Polyhexamethylene guanidine phosphate induces lung fibrosis and cancer via the TAK1-related signaling pathway

초록

Polyhexamethylene guanidine phosphate (PHMG-p) is a commonly utilized compound in a range of household items, including shampoos, swimming pools, wipes, and humidifier disinfectant (HD). Regrettably, it gained notoriety as the primary causation in the tragic HD disaster in South Korea. Following a comprehensive national-level epidemiological investigation, a significant number of lung cancer cases were identified among users of HDs. However, to date, there has been an absence of research into the carcinogenic effect of PHMG-p in relation to lung cancer. The Organization for Economic Co-operation and Development (OECD) proposes test guidelines (TG) for predicting the carcinogenicity of chemicals, which is recognized as an international standard. Three genotoxicity tests (OECD TG 471, 473, and 474) were conducted for PHMG-p. The results of the TG 471 and TG 474 were negative, whereas the TG 473 was positive. Consequently, no further carcinogenicity tests were conducted. Therefore, we aimed to find out whether PHMG-p has lung carcinogenicity. In this study, lung lesion changes were observed at 20, 40, and 54 weeks after PHMG-p was instilled through intratracheal intubation using a rat model. We are the first to discover that lung cancer can occur even long after exposure has stopped. Furthermore, we discovered the TAK1 protein by investigating which proteins this chemical binds to, and fundamentally explored the molecular mechanisms involved. In addition to the well-known somatic mutations (Tp53, Sos1, Kmt2d, Mdm2, etc.) associated with lung cancer, we found novel mutations (Rab31, Washc1, Ddx11, etc.) that occurred at a higher frequency, and we found that they were mainly related to the DNA repair system. We also found that exposure to PHMG-p in human lung cells activated TAK1-related key signals, including necroptosis and MAPK signaling pathways, while inhibiting apoptosis. In addition, we identified four genes (PLAU, HMGA2, TBX4, and GPX3) that were commonly altered in human pulmonary alveolar epithelial cells and rat lung cancer tissue.These findings will be used as a part of the toxicological evidence base for the South Korean Ministry of Environment (National Institute of Environmental Research) to list PHMG-p as a Group 1 carcinogen, classified by the International Agency for Research on Cancer.