Abstract
Exposure to fire smoke has become a global health concern and is associated with increased morbidity and mortality. There is a lack of understanding of the specific immune mechanisms involved in smoke exposure, with preventive and targeted interventions needed. After exposure to fire smoke, which includes PM2.5, toxic metals and perfluoroalkyl and polyfluoroalkyl substances, epidemiology-based studies have demonstrated increases in respiratory (for example, asthma exacerbation), cardiac (for example, myocardial infarction, arrhythmias), neurological (for example, stroke) and pregnancy-related (for example, low birthweight, premature birth) outcomes. However, mechanistic studies exploring how smoke exposure disrupts cellular homeostasis are lacking. Therefore, we collected blood from smoke-exposed individuals (n = 31) and age-matched and sex-matched non-smoke-exposed controls (n = 29), and investigated these complex interactions using a single-cell exposomic approach based on both methylation and mass cytometry. Overall, our data demonstrated a strong association between smoke exposure and methylation at 133 disease-relevant gene loci, while immunophenotyping showed increased homing and activation biomarkers. We developed an application of mass cytometry to analyze single-cell/metal binding and found, for example, increased levels of mercury in dead cells and cadmium in the live and dead cell populations. Moreover, mercury levels were associated with years of smoke exposure. Several epigenetic sites across multiple chromosomes were associated with individual toxic metal isotopes in single immune cells. Our methods for detecting the effect of smoke exposure at the single-cell level and the study results may help to determine the timing of exposure and identify specific molecular targets that could be modified to prevent and manage exposure to smoke.
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Data availability
The DNA methylation and mass cytometry datasets (including manually gated live single cells and cell subsets) generated during the current study are available via the Harvard Dataverse data repository at https://doi.org/10.7910/DVN/5PWZJM. Source data are provided with this paper.
Code availability
The R code needed to reproduce the results of the study is available at https://github.com/knadeaulab/Smoke_Exposure_Study.
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Acknowledgements
We thank the firefighters for their service and commitment to health research and the San Francisco Cancer Prevention Foundation for their support. The following sources of funding were used: AIRHEALTH PPG P01HL152953 (K.C.N.); the San Francisco Cancer Prevention Foundation (K.C.N.); Pregnancy R01 ES032253 (K.C.N.); the Asthma and Allergic Diseases Cooperative Research Center (K.C.N.); grant no. U19AI167903 (K.C.N.); T32 (E. Simonin); and the Keck Foundation (M. Burke). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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M.M.J. conceived the study design, managed all aspects of the study, performed the data collection and developed and wrote the manuscript. A.K. designed and executed the data analysis workflow and interpretation, created the figures and wrote the manuscript. O.A.K. contributed to sample collection and processing, and performed the mass cytometry, data analysis and manuscript development. E.Smith assisted with the study design, firefighter recruitment and performed the data collection. Y.P. and L.B. performed the mass cytometry. S.A. and J.A. performed the data collection. X.Z. contributed to data analysis and results interpretation. E. Simonin, J.A., A.F., M.C., O.B., R.S.C., E.P., M.S., C.A.A., M. Burke and M. Bondy reviewed the manuscript. M.A. and C.A.A. supervised the mass cytometry and provided critical revisions of the manuscript. K.C.N. conceived the study design, supervised all aspects of the study and wrote and finalized the manuscript. All authors reviewed and approved the manuscript.
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Johnson, M.M., Kaushik, A., Kline, O.A. et al. Immune impacts of fire smoke exposure. Nat Med (2025). https://doi.org/10.1038/s41591-025-03777-6
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DOI: https://doi.org/10.1038/s41591-025-03777-6
