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Network-based integrated analysis for toxic effects of high-concentration formaldehyde inhalation exposure through the toxicogenomic approach.

ABSTRACT: Formaldehyde is a colorless, pungent, highly reactive, and toxic environmental pollutant used in various industries and products. Inhaled formaldehyde is a human and animal carcinogen that causes genotoxicity, such as reactive oxygen species formation and DNA damage. This study aimed to identify the toxic effects of inhaled formaldehyde through an integrated toxicogenomic approach utilizing database information. Microarray datasets (GSE7002 and GSE23179) were collected from the Gene Expression Omnibus database, and differentially expressed genes were identified. The network analyses led to the construction of the respiratory system-related biological network associated with formaldehyde exposure, and six upregulated hub genes (AREG, CXCL2, HMOX1, PLAUR, PTGS2, and TIMP1) were identified. The expression levels of these genes were verified via qRT-PCR in 3D reconstructed human airway tissues exposed to aerosolized formaldehyde. Furthermore, NRARP was newly found as a potential gene associated with the respiratory and carcinogenic effects of formaldehyde by comparison with human in vivo and in vitro formaldehyde-exposure data. This study improves the understanding of the toxic mechanism of formaldehyde and suggests a more applicable analytic pipeline for predicting the toxic effects of inhaled toxicants.

SUBMITTER: Kang DS

PROVIDER: S-EPMC8979994 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Network-based integrated analysis for toxic effects of high-concentration formaldehyde inhalation exposure through the toxicogenomic approach.

Kang Doo Seok DS Lee Nahyun N Shin Dong Yeop DY Jang Yu Jin YJ Lee Su-Hyon SH Lim Kyung-Min KM Ahn Yeon-Soon YS Lee Cheol Min CM Seo Young Rok YR

Scientific reports 20220404 1

Formaldehyde is a colorless, pungent, highly reactive, and toxic environmental pollutant used in various industries and products. Inhaled formaldehyde is a human and animal carcinogen that causes genotoxicity, such as reactive oxygen species formation and DNA damage. This study aimed to identify the toxic effects of inhaled formaldehyde through an integrated toxicogenomic approach utilizing database information. Microarray datasets (GSE7002 and GSE23179) were collected from the Gene Expression O ...[more]

PMID: 35379891

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Project description:ObjectiveTo assess health risks associated with inhalation exposure to formaldehyde and benzene mainly emitted from building and decoration materials in newly remodeled indoor spaces in Beijing.MethodsWe tested the formaldehyde and benzene concentrations in indoor air of 410 dwellings and 451 offices remodeled within the past year, in which the occupants had health concerns about indoor air quality. To assess non-carcinogenic health risks, we compared the data to the health guidelines in China and USA, respectively. To assess carcinogenic health risks, we first modeled indoor personal exposure to formaldehyde and benzene using the concentration data, and then estimated the associated cancer risks by multiplying the indoor personal exposure by the Inhalation Unit Risk values (IURs) provided by the U.S. EPA Integrated Risk Information System (U.S. EPA IRIS) and the California Office of Environmental Health Hazard Assessment (OEHHA), respectively.Results(1) The indoor formaldehyde concentrations of 85% dwellings and 67% offices were above the acute Reference Exposure Level (REL) recommended by the OEHHA and the concentrations of all tested buildings were above the chronic REL recommended by the OEHHA; (2) The indoor benzene concentrations of 12% dwellings and 32% offices exceeded the reference concentration (RfC) recommended by the U.S. EPA IRIS; (3) The median cancer risks from indoor exposure to formaldehyde and benzene were 1,150 and 106 per million (based on U.S. EPA IRIS IURs), 531 and 394 per million (based on OEHHA IURs).ConclusionsIn the tested buildings, formaldehyde exposure may pose acute and chronic non-carcinogenic health risks to the occupants, whereas benzene exposure may pose chronic non-carcinogenic risks to the occupants. Exposure to both compounds is associated with significant carcinogenic risks. Improvement in ventilation, establishment of volatile organic compounds (VOCs) emission labeling systems for decorating and refurbishing materials are recommended to reduce indoor VOCs exposure.

Project description:Introduction: Here, we describe the generation of hypotheses for grouping nanoforms (NFs) after inhalation exposure and the tailored Integrated Approaches to Testing and Assessment (IATA) with which each specific hypothesis can be tested. This is part of a state-of-the-art framework to support the hypothesis-driven grouping and read-across of NFs, as developed by the EU-funded Horizon 2020 project GRACIOUS. Development of Grouping Hypotheses and IATA: Respirable NFs, depending on their physicochemical properties, may dissolve either in lung lining fluid or in acidic lysosomal fluid after uptake by cells. Alternatively, NFs may also persist in particulate form. Dissolution in the lung is, therefore, a decisive factor for the toxicokinetics of NFs. This has led to the development of four hypotheses, broadly grouping NFs as instantaneous, quickly, gradually, and very slowly dissolving NFs. For instantaneously dissolving NFs, hazard information can be derived by read-across from the ions. For quickly dissolving particles, as accumulation of particles is not expected, ion toxicity will drive the toxic profile. However, the particle aspect influences the location of the ion release. For gradually dissolving and very slowly dissolving NFs, particle-driven toxicity is of concern. These NFs may be grouped by their reactivity and inflammation potency. The hypotheses are substantiated by a tailored IATA, which describes the minimum information and laboratory assessments of NFs under investigation required to justify grouping. Conclusion: The GRACIOUS hypotheses and tailored IATA for respiratory toxicity of inhaled NFs can be used to support decision making regarding Safe(r)-by-Design product development or adoption of precautionary measures to mitigate potential risks. It can also be used to support read-across of adverse effects such as pulmonary inflammation and subsequent downstream effects such as lung fibrosis and lung tumor formation after long-term exposure.

Project description:Background/Objectives: Despite current treatments extending the lifespan of Glioblastoma (GBM) patients, the average survival time is around 15-18 months, underscoring the fatality of GBM. This study aims to investigate the impact of sample heterogeneity on gene expression in GBM, identify key metabolic pathways and gene modules, and explore potential therapeutic targets. Methods: In this study, we analysed GBM transcriptome data derived from The Cancer Genome Atlas (TCGA) using genome-scale metabolic models (GEMs) and co-expression networks. We examine transcriptome data incorporating tumour purity scores (TPSs), allowing us to assess the impact of sample heterogeneity on gene expression profiles. We analysed the metabolic profile of GBM by generating condition-specific GEMs based on the TPS group. Results: Our findings revealed that over 90% of genes showing brain and glioma specificity in RNA expression demonstrate a high positive correlation, underscoring their expression is dominated by glioma cells. Conversely, negatively correlated genes are strongly associated with immune responses, indicating a complex interaction between glioma and immune pathways and non-tumorigenic cell dominance on gene expression. TPS-based metabolic profile analysis was supported by reporter metabolite analysis, highlighting several metabolic pathways, including arachidonic acid, kynurenine and NAD pathway. Through co-expression network analysis, we identified modules that significantly overlap with TPS-correlated genes. Notably, SOX11 and GSX1 are upregulated in High TPS, show a high correlation with TPS, and emerged as promising therapeutic targets. Additionally, NCAM1 exhibits a high centrality score within the co-expression module, which shows a positive correlation with TPS. Moreover, LILRB4, an immune-related gene expressed in the brain, showed a negative correlation and upregulated in Low TPS, highlighting the importance of modulating immune responses in the GBM mechanism. Conclusions: Our study uncovers sample heterogeneity's impact on gene expression and the molecular mechanisms driving GBM, and it identifies potential therapeutic targets for developing effective treatments for GBM patients.

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Network-based integrated analysis for toxic effects of high-concentration formaldehyde inhalation exposure through the toxicogenomic approach.

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Network-based integrated analysis for toxic effects of high-concentration formaldehyde inhalation exposure through the toxicogenomic approach.

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