Early-life exposure to polyhexamethyleneguanindine phosphate resulted in persistent inflammation and alterations of lung structure later in life

• Exposure to PHMG-P in neonatal mice induced only minor toxicity at early age. • Early-life Exposure to PHMG-P resulted in persistent inflammation over time. • Early-life Exposure to PHMG-P led to alteration of lung architecture over time. • Early-life Exposure to PHMG-P can have lifelong health consequences. Exposure of neonates or infants to toxicants can cause irreversible damage due to their rapid developmental stage. Consequently, toxicity testing in neonatal and juvenile laboratory animals must include evaluation of both immediate adverse effects and potential delayed-onset consequence of the toxicant. To evaluate the long-term impacts of early-life exposure to polyhexamethyleneguanindine phosphate (PHMG-P), one of the humidifier disinfectants implicated in fatal lung disease, neonatal mice were intranasally instilled with 0.9 mg/kg and 1.5 mg/kg PHMG-P. Adverse effects were assessed at days 15, 64, and 370. PHMG-P exposure caused minor toxicity at day 15, but led to persistent inflammation, formation of foamy macrophages, and hyperplasia of alveolar epithelial cells at days 64 and 370. RNA-sequencing revealed that the expression of genes related to innate immune response on day 15, while genes related to innate and adaptive immune response increased at day 64 and 370. Additionally, the expression of genes involved in lung structure, such as blood vessel morphogenesis or myofibril assembly, were substantially diminished. Elevated reactive oxygen species from iron deposition, lipid peroxidation, and endogenous cholesterol crystals contributed to increased cytokine and chemokine production and persistent chronic inflammation. Dysregulated epithelial regeneration led to alveolar bronchiolization and airway obstruction. This study emphasizes that early-life exposure to household chemicals can have lifelong effects on health.