described but the aetiology still needs to be fully examined. Given the latent period of e.g. leukemia, its very early onset in childhood might indicate the foetal period as a critical period. We consequently hypothesize that gender-specific differences in childhood cancer incidence (males have a much higher incidence of leukaemia and lymphomas) may be due to gender-specific responses to exposure to environmental carcinogens in utero. We considered that whole genome transcriptomics analysis in cord blood may provide mechanistic insight into possible gender-specific effects of carcinogen exposure in utero. Thus, the objective of the current study was to investigate whether transcriptomic responses to dietary genotoxic and non-genotoxic carcinogens (i.e. acrylamide and endocrine disruptors) as analyzed in umbilical cord blood samples, demonstrate gender-specific mechanisms-of-action relevant for chemical carcinogenesis. For internal exposure assessment, the CALUX® assay was applied for measuring dioxin(-like), androgen(-like) and estrogen(-like) exposure, and acrylamide-hemoglobin adduct levels were determined by mass spectrometry. To link gene expression to an established phenotypic biomarker of cancer risk, micronuclei frequencies were investigated in T-lymphocytes. While exposure levels did not differ significantly between sexes at birth, important gender-specific differences were observed in gene expressions associated with these exposures. These genes appeared linked with cell cycle-related processes and general cellular processes such as (post) translation, as well as with immune-related pathways. Moreover, oppositely correlating leukemia and lymphoma genes between male and female newborns were identified in relation to the different biomarkers of exposure which might be relevant to male-specific predisposition to develop these cancers in childhood. 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 the male predominance in the incidence of childhood leukemia. Umbilical cord blood samples were collected immediately after birth from the cord vein of 45 male and 66 female babies whose mothers participated in the Norwegian BraMat cohort. For analyses, each individual cord blood sample was labelled by means of Cyanine-5 and competitively hybridized against a common reference sample (pooled RNA cord blood samples, labelled with Cyanine-3) onto Agilent 4x44k human oligonucleotide microarrays (Agilent Technologies, Palo Alto, CA, USA) according to the manufacturer’s instructions.

ORGANISM(S): Homo sapiens  

SUBMITTER: Danitsja M van Leeuwen   Harrie Besselink  Ellen Namork  Hans Gmuender  Jos C Kleinjans  Hans von Stedingk  Joost H van Delft  Ilse Decordier  Per Rydberg  Unni C Nygaard  Berit Granum  Kim Vande Loock  Kevin Hochstenbach  Margerata Törnqvist  Ralph R Gottschalk  Micheline Kirsch-Volders  Martinus LÃ vik  Henk van Loveren 

PROVIDER: E-GEOD-31836 | ArrayExpress | 2012-06-26



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