Deciphering the toxicity of polyhexamethylene guanidine phosphate in lung carcinogenesis: Mutational profiles and molecular mechanisms.

Polyhexamethylene guanidine (PHMG) is widely utilized in personal hygiene products due to its bactericidal, non-volatile, and hydrophilic properties. However, the long-term toxic effects and underlying mechanisms associated with respiratory exposure to the commonly used form, PHMG phosphate (PHMG-p), are still insufficiently understood. This study aims to elucidate the types of pulmonary lesions and the incidence of lung cancer associated with varying concentrations of PHMG-p and observation periods, along with the molecular mechanisms underlying this relationship. To assess these effects, CT scans and pathological analyses were conducted for up to 54 weeks following initial exposure to PHMG-p. Furthermore, to investigate the underlying causes of pulmonary toxicity, TGF-beta-activated kinase 1 was identified as a PHMG-p-binding protein, and its associated signaling pathways, including necroptosis, apoptosis, and MKK7, were explored. Somatic mutational signature, and gene ontology (GO) analyses were performed to investigate the genetic characteristics of PHMG-p-induced lung carcinogenesis. PHMG-p exposure led to somatic mutations in lung cancer-related genes, including TP53, SOS1, KMT2D, MDM2, ERBB2, SETD2, MET, ARID1A, RBM10, and CDKN2A as well as in genes such as RAB31, WASHC1, DDX11, ECD, STAB2, MUC2, and MUC5AC. The mutated genes were primarily associated with impaired DNA repair mechanisms. GO analysis highlighted the activation of pathways related to cell cycle checkpoints, necroptosis, MAPK, and idiopathic pulmonary fibrosis, while also revealing the suppression of signaling pathways associated with natural killer cells, GADD45, LXR/RXR activation, and IL-15 production. Gain-of-function experiments confirmed the oncogenic roles of PLAU and HMGA2, as well as the tumor-suppressive functions of TBX4 and GPX3. These findings suggest that PHMG-p activates necroptosis and MAPK signaling, increases the frequency of somatic mutations, and inhibits apoptosis, thus fostering an environment conducive to carcinogenesis. This underscores the importance of understanding the potential health risks associated with PHMG-p exposure and provides insights for future research and regulatory considerations regarding the safety of personal hygiene products.