Project description: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 CALUXM-BM-. 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 manufacturerM-bM-^@M-^Ys instructions.

Project description: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.

Project description:The prevalence of immune-mediated diseases such as allergies and autoimmune diseases is on the rise in the developed world. Microbial exposure is known to modulate the risk for these diseases. In order to explore differences in the gene expression patterns induced in utero in infants born in contrasting standards of living and hygiene, we collected umbilical cord blood RNA samples from full-term newborn infants born with normal vaginal delivery in Finland (modern society), Estonia (rapidly developing society) and the Republic of Karelia, Russia (poor economical conditions). Transcriptomic profiles were analyzed using whole genome microarrays including gender, gestational age, birth month and HLA allele genotype as confounding variables in the analysis. The data revealed that the whole blood transcriptome of Finnish and Estonian neonates differ from their Karelian counterparts. Samples from Karelian infants had an increase in transcripts associated with LPS induction and bacterial sepsis observed in 1-year-old infants in earlier studies. The results suggest exposure to toll like receptor (TLR) ligands and a more matured immune response in infants born in Petrozavodsk compared to the Finnish and Estonian infants. These results further support the concept of a conspicuous plasticity in the developing immune system: the environmental factors that play a role in the susceptibility/protection towards immune-mediated diseases begin to shape the neonatal immunity already in utero and direct the maturation of both the adaptive and the innate immune responses in accordance with the surrounding microbial milieu. Umbilical cord blood was drawn into Tempus Blood RNA tubes (Applied Biosystems) from children born between January and May 2010 at the maternity unit of Jorvi hospital (Espoo, Finland; n=48), maternity units of Tartu and PM-CM-5lva (Estonia; n=25), or two maternity departments in Petrozavodsk (capital of the Republic of Karelia, Russian Federation; n=40) according to the manufacturerM-BM-4s protocol and then stored in M-bM-^HM-^R70 M-BM-0C until analyzed. All newborn infants were full-term (>36 gestational weeks) and born vaginally. 113 cord blood RNA samples were analyzed with Affymetrix U219 gene array. Gender, pregnancy week, month of birth and HLA risk class were included as confounding factors in the analysis model.

Project description:The prevalence of immune-mediated diseases such as allergies and autoimmune diseases is on the rise in the developed world. Microbial exposure is known to modulate the risk for these diseases. In order to explore differences in the gene expression patterns induced in utero in infants born in contrasting standards of living and hygiene, we collected umbilical cord blood RNA samples from full-term newborn infants born with normal vaginal delivery in Finland (modern society), Estonia (rapidly developing society) and the Republic of Karelia, Russia (poor economical conditions). Transcriptomic profiles were analyzed using whole genome microarrays including gender, gestational age, birth month and HLA allele genotype as confounding variables in the analysis. The data revealed that the whole blood transcriptome of Finnish and Estonian neonates differ from their Karelian counterparts. Samples from Karelian infants had an increase in transcripts associated with LPS induction and bacterial sepsis observed in 1-year-old infants in earlier studies. The results suggest exposure to toll like receptor (TLR) ligands and a more matured immune response in infants born in Petrozavodsk compared to the Finnish and Estonian infants. These results further support the concept of a conspicuous plasticity in the developing immune system: the environmental factors that play a role in the susceptibility/protection towards immune-mediated diseases begin to shape the neonatal immunity already in utero and direct the maturation of both the adaptive and the innate immune responses in accordance with the surrounding microbial milieu. These 15 rehybridized samples were only utilized in the batch correction and excluded from any further analysis steps. Umbilical cord blood was drawn into Tempus Blood RNA tubes (Applied Biosystems) from children born at the maternity unit of Jorvi hospital (Espoo, Finland; n=4), maternity units of Tartu and PM-CM-5lva (Estonia; n=4), or two maternity departments in Petrozavodsk (capital of the Republic of Karelia, Russian Federation; n=7) according to the manufacturerM-BM-4s protocol and then stored in -70 M-BM-0C until analyzed.

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