Formaldehyde-induced changes in microRNA signaling [Affymetrix]
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ABSTRACT:
SUBMITTER: Rebecca Fry
PROVIDER: E-GEOD-42394 | BioStudies | 2014-01-07
SECONDARY ACCESSION(S): GSE42394
REPOSITORIES: biostudies
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Project description:In addition to gaining knowledge on in vivo miRNA responses to formaldehyde, we set out to relate these miRNA responses to transcriptional profiles modified by formaldehyde. Rats were exposed by inhalation to either 0 or 2 ppm formaldehyde (6 hours/day) for 28 days. Genome-wide transcriptional profiles and associated signaling pathways were assessed within the nasal respiratory mucosa and circulating mononuclear white blood cells (WBC). Male Fischer rats received nose-only inhalation exposures of 2 ppm formaldehyde for 7 days or 28 days (6 hours/day). Control (unexposed) rats were placed in nose-only exposure tubes containing room air for the same duration. After the last exposure period, animals were euthanized. RNA were assessed from sampes collected from the nasal epithelium and circulating white blood cells. Genome-wide mRNA expression profiles were evaluated using microarrays.
2014-01-07 | E-GEOD-42394 | ArrayExpress
Project description:MicroRNAs (miRNAs) are critical regulators of gene expression, yet much remains unknown regarding miRNA changes resulting from environmental exposures and whether they influence pathway signaling across various tissues and time. To gain knowledge on these novel topics, we set out to investigate in vivo miRNA responses to inhaled formaldehyde, an important air pollutant known to disrupt miRNA expression profiles. Rats were exposed by inhalation to either 0 or 2 ppm formaldehyde (6 hours/day) for 7 days, 28 days, or 28 days followed by a 7 day recovery. Genome-wide miRNA expression profiles and associated signaling pathways were assessed within the nasal respiratory mucosa, circulating mononuclear white blood cells (WBC), and bone marrow (BM). Overall design: Male Fischer rats received nose-only inhalation exposures of 2 ppm formaldehyde. Three exposure durations were investigated: (1) 2 ppm formaldehyde exposure, 6 hours/day, for 7 days (7-day group), (2) 2 ppm formaldehyde exposure, 6 hours/day, for 28 days (28-day group), and (3) 2 ppm formaldehyde exposure, 6 hours/day, for 28 days, with a 7 day recovery period following the last exposure (28-day plus recovery group). Control (unexposed) rats were placed in nose-only exposure tubes containing room air for the same duration. After the last exposure period (or the last recovery period for the 28-day plus recovery group), animals were euthanized. RNA were assessed from sampes collected from the nasal epithelium, circulating white blood cells, and bone marrow cells. Genome-wide miRNA expression profiles were evaluated using microarrays.
| GSE42393 | GEO
Project description:MicroRNAs (miRNAs) are critical regulators of gene expression, yet much remains unknown regarding their changes resulting from environmental exposures as they influence cellular signaling across various tissues. We set out to investigate miRNA responses to formaldehyde, a critical air pollutant and known carcinogen that disrupts miRNA expression profiles. Rats were exposed by inhalation to either 0 or 2 ppm formaldehyde for 7, 28, or 28 days followed by a 7-day recovery. Genome-wide miRNA expression profiles were assessed within the nasal respiratory epithelium, circulating white blood cells (WBC), and bone marrow (BM). miRNAs showed altered expression in the nose and WBC but not in the BM. Notably in the nose, miR-10b and members of the let-7 family, known nasopharyngeal carcinoma players, showed decreased expression. To integrate miRNA responses with transcriptional changes, genome-wide messenger RNA profiles were assessed in the nose and WBC. Although formaldehyde-induced changes in miRNA and transcript expression were largely tissue specific, pathway analyses revealed an enrichment of immune system/inflammation signaling in the nose and WBC. Specific to the nose was enrichment for apoptosis/proliferation signaling, involving let-7a, let-7c, and let-7f. Across all tissues and time points assessed, miRNAs were predicted to regulate between 7% and 35% of the transcriptional responses and were suggested to play a role in signaling processes including immune/inflammation-related pathways. These data inform our current hypothesis that formaldehyde-induced inflammatory signals originating in the nose may drive WBC effects.
2014-01-01 | S-EPMC3930361 | BioStudies
Project description:MicroRNAs (miRNAs) are critical regulators of gene expression, yet much remains unknown regarding miRNA changes resulting from environmental exposures and whether they influence pathway signaling across various tissues and time. To gain knowledge on these novel topics, we set out to investigate in vivo miRNA responses to inhaled formaldehyde, an important air pollutant known to disrupt miRNA expression profiles. Rats were exposed by inhalation to either 0 or 2 ppm formaldehyde (6 hours/day) for 7 days, 28 days, or 28 days followed by a 7 day recovery. Genome-wide miRNA expression profiles and associated signaling pathways were assessed within the nasal respiratory mucosa, circulating mononuclear white blood cells (WBC), and bone marrow (BM). Male Fischer rats received nose-only inhalation exposures of 2 ppm formaldehyde. Three exposure durations were investigated: (1) 2 ppm formaldehyde exposure, 6 hours/day, for 7 days (7-day group), (2) 2 ppm formaldehyde exposure, 6 hours/day, for 28 days (28-day group), and (3) 2 ppm formaldehyde exposure, 6 hours/day, for 28 days, with a 7 day recovery period following the last exposure (28-day plus recovery group). Control (unexposed) rats were placed in nose-only exposure tubes containing room air for the same duration. After the last exposure period (or the last recovery period for the 28-day plus recovery group), animals were euthanized. RNA were assessed from sampes collected from the nasal epithelium, circulating white blood cells, and bone marrow cells. Genome-wide miRNA expression profiles were evaluated using microarrays.
2014-01-07 | E-GEOD-42393 | ArrayExpress
Project description:Formaldehyde is an air pollutant present in both indoor and outdoor atmospheres. Because of its ubiquitous nature, it is imperative to understand the mechanisms underlying formaldehyde-induced toxicity and carcinogenicity. MicroRNAs (miRNAs) can influence disease caused by environmental exposures, yet miRNAs are understudied in relation to formaldehyde. Our previous investigation demonstrated that formaldehyde exposure in human lung cells caused disruptions in miRNA expression profiles in vitro.Using an in vivo model, we set out to test the hypothesis that formaldehyde inhalation exposure significantly alters miRNA expression profiles within the nasal epithelium of nonhuman primates.Cynomolgus macaques were exposed by inhalation to approximately 0, 2, or 6 ppm formaldehyde for 6 hr/day for 2 consecutive days. Small RNAs were extracted from nasal samples and assessed for genome-wide miRNA expression levels. Transcriptional targets of formaldehyde-altered miRNAs were computationally predicted, analyzed at the systems level, and assessed using real-time reverse transcriptase polymerase chain reaction (RT-PCR).Expression analysis revealed that 3 and 13 miRNAs were dysregulated in response to 2 and 6 ppm formaldehyde, respectively. Transcriptional targets of the miRNA with the greatest increase (miR-125b) and decrease (miR-142-3p) in expression were predicted and analyzed at the systems level. Enrichment was identified for miR-125b targeting genes involved in apoptosis signaling. The apoptosis-related targets were functionally tested using RT-PCR, where all targets showed decreased expression in formaldehyde-exposed samples.Formaldehyde exposure significantly disrupts miRNA expression profiles within the nasal epithelium, and these alterations likely influence apoptosis signaling.
2013-01-01 | S-EPMC3621188 | BioStudies
Project description:We set out to test the hypothesis that formaldehyde inhalation exposure significantly alters miRNA expression profiles within the nasal epithelium of nonhuman primates. Here, cynomolgus macaques were exposed to 0, 2, and 6 ppm formaldehyde for 6 hours/day across two consecutive days. RNA was extracted from the nasal maxilloturbinate region, a direct target of formaldehyde inhalation exposure. Genome-wide miRNA expression levels were assessed using microarrays. Cynomolgus macaques (Macaca fascicularis) were exposed to 0, 2 and 6 ppm formaldehyde for 6 hours/day across two consecutive days using whole body exposure chambers. RNA was extracted from the nasal maxilloturbinate region, a direct target of formaldehyde inhalation exposure. Genome-wide miRNA expression levels were assessed using microarrays.
2012-09-01 | E-GEOD-34978 | ArrayExpress
Project description:Formaldehyde, an important industrial chemical, is used for multiple commercial purposes throughout the industrialized world. This simple, one carbon aldehyde is a natural metabolite formed in cells throughput the body. However, it is also a rodent nasal carcinogen, when inhaled by rats every day for two-years at irritant concentrations. High tumor incidences occur at concentration of 10 ppm and above; no tumors are observed at concentrations below 6.0 ppm. The US Environmental Protection Agency (US EPA) is now (2007) conducting a risk assessment to try to evaluate possible cancer risks for much lower levels of human exposure. Sensitive methods are needed to evaluate tissue responses below those concentrations that are clearly irritant or carcinogenic. This microarray study was undertaken to evaluate the mode of action for nasal responses to inhaled formaldehyde in Fisher 344 rats over a range of exposure concentrations. The range of concentrations used spanned those at which virtually no tissue responses were observed (0.7 ppm) to those that represent the highest concentration in the cancer studies (15 ppm) that produced nasal tumors in half the exposed group of rats. The study identified doses at which there were no statistically significant changes in gene expression; intermediate doses with changes in a small number of genes not easily grouped by function; and then concentrations where changes were consistent with irritation and cell stress responses. Experiment Overall Design: Eight week old male F344/NCrl rats were exposed to formaldehyde through either instillation or inhalation. For animals exposed via instillation, 40 ul per nostril of 400 mM formaldehyde was instilled intranasally. Vehicle control animals were instilled with 40 ul per nostril of distilled water. All animals exposed via instillation were sacrificed 6 hours post-exposure. For animals exposed via inhalation, whole-body exposures were performed at doses of 0, 0.7, 2, 6, and 15 ppm (6 hours per day, 5 days per week). Inhalation animals were sacrified at 6 hours, 24 hours, 5 days, and 19 days following initiation of exposure except for the 15 ppm concentration which was sacrificed at only the 6 hour time point. Following sacrifice, tissue from the Level II region of the nose was dissected and digested with a mixture of proteases to remove the epithelial cells. The epithelial cells scquired from this section of the nose consisted primarily of transitional epithelium with some respiratory epithelium. Microarray analysis was performed on the epithelial cells.
2007-10-25 | E-GEOD-7002 | ArrayExpress
Project description:Although formaldehyde is a normal constituent of tissues, lifetime inhalation exposures at 6?h/day, 5?days/week at concentrations ?6?ppm caused a nonlinear increase in nasal tumors in rats with incidence reaching close to 50% at 15?ppm. Studies with heavy isotope labeled [13CD2]-formaldehyde permit quantification of both the mass-labeled exogenous and endogenous DNA-formaldehyde reaction products. An existing pharmacokinetic model developed initially to describe 14C-DNA-protein crosslinks (DPX) provided a template for describing the time course of mass-labeled adducts. Published datasets included both DPX and N2-HO13CD2-dG adducts measured after a single 6-h exposure to 0.7, 2, 6, 9, 10, or 15?ppm formaldehyde, after multi-day exposures to 2?ppm for 6?h/day, 7?days/week with interim sacrifices up to 28?days, and after 28-day exposures for 6?h/day, 7?days/week to 0.3, 0.03, or 0.001?ppm. The existing kinetic model overpredicted endogenous adducts in the nasal epithelium after 1-day [13CD2]-formaldehyde exposure, requiring adjustment of parameters for rates of tissue metabolism and background formaldehyde. After refining tissue formaldehyde parameters, we fit the model to both forms of adducts by varying key parameters and optimizing against all 3 studies. Fitting to all these studies required 2 nonlinear pathways-one for high-exposure saturation of clearance in the nasal epithelial tissues and another for extracellular clearance that restricts uptake into the epithelial tissue for inhaled concentrations below 0.7?ppm. This refined pharmacokinetic model for endogenous and exogenous formaldehyde acetal adducts can assist in updating biologically based dose-response models for formaldehyde carcinogenicity.
2020-01-01 | S-EPMC7548285 | BioStudies
Project description:Exogenous formaldehyde disrupts genomic/epigenomic profiles in the rodent nose and white blood cells (WBCs) related to inflammation and immune signaling, although it does not reach the circulating blood. We aimed to compare and contrast alterations in genomic signaling in the nose and circulating blood of non-human primates exposed to formaldehyde. We used microarrays to identify transcripts that were diffentially expressed in response to formaldehyde inhalation exposure. A total of 14 primates received two consecutive days of 6-hour whole body inhalation exposures consisting of either filtered air (n = 6) or a target of 6 ppm formaldehyde (n = 8). To assess formaldehyde-induced changes in genome-wide gene expression profiles, RNA samples extracted from the nasal epithelium and circulating WBCs were labeled and hybridized to the Affymetrix Cynomolgus Macaque Gene 1.0 ST Array.
2016-06-30 | E-GEOD-75759 | ArrayExpress
Project description:Formaldehyde (FA), an endogenous cellular aldehyde, is a rat nasal carcinogen. In this study, concentration- and exposure-duration transitions in FA mode of action (MOA) were examined with pharmacokinetic (PK) modeling for tissue formaldehyde acetal (FAcetal) and glutathione (GSH) and with histopathology and gene expression studies for tissue responses in nasal epithelium from rats exposed to 0, 0.7, 2, 6, 10 or 15 ppm FA 6 hr/day for 1, 4 or 13 weeks. The study had two goals. The first goal was to develop a basic PK model to estimate various forms of tissue formaldehyde and tissue glutathione (GSH). The second goal was to compare histopathology and gene expression changes in nasal tissues caused by inhalation of FA with changes in tissue FAcetal and free GSH calculated from the PK model. Patterns of gene expression varied with concentration and with duration. At 0.7 and 2 ppm, sensitive response genes (SRGs) - associated with cellular stress, thiol transport/reduction, inflammation, and cell proliferation - were similarly upregulated at all exposure durations. At 6 ppm and greater, gene expression changes showed enrichment of pathways involved in cell cycle, DNA repair, and apoptosis processes. ERBB, EGFR, WNT, TGF-β, Hedgehog, and Notch signaling were also enriched in differentially expressed genes. Benchmark doses (BMDs) for genes in significantly enriched pathways were lower at 13 weeks than at 1 or 4-week. The transcriptional and histological changes corresponded to PK model-predicted changes in free GSH at 0.7 and 2 ppm and in FAcetal at 6 ppm. DNA-replication stress, enhanced proliferation, metaplasia, and stem cell-niche activation appear to be associated with FA carcinogenesis at 6 ppm and above. Dose dependencies in MOA, the presence of high physiological FAcetal, and non-linear FAcetal/GSH tissue kinetics indicate that FA concentrations below 150 ppb (and probably any concentrations below irritant levels, i.e., ~ 1 ppm) would not increase cancer risks of inhaled FA in the nose or any other tissue. Closer examination of dose response relationships for endogenous compound toxicity could help guide biologically relevant approaches for chemical risk assessment. Overall design: Eight week old male F344/CrlBR rats were exposed to formaldehyde through whole body inhalation. Whole-body exposures were performed at doses of 0, 0.7, 2, 6, 10, and 15 ppm (6 hours per day, 5 days per week). Inhalation animals were sacrified at 1, 4, and 13 weeks following initiation of exposure. Following sacrifice, tissue from the Level II region of the nose was dissected and digested with a mixture of proteases to remove the epithelial cells. The epithelial cells acquired from this section of the nose consisted primarily of transitional epithelium with some respiratory epithelium. Gene expression microarray analysis was performed on the epithelial cells.
2010-07-28 | GSE23179 | GEO