Protective Antioxidant Effects of Ganoderma lucidum Against Prenatal Chlorpyrifos-Induced Developmental Nephrotoxicity in Rats

Background/Objectives: Chlorpyrifos (CPF), a widely used organophosphate pesticide, has been associated with oxidative stress-mediated renal injury. Prenatal exposure may pose a risk for developmental nephrotoxicity; however, data regarding protective natural agents remain limited. This study evaluated the protective effects of Ganoderma lucidum (GNL) against CPF-induced renal alterations in rat offspring. Methods: Pregnant rats received CPF (5 mg/kg) and/or GNL (400 mg/kg) orally throughout gestation. On postnatal day 28, blood and kidney tissues from male offspring were collected for biochemical, ELISA, histopathological, immunohistochemical, and stereological analyses. Results: Prenatal CPF exposure significantly elevated serum urea and creatinine levels and induced oxidative stress, evidenced by increased malondialdehyde (MDA) and nitric oxide (NO) levels and decreased antioxidant enzyme activities (Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH)) (all p < 0.05). Renal TNF-α and IL-6 levels were significantly increased, indicating inflammatory activation. Apoptotic signaling was enhanced, demonstrated by elevated cleaved caspase-3 levels and an altered Bax/Bcl-2 ratio. Tubular injury biomarkers, kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), were markedly increased. Histopathological findings revealed tubular degeneration, while stereological analysis confirmed significant increases in cortical and glomerular volumes. GNL co-treatment attenuated oxidative stress, suppressed inflammatory cytokines, reduced caspase-3 activation, lowered KIM-1 and NGAL levels, and preserved renal structure. Conclusions: Prenatal CPF exposure induces developmental nephrotoxicity through interconnected oxidative, inflammatory, and apoptotic mechanisms. Ganoderma lucidum mitigates these alterations by restoring antioxidant defense systems, modulating the Bax/Bcl-2 apoptotic balance, suppressing pro-inflammatory cytokine production, reducing tubular injury markers, and normalizing stereologically detected renal structural changes.