ABSTRACT
Information is lacking regarding the biological response to environmental chemicals in the context of pre-existing disease. Benzo(alpha)pyrene (BaP), a polycyclic aromatic hydrocarbon, is a byproduct of combustion that causes renal injury and elicits a nephropathic response. This study evaluated the nephrotoxicity of BaP in normoglycemic and diabetic rats. Female Sprague Dawley rats were divided into four groups: normoglycemic-vehicle (NV), normoglycemic-BaP (N-BaP), diabetic-vehicle (DV) and diabetic-BaP (D-BaP). Diabetes was induced by intraperitoneal (ip) injection of streptozotocin (60 mg/kg, 1 ml/kg). Rats were injected (ip) with vehicle or 10 mg/kg BaP (1 ml/kg) once per week for 5 weeks. Urinary protein and albumin, plasma creatinine and light microscopy were performed to assess the effects of BaP on kidney function. Diabetes was confirmed by plasma glucose levels >400 mg/dl in the DV and D-BaP groups. BaP increased kidney weight and blood urea nitrogen (BUN) levels in the D-BaP relative to the DV group. No change in BUN was observed following 5 weeks of BaP treatment in the normoglycemic animals, however, kidney weight was increased (p=0.013) in the N-BaP relative to the NV animals. STZ diabetes increased susceptibility to BaP mediated renal damage following repeated treatment for 5 weeks when compared to age matched normoglycemic rats.
Subject(s)
Benzo(a)pyrene/toxicity , Diabetes Mellitus, Experimental/complications , Environmental Pollutants/toxicity , Kidney Diseases/etiology , Animals , Blood Glucose/analysis , Body Weight/drug effects , Disease Susceptibility , Female , Kidney/drug effects , Kidney/pathology , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Kidney Function Tests , Rats , Rats, Sprague-DawleyABSTRACT
The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity in mammals characterized as polyuric renal failure and proximal tubular necrosis. Recent studies have suggested that NDPS-induced nephrotoxicity may be mediated by metabolites arising from the nephrotoxic NDPS metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and/or N-(3,5-dichlorophenyl)-2-succinamic acid (2-NDHSA). The purpose of this study was to examine the effects of N-acetylcysteine (NAC), a nucleophilic agent, and two nonnucleophilic N-acetylamino acids, N-acetylserine (NAS) and N-acetylalanine (NAA), on NDPS and NDPS metabolite-induced nephrotoxicity. Male Fischer 344 rats (4-8/group) were administered intraperitoneally (ip) an N-acetylamino acid (1 mmol/kg) 2 h before an ip injection of NDPS (0.4 mmol/kg), NDHS (0.1 mmol/kg), 2-NDHSA (0.1 mmol/kg), or vehicle. Renal function was then monitored at 24 and 48 h. NAC pretreatment markedly attenuated NDPS-, NDHS-, and 2-NDHSA-mediated nephrotoxicity. The nonnucleophilic N-acetylamino acids (NAS, NAA) only partly reduced NDPS and NDHS nephrotoxicity, and they had little effect on 2-NDHSA nephrotoxicity. These results suggest that reactive NDPS metabolites may be formed from NDHS and 2-NDHSA and that nucleophilic substrates (e.g., NAC) may offer protection from NDPS-induced nephrotoxicity. However, mechanisms other than chemical neutralization of reactive NDPS metabolites may also be contributing to the attenuation of NDPS nephrotoxicity, since nonnucleophilic N-acetylamino acids (e.g., NAA) also provided some protection against NDPS and NDHS nephrotoxicity.
