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Integration of transcriptomics, proteomics and metabolomics identifies biomarkers for pulmonary injury by polyhexamethylene guanidine phosphate (PHMG-p), a humidifier disinfectant, in rats

  • Organ Toxicity and Mechanisms
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Abstract

Polyhexamethylene guanidine phosphate (PHMG-p) was used as a humidifier disinfectant in Korea. PHMG induced severe pulmonary fibrosis in Koreans. The objective of this study was to elucidate mechanism of pulmonary toxicity caused by PHMG-p in rats using multi-omics analysis. Wistar rats were intratracheally instilled with PHMG-p by single (1.5 mg/kg) administration or 4-week (0.1 mg/kg, 2 times/week) repeated administration. Histopathologic examination was performed with hematoxylin and eosin staining. Alveolar macrophage aggregation and granulomatous inflammation were observed in rats treated with single dose of PHMG-p. Pulmonary fibrosis, chronic inflammation, bronchiol–alveolar fibrosis, and metaplasia of squamous cell were observed in repeated dose group. Next generation sequencing (NGS) was performed for transcriptome profiling after mRNA isolation from bronchiol–alveoli. Bronchiol–alveoli proteomic profiling was performed using an Orbitrap Q-exactive mass spectrometer. Serum and urinary metabolites were determined using 1H-NMR. Among 418 differentially expressed genes (DEGs) and 67 differentially expressed proteins (DEPs), changes of 16 mRNA levels were significantly correlated with changes of their protein levels in both single and repeated dose groups. Remarkable biological processes represented by both DEGs and DEPs were defense response, inflammatory response, response to stress, and immune response. Arginase 1 (Arg1) and lipocalin 2 (Lcn2) were identified to be major regulators for PHMG-p-induced pulmonary toxicity based on merged analysis using DEGs and DEPs. In metabolomics study, 52 metabolites (VIP > 0.5) were determined in serum and urine of single and repeated-dose groups. Glutamate and choline were selected as major metabolites. They were found to be major factors affecting inflammatory response in association with DEGs and DEPs. Arg1 and Lcn2 were suggested to be major gene and protein related to pulmonary damage by PHMG-p while serum or urinary glutamate and choline were endogenous metabolites related to pulmonary damage by PHMG-p.

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Funding

This research was support by a Grant (2017001360001) from Korea Environmental Industry and Technology Institute.

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Authors and Affiliations

  1. Department of Pharmacy, Division of Toxicology, Sungkyunkwan University, 2066 Sebu-ro, Suwon, Gyeonggi, 16419, Republic of Korea

    Jung Dae Lee, In Hwan Tae, Su Hyun Lee, Hae Ri Kim, Hyung Sik Kim & Byung-Mu Lee

  2. Toxicology, College of Pharmacy, Dankook University, 119 Dandae-ro, Cheonan, Chungnam, 31116, Republic of Korea

    Hyang Yeon Kim & Kyu-Bong Kim

  3. Department of Microbiology, College of Natural Sciences, Dankook University, Cheonan, Republic of Korea

    Keunsoo Kang

  4. College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea

    Hye Gwang Jeong

  5. National Center for Efficacy Evaluation for Respiratory Disease Product, Korea Institute of Toxicoloy, Jeonbuk, Republic of Korea

    Mi-Kyung Song & Kyuhong Lee

  6. Korea Brain Research Institute (KBRI), Daegu, Republic of Korea

    Sehyun Chae

  7. Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea

    Daehee Hwang

  8. Department of Chemistry and Chemistry Institute of Functional Materials, Pusan National University, Busan, Republic of Korea

    Suhkmann Kim

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  15. Byung-Mu Lee
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Lee, J.D., Kim, H.Y., Kang, K. et al. Integration of transcriptomics, proteomics and metabolomics identifies biomarkers for pulmonary injury by polyhexamethylene guanidine phosphate (PHMG-p), a humidifier disinfectant, in rats. Arch Toxicol 94, 887–909 (2020). https://doi.org/10.1007/s00204-020-02657-x

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