Sub-acute intraperitoneal quercetin administration causes dose-dependent organ histopathology and oxidative stress in healthy rats: dissociation between serum biomarkers and tissue-level structural injury

Quercetin is widely used in dietary supplements, yet its sub-acute organ safety profile in healthy organisms remains incompletely characterized. This study evaluated dose-dependent effects of intraperitoneal quercetin administration in healthy female Wistar rats (n = 6/group) receiving normal saline (control) or quercetin (5, 10, 20, or 30 mg/kg) every 72 h for 21 days. Endpoints included body and organ weights, serum biochemistry, hematology, systemic and tissue oxidative stress markers, and semi-quantitative multi-organ histopathology. Quercetin at ≥ 20 mg/kg significantly reduced percent weight gain (Dunn's test vs. control: p = 0.041 and p = 0.008, respectively) and increased liver, kidney, and spleen relative weight, with concurrent leukocytosis and lymphocytosis. Despite these changes, all serum hepatic, renal, and systemic oxidative stress markers were preserved across groups (Kruskal-Wallis, all p > 0.05). In contrast, liver and kidney tissue at ≥ 20 mg/kg showed elevated glutathione, superoxide dismutase, and catalase alongside reduced malondialdehyde. Histopathology revealed dose-related structural alterations in kidney, liver, and spleen at doses ≥ 20 mg/kg; cardiac changes were mild-to-moderate only at 30 mg/kg. Serum biomarkers consistently indicated preserved organ function despite concurrent tissue-level injury, demonstrating that conventional markers underestimate early structural damage. The co-occurrence of tissue antioxidant upregulation with histological lesions reflects a compensatory stress response consistent with hormesis. These findings underscore the value of integrating histopathological endpoints into preclinical safety evaluation of quercetin.