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Multi-omics study to elucidate molecular mechanism of polyhexamethylene guanidine phosphate (PHMG-p)-induced
Jung Dae Lee1,2, Hyang Yeon Kim1,2, Jueng-Eun Im1
1Toxicology, College of Pharmacy, Dankook University, Cheonan, Republic of Korea.
Abstract:
Polyhexamethylene guanidine phosphate (PHMG-p), a cationic disinfectant previously used in humidifiers, has been linked to severe pulmonary diseases in Korea. This study aimed to elucidate the molecular mechanisms underlying PHMG-p-induced lung toxicity using an integrated multi-omics approach. BALB/c mice were intratracheally instilled with PHMG-p (0, 0.03, 0.1 mg/kg, twice weekly for 4 weeks). Histopathology revealed dose-dependent pulmonary lesions, including inflammatory infiltration, alveolar wall hyperplasia, and fibrosis. Transcriptomic profiling identified 213 and 1,506 differentially expressed genes (DEGs) in the low- and high-dose groups, respectively, with enriched pathways related to immune activation, cytokine signaling, and cellular stress responses. Proteomic analysis detected 148 and 1,168 differentially expressed proteins (DEPs), many of which overlapped with DEGs and were associated with chemokine signaling, protein refolding, and ion transport dysregulation. Metabolomic profiling of serum samples identified dose-responsive alterations in amino acid and energy metabolism, with notable increases in glutamate, leucine, serine, and related metabolites. Integrated omics analysis revealed consistent up-regulation of CDKN1A, HSP90AA1, HSPA1A, HSPA8, and HSPH1, and down-regulation of FPR1, suggesting their roles as potential biomarkers of PHMG-p-induced pulmonary injury. Pathway convergence indicated activation of inflammatory and fibrotic remodeling processes, as well as metabolic reprogramming involving glutamate and branched-chain amino acid pathways. These findings provide mechanistic insight into PHMG-p-induced lung toxicity and highlight multi-omics signatures that may serve as biomarkers for monitoring or predicting pulmonary damage caused by cationic polymer biocides.
Insights
Polyhexamethylene guanidine phosphate (PHMG-p) causes lung damage by triggering inflammation and fibrosis. Multi-omics analysis identified key molecular pathways and potential biomarkers for PHMG-p-induced pulmonary toxicity.
Area of Science:
- Toxicology
- Pulmonary Medicine
- Molecular Biology
Background:
- Polyhexamethylene guanidine phosphate (PHMG-p), a cationic disinfectant, has been associated with severe lung diseases.
- Understanding the molecular mechanisms of PHMG-p-induced lung toxicity is crucial for public health.
Purpose of the Study:
- To elucidate the molecular mechanisms of PHMG-p-induced lung toxicity.
- To identify potential biomarkers for PHMG-p-induced pulmonary injury using an integrated multi-omics approach.
Main Methods:
- BALB/c mice were exposed to PHMG-p via intratracheal instillation.
- Histopathology, transcriptomics, proteomics, and metabolomics were employed to analyze lung tissue and serum.
- Integrated omics analysis was performed to identify molecular signatures.
Main Results:
- PHMG-p induced dose-dependent pulmonary lesions, including inflammation, hyperplasia, and fibrosis.
- Transcriptomic and proteomic analyses revealed significant alterations in immune response, cellular stress, and signaling pathways.
- Metabolomic profiling showed dysregulation in amino acid and energy metabolism.
- Consistent up-regulation of heat shock proteins and down-regulation of FPR1 were observed, suggesting their role as biomarkers.
Conclusions:
- PHMG-p exposure leads to significant pulmonary inflammation and fibrosis through complex molecular pathways.
- Integrated multi-omics analysis provides mechanistic insights into PHMG-p lung toxicity.
- Identified molecular signatures, including specific genes and proteins, may serve as biomarkers for PHMG-p-induced pulmonary damage.
