Seasonal fluctuations in ambient particulate matter2.5 exposure differentially regulate JAK2/STAT3 signaling in never smoking rural and urban cohorts.

Ambient particulate matter ≤2.5 μm in aerodynamic diameter (PM2.5) is a major environmental carcinogen, yet alterations in the pro-carcinogenic signaling pathways in asymptomatic never smokers remain poorly defined. This study examined the effect of seasonal fluctuations of PM2.5 on genotoxic stress and pro-oncogenic signaling in rural (RU) and urban (UR) cohorts from West Bengal, India. Environmental monitoring revealed high PM2.5 and associated benzo[α]pyrene in UR, during winter, induced genotoxic stress in sputum-derived airway cells and peripheral blood mononuclear cells as evidenced from comet assay and 8-hydroxy-2' -deoxyguanosine analysis. RNA sequencing, real-time polymerase chain reaction, indirect enzyme-linked immunosorbent assay and immunoblotting identified activation of the interleukin-6/epidermal growth factor receptor-driven Janus kinase (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling and associated crosstalk with the rat sarcoma/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase pathways in airway cells and leukocytes of the UR cohort. This signaling activation coincided with upregulation of pro-survival effectors (B-cell lymphoma-2, myeloid cell leukemia-1, MYC proto-oncogene, Cyclin D1) and repression of apoptosis regulator, BCL2-associated X, p21 and endogenous JAK/STAT pathway inhibitors (protein inhibitor of activated STAT 2 and suppressor of cytokine signaling 2). Linear mixed-effects regression models linked winter PM2.5 surges with increased genotoxic damage and altered JAK2/STAT3 cues in the UR cohort. Risk modeling further predicted higher PM2.5-attributed lung cancer mortality in the UR population. Collectively, these findings indicated that elevated PM2.5 exposure was associated with early genotoxic and JAK2/STAT3-associated pro-carcinogenic alterations in airway cells and leukocytes of asymptomatic individuals, reflecting heightened biological sensitivity in the UR population.