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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE31836 | GEO | 2012/06/27

SECONDARY ACCESSION(S): PRJNA145113

REPOSITORIES: GEO

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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:Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Methylated sperm DNA was isolated from rats ancestrally exposed to methoxychlor. Three independent samples from each treatment group were obtained. Differential DNA methylation between treatment groups was determined using Nimblegen microarrays. Treated samples were paired with control samples and hybridized together on arrays, resulting in three arrays for the treatment.

Project description:Acrylamide is a type-2 alkene monomer with established human neurotoxic effects. While the primary source of human exposure to acrylamide is occupational, other exposure sources include food, drinking water, and smoking. In this study, neurobehavioral assays coupled with transcriptional profiling analysis were conducted to assess both behavioral and gene expression effects induced by acrylamide neurotoxicity in rats when administered during early postnatal life. Acrylamide administration in rat pups induced significant characteristic neurotoxic symptoms including increased heel splay, decrease in grip strength, and decrease in locomotor activity. Transcriptome analysis with the Affymetrix Rat Genome 230 2.0 array indicated that acrylamide treatment caused a significant alteration in the expression of genes involved in muscle contraction, pain regulation, and dopaminergic neuronal pathways. First, in agreement with the observed behavioral effects, expression of the Mylpf gene involved in muscle contraction was downregulated in the spinal cord in response to acrylamide. Second, in sciatic nerves, acrylamide repressed the expression of the opioid receptor gene Oprk1 that is known to play a role in neuropathic pain regulation. Finally, in the cerebellum, acrylamide treatment caused a decrease in the expression of the nuclear receptor gene Nr4a2 that is required for development of dopaminergic neurons. Thus, our work examining the effect of acrylamide at the whole-genome level on a developmental mammalian model has identified novel genes previously not implicated in acrylamide neurotoxicity that can be further developed into biomarkers for assessing the risk of acrylamide exposure. Three-week-old male Wistar rat pups were treated with either acrylamide or saline daily (30 mg/kg) for 21 days, then tissues (cerebellum, spinal cord, and sciatic nerve) were harvested and frozen. Two biological replicate samples, each sample consisting of pooled tissue from 2 rats, were analyzed for each treatment.

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

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