Prior HFPO-DA exposure compromises acute hypoxia tolerance in the critically endangered Chinese sturgeon (Acipenser sinensis).

Sturgeons rank among the most hypoxia-sensitive endangered fish taxa, representing a global conservation priority. Although increasing hypoxia in critical habitats poses a substantial threat to population persistence, whether concurrent exposure to emerging contaminants further compromises hypoxia tolerance remains unclear. Here, we evaluated the effects of HFPO-DA, an emerging per- and polyfluoroalkyl substance (PFAS) alternative, on the hypoxia tolerance of the Chinese sturgeon (Acipenser sinensis) and elucidated the underlying mechanisms through integrated physiological and multi-omics analyses. After a 14-day HFPO-DA exposure, sturgeons exhibited a significantly higher incidence of loss of equilibrium during subsequent hypoxia exposure, indicating reduced hypoxia tolerance. Histological examinations revealed pronounced gill injury, including epithelial hyperplasia and lamellar fusion, which may compromise respiratory gas exchange. Multi-omics analyses further demonstrated that HFPO-DA exposure reshaped the magnitude and temporal trajectories of hypoxia responses. Compared with controls, HFPO-DA-exposed fish exhibited earlier and more profound hypoxia-induced transcriptomic and metabolic perturbations, characterized by an accelerated activation of anaerobic metabolism and exacerbated energy deficits. Furthermore, HFPO-DA exposure compromised antioxidant defense and amplified the dysregulation of redox-regulatory metabolism under hypoxia, which may exacerbate cellular damage, as supported by earlier transcriptional activation of cell death and DNA repair pathways. This study provides the first mechanistic evidence that elevated HFPO-DA exposure increases hypoxia vulnerability in endangered sturgeons. These findings indicate that impaired physiological resilience to environmental extremes may represent an underappreciated toxicological outcome of emerging PFAS exposure, with important implications for endangered migratory sturgeon species inhabiting estuarine habitats increasingly challenged by concurrent contaminants and climate-change related stressors.