title: Distinct genotype-dependent differences in transcriptome responses in humans exposed to environmental carcinogens.
abstract: Considering genetic variability in population studies focusing on the health risk assessment of exposure to environmental carcinogens may provide improved insights in individual environmental cancer risks. Therefore, the current study aims to determine the impact of genetic polymorphisms on the relationship between exposure and gene expression, by identifying exposure-dependently coregulated genes and genetic pathways. Statistical analysis based on mixed models, was performed to relate gene expression data from 134 subjects to exposure measurements of multiple carcinogens, 28 polymorphisms, age, sex and biomarkers of cancer risk. We evaluated the combined exposure to cadmium, lead, polychlorinated biphenyls, p,p'-dichlorodiphenyldichloroethylene, hexachlorobenzene and 1-OH-pyrene, and the outcome was biologically interpreted by using ConsensusPathDB, thereby focusing on carcinogenesis-related pathways. We found generic and carcinogenesis-related pathways deregulated in both sexes, but males showed a stronger transcriptome response than females. We highlighted NOTCH1, CBR1, ITGB3, ITGA4, ADI1, HES1, NCOA2 and SMARCA2 in view of their direct link with cancer development. Two of these, NOTCH1 and ITGB3, are also known to respond to PCBs and cadmium chloride exposure in rodents and to lead in humans. Subjects carrying a high number of risk alleles appear more responsive to combined carcinogen exposure with respect to the induced expression of some of these cancer-related genes, which may be indicative of increased cancer risk as a consequence of environmental factors.
authors.forename: Almudena
authors.initials: A
authors.lastname: Espín-Pérez
authors.forename: Theo M C M
authors.initials: TM
authors.lastname: de Kok
authors.forename: Danyel G J
authors.initials: DG
authors.lastname: Jennen
authors.forename: Diana M
authors.initials: DM
authors.lastname: Hendrickx
authors.affiliation: Department of Public Health, Ghent University, 9000 Ghent, Belgium.
authors.forename: Sam
authors.initials: S
authors.lastname: De Coster
authors.affiliation: Environmental Health and Risk, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium and.
authors.forename: Greet
authors.initials: G
authors.lastname: Schoeters
authors.affiliation: Department of Analytical and Environmental Chemistry (ANCH), 1050 Free University of Brussels (VUB), Brussels, Belgium.
authors.forename: Willy
authors.initials: W
authors.lastname: Baeyens
authors.affiliation: Department of Public Health, Ghent University, 9000 Ghent, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: van Larebeke
authors.forename: Jos C S
authors.initials: JC
authors.lastname: Kleinjans
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002274:Carcinogens, Environmental / Q000633:toxicity*; D004781:Environmental Exposure; D004784:Environmental Monitoring; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D018570:Risk Assessment; D059467:Transcriptome / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D002274:Carcinogens, Environmental; D009363:Neoplasm Proteins; D011078:Polychlorinated Biphenyls