Unique renal tubule changes induced in rats and mice by the peroxisome proliferators 2,4-dichlorophenoxyacetic acid (2,4-D) and WY-14643.
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.
Ozaki
K
K
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Mahler
J F
JF
Haseman
J K
JK
Moomaw
C R
CR
Nicolette
M L
ML
Nyska
A
A
D015084:2,4-Dichlorophenoxyacetic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002374:Catalase / Q000032:analysis / Q000276:immunology; D006224:Cricetinae; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D007679:Kidney Medulla / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D007684:Kidney Tubules / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008871:Microvilli / Q000187:drug effects / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D006899:Mixed Function Oxygenases / Q000032:analysis / Q000276:immunology; D009929:Organ Size / Q000187:drug effects; D020025:Peroxisome Proliferators / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013997:Time Factors
D020025:Peroxisome Proliferators; D018809:Proliferating Cell Nuclear Antigen; D011743:Pyrimidines; D015084:2,4-Dichlorophenoxyacetic Acid; C006253:pirinixic acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D002374:Catalase; D042926:Cytochrome P-450 CYP4A