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Fin Whale as a Sink of Legacy and Emerging Contaminants: First Integrated Chemical Exposomics and Gene Expression Analysis in Cetaceans Cetaceans face numerous anthropogenic chemical stressors in global oceans, yet there is a lack of studies that simultaneously assess their cumulative exposure to both legacy and emerging contaminants and their combined effects. To evaluate the susceptibility of fin whale (Balaenoptera physalus) to chemical pollution, this study employed for the first time a multidiagnostic molecular approach that integrates chemical exposomics and gene expression analysis in live-sampled skin and blubber biopsies from two distinct populations: the endangered Mediterranean subpopulation (Italy) and the vulnerable population from the Sea of Cortez (Mexico). Both marine regions are biodiversity hotspots characterized by different anthropogenic impacts, making them ideal for the assessment of heterogeneous contaminants exposure and their effects. Results revealed distinct exposure profiles in the two populations, with Mediterranean fin whales exhibiting higher concentrations of legacy pollutants such as polychlorinated biphenyls (PCBs), as well as plasticizers, perfluoroalkyl substances (PFAS), while both populations showed traces of pharmaceuticals and lifestyle-related chemicals (e.g., paracetamol, diclofenac, nicotine, UV filters) and other substances not previously reported in whales. Supported by 32 network correlations with gene expression relevant to transcriptional regulation, endocrine disruption, lipid homeostasis, and inflammation, our findings suggest that complex anthropogenic chemical exposures may compromise the health and reproductive viability of the endangered Mediterranean fin whales, affirming their importance as a global sentinel species, which reflects marine ecosystem integrity within the “One Health” framework. https://pubs.acs.org/doi/10.1021/acs.est.5c00844