Mechanistic toxicology of emerging pollutants under changing climatic conditions

Environmental pollution due to contaminants, such as fine particulate matter (PM2.5), polyfluoroalkyl substances (PFAS), microplastics (MPs), heavy metals, pharmaceuticals and personal care products (PPCPs), and nitrate-driven eutrophication, creates a critical global public health threat. Climate change is an important amplifier of these risks by driving emissions, altering chemical fate and bioavailability, and increasing exposures through extreme weather events. This review aims to discuss the current evidence on the major environmental pollutants, their interaction with climate change, and the molecular and cellular pathways through which they induce toxicity, and to highlight integrated health risks and biological mechanisms. Exposure to PM2.5 leads to cardiopulmonary diseases through oxidative stress, inflammation, and the activation of multiple cell death pathways (apoptosis, autophagy, pyroptosis, ferroptosis). PFAS disturb lipid metabolism and the signaling of nuclear receptors, for example, through PPAR pathways, resulting in metabolic and organ-specific toxicities. Mitochondrial dysfunction, genotoxicity, inflammatory immune responses, and disruption of endocrine function can be caused by MPs through oxidative stress and receptor interactions. Heavy metals can cause organ damage and/or carcinogenesis through several critical biological pathways, including inhibition of enzyme activity, protein misfolding, induction of oxidative stress, and disruption of metal ion homeostasis. Climate change commonly exacerbates these effects through increased pollutant mobilization, altered chemical speciation, and compounded exposures via specific events, such as wildfires, floods, and harmful algal blooms. Environmental pollutants, enhanced by climate change, converge on common mechanistic pathways principally through the induction of oxidative stress, immune dysregulation, and mitochondrial impairment to produce a range of disease outcomes. There is an urgent need for an integrated approach to monitoring, regulation, and public health intervention that adequately addresses these complex and escalating risks to human and ecosystem health.