Weanling rats were placed on one of four diets [5K-96 (soy-free), AIN-CAS (AIN-93G with casein, soy-free), AIN-SPI (AIN-93G with soy protein isolate) and Purina 5001 (P5001 with soy meal)], and mated within diet groups. On GD 7, half of the dams in each diet group had 2000 ppm NP introduced into the diet. Pups were exposed during gestation and lactation and were reared after weaning (PND 21) on the diet fed their dam (NP or control) until termination. Pups were terminated on PND 2, 14, 21, or 50. Body weights were generally higher in animals fed P5001, and NP lowered terminal body weight of PND 50 animals in all diet groups. Relative kidney weights were elevated by NP in PND 50 pups in 5K96 and AIN-cas groups (about 2-fold) and in the AIN-spi group (about 30%), but not in the P5001 group. Renal injury was indicated by increases in urine volume, NAG (N-acetyl-β-D-glucosaminidase),and NAG/g creatinine. Cysts were observed in NP-treated pups only at PND 50. Incidence and severity, as well as total cyst area, followed the same pattern, with 5K96 ≈ AIN-CAS > AIN-SPI > P5001. Serum isoflavone levels were negligible in the soy-free diets and approximately 7x higher in P5001 than AIN-SPI. Cell proliferation (IHC staining for Ki-67 antigen) and apoptosis (TUNEL assay) were measured in renal sections from PND 14,21, and 50 pups in all diet groups. At all ages, NP increased numbers of apoptotic bodies in the soy-free diet groups. Increased apoptosis at PND 14 and 21 was evident prior to cyst formation, consistent with a role in NP-induced cystogenesis. Renal levels of anti-apoptotic Bcl-2 and pro-apoptotic Bax from PND 21 and 50 pups were not affected by diet or NP treatment. NP reduced CAT and GPx activity at PND50 in cystic kidneys of soy-free fed rats, but Mn-SOD activity was not affected by NP. Although precise mechanisms remain to be determined, the level of renal toxicity of NP is clearly modulated by diet and soy content is associated with protection. The results underline the importance of base diet in toxicity evaluations.
|Advisor:||Delclos, K. Barry|
|Commitee:||Gandy, Jay, Hinson, Jack A., MacMillan-Crow, Lee Ann, Mayeux, Phli|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 72/12, Dissertation Abstracts International|
|Keywords:||Dietary modulation, Nonylphenol, Polycystic kidneys, Renal toxicity|
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