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

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.