Fine Particulate Matter (PM2.5), the Exposome, and Cumulative Health Risk: A Life-course Perspective.

Fine particulate matter (PM2.5; aerodynamic diameter ≤2.5 μm) is a leading contributor to the global burden of disease and is associated with substantial morbidity and mortality. However, its health effects are often evaluated within single-exposure frameworks, limiting causal inference and reducing the translational relevance of evidence for policy development. In this study, we reconceptualise PM2.5 within the exposome framework by integrating external exposures, internal biological responses, and structural determinants of health across the life course. PM2.5 comprises a complex and dynamic mixture of pollutants from ambient and household sources, including biomass combustion, traffic emissions, and industrial activities. After inhalation, PM2.5 particles can penetrate the respiratory tract, and finer fractions may enter the systemic circulation, where they induce oxidative stress, inflammation, epigenetic dysregulation, and endocrine disruption. These mechanisms contribute to a broad spectrum of adverse health outcomes, including cardiovascular, respiratory, metabolic, and neurodegenerative diseases as well as cancers. The multi-level and temporally accumulated nature of these effects highlights the limitations of reductionist exposure assessment and underscores the need for integrative, systems-based approaches. Integrating cumulative impact assessment with exposome-wide approaches that leverage satellite, clinical, land-use, urban planning, and socioeconomic data can improve the characterization of context-specific cumulative health effects. Positioning PM2.5 as a sentinel indicator of cumulative environmental risk provides a unifying framework for exposome-informed science and supports the development of more precise, equitable, and policy-relevant interventions.