Ozaki K, Mahler J F, Haseman J K, Moomaw C R, Nicolette M L, Nyska A
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Toxicol Pathol. 2001 Jul-Aug;29(4):440-50. doi: 10.1080/01926230152499791.
Peroxisome proliferators are non-mutagenic carcinogens in the liver of rodents, acting both as initiators and promoters. The National Toxicology Program (NTP) conducted a study of several peroxisome proliferators (PPs), including Wyeth (WY)-14643 as a prototypical PP and 2,4-dichlorophenoxyacetic acid (2,4-D) as a weak PP, in Sprague-Dawley rats. B6C3F1 mice, and Syrian hamsters. In the kidney, an unusual change was observed in the outer stripe of the outer medulla, especially in rats treated with 2,4-D or WY-14643. This change was characterized by foci of tubules that were partially or completely lined by basophilic epithelial cells with decreased cytoplasm and high nuclear density. Changes typical of chronic nephropathy such as interstitial fibrosis or basement membrane thickening were not associated with these foci. Results of immunohistochemical staining for catalase and cytochrome P-450 4A in the kidney indicated increased staining intensity in renal tubular epithelial cells primarily in the region where the affected tubules were observed: however, the altered cells were negative for both immunohistochemical markers. Ultrastructurally, affected cells had long brush borders typical of the P3 tubule segment. The most distinguishing ultrastructural change was a decreased amount of electronlucent cytoplasm that contained few differentiated organelles and, in particular, a prominent reduced volume and number of mitochondria; changes in peroxisomes were not apparent. In addition to the lesion in rats, mice treated with the highest dose of 2,4-D, but not WY-14643, manifested similar renal tubular changes as seen by light microscopy. Neither chemical induced renal tubular lesions in hamsters. Hepatocellular changes characteristic of PPs were present in all 3 species treated with WY-14643, but not 2,4-D. These results indicate that the rat is the species most sensitive to the nephrotoxic effects of PPs and there is a site specificity to this toxicity related to areas of PP-related enzyme induction. Although 2,4-D is considered a weak PP for the liver, it was the most effective at inducing renal lesions, indicating that the toxic potency of various PPs will depend on the target organ.
过氧化物酶体增殖剂是啮齿动物肝脏中的非致突变性致癌物，兼具引发剂和促进剂的作用。美国国家毒理学计划（NTP）对几种过氧化物酶体增殖剂（PPs）进行了研究，其中包括典型的PPs——惠氏（WY）-14643以及弱PPs——2,4-二氯苯氧乙酸（2,4-D），研究对象为斯普拉格-道利大鼠、B6C3F1小鼠和叙利亚仓鼠。在肾脏中，在外髓质的外带观察到一种异常变化，尤其是在用2,4-D或WY-14643处理的大鼠中。这种变化的特征是肾小管灶，部分或完全由嗜碱性上皮细胞衬里，细胞质减少，核密度高。慢性肾病的典型变化，如间质纤维化或基底膜增厚，与这些病灶无关。肾脏中过氧化氢酶和细胞色素P-450 4A的免疫组织化学染色结果表明，肾小管上皮细胞的染色强度增加，主要在观察到受影响肾小管的区域；然而，改变的细胞对两种免疫组织化学标记物均呈阴性。超微结构上，受影响的细胞具有P3肾小管段典型的长刷状缘。最显著的超微结构变化是电子透明细胞质的数量减少，其中含有很少的分化细胞器，特别是线粒体的体积和数量显著减少；过氧化物酶体的变化不明显。除了大鼠的病变外，用最高剂量的2,4-D处理的小鼠，但不是WY-14643，通过光学显微镜观察到类似的肾小管变化。两种化学物质均未在仓鼠中诱发肾小管病变。在用WY-14643处理的所有3个物种中都出现了PPs特有的肝细胞变化，但用2,4-D处理的则没有。这些结果表明，大鼠是对PPs肾毒性作用最敏感的物种，并且这种毒性存在与PP相关酶诱导区域相关的位点特异性。尽管2,4-D被认为是肝脏的弱PPs，但它在诱导肾脏病变方面最有效，表明各种PPs的毒性效力将取决于靶器官。
