Interactive renal toxicity of perfluorooctanoic acid and ethanol: Impairment of epithelial transport and redox homeostasis in male Sprague–Dawley rats

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Perfluorooctanoic acid (PFOA), a persistent environmental contaminant, often co-occurs with ethanol (EtOH), a common lifestyle factor. However, the interactive mechanisms underlying their combined renal toxicity remain poorly understood. This study investigated the nephrotoxic effects of 28-day sub-chronic co-exposure to PFOA and EtOH in male Sprague–Dawley rats. Compared with single-exposure groups, the co-exposure group exhibited significantly exacerbated notable interactive renal impairment, characterized by increased relative kidney weights without overt histopathological lesions, consistent elevations in nitrogen metabolism (BUN), and pronounced hyponatremia. At the molecular level, co-exposure induced an interactive and profound disruption of tubular epithelial integrity and transport systems. Immunofluorescence and western blot analyses revealed a coordinated downregulation of key transport proteins—aquaporin 1, aquaporin 2, and Na + /K + -ATPase—specifically localized within the renal tubules. This suppression was significantly more pronounced in the co-exposure group than in the PFOA-only group. Furthermore, a significant decrease in E-cadherin expression, without a robust increase in N-cadherin, indicated early-stage epithelial instability and compromised barrier integrity rather than a full mesenchymal transition. Notably, this structural remodeling was accompanied by an atypical suppression of redox homeostasis, evidenced by the simultaneous decline in catalase and 4-hydroxynonenal (4-HNE) levels, suggesting a state of metabolic depression. Collectively, our findings demonstrate that the interaction between PFOA and EtOH exacerbates subclinical renal vulnerability by dismantling tubular transport and structural frameworks. This study underscores the critical importance of incorporating pollutant–lifestyle interactions and internal dosimetry into future mixture-based risk assessment frameworks.

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