Mechanisms of extrahepatic tumor induction by peroxisome proliferators in male CD rats.

  title={Mechanisms of extrahepatic tumor induction by peroxisome proliferators in male CD rats.},
  author={Lisa B. Biegel and Mark E. Hurtt and S. Randall Frame and John C O'Connor and Jon C. Cook},
  journal={Toxicological sciences : an official journal of the Society of Toxicology},
  volume={60 1},
  • L. Biegel, M. Hurtt, J. Cook
  • Published 1 March 2001
  • Biology, Medicine
  • Toxicological sciences : an official journal of the Society of Toxicology
Wyeth-14,643 (WY) and ammonium perfluorooctanoate (C8) belong to a diverse class of compounds which have been shown to produce hepatic peroxisome proliferation in rodents. From previous work, WY, but not C8, has been shown to produce hepatocellular carcinoma in rats, while C8 has been shown to produce Leydig cell adenomas. In addition, based on a review of bioassay data a relationship appears to exist between peroxisome-proliferating compounds and Leydig cell adenoma and pancreatic acinar cell… 
It is indicated that goats are weak responders to the hepatic peroxisome proliferator effects of Wyeth-14,643, and the slight serum hypolipidemic effect does not impact milk production or nutritional value.
Genomic Profiling Reveals an Alternate Mechanism for Hepatic Tumor Promotion by Perfluorooctanoic Acid in Rainbow Trout
The data suggest that the tumor-promoting activities of PFOA in trout are due to novel mechanisms involving estrogenic signaling and are independent of peroxisome proliferation.
Human Relevance of Rodent Leydig Cell Tumors
This chapter examines the mechanisms of action that induce LCTs in rats and humans and presents data on incidence, physiology, human endocrine disease, and comparative epidemiological studies that strongly indicate L CTs in rodents, in particular the rat, are of little relevance to human health.
Rodent Carcinogenicity of Peroxisome Proliferators and Issues on Human Relevance
  • D. Lai
  • Biology
    Journal of environmental science and health. Part C, Environmental carcinogenesis & ecotoxicology reviews
  • 2004
Review of the existing evidence on PPAR-,agonists by a recent International Life Science Institute workgroup following a human relevance mode of action (MOA) framework has concluded that it is unlikely that the proposed MOA for rodent tumors is plausible in humans, taking into account kinetic and dynamic factors.
The Toxicology of Perfluorooctanoate
The hepatocellular tumors observed in rats are likely to have been the result of the activation of the peroxisome proliferator activated receptor α (PPARα), and the proposed mechanism for Leydig-cell tumor formation is of questionable relevance to humans.
Toxicity of Peroxisome Proliferators
The current understanding of how PPARs are involved in tumorigenesis, and what this may mean to human risk assessment will be discussed.
Exposure to peroxisome proliferators: reassessment of the potential carcinogenic hazard.
It appears that there are no remaining concerns about the human carcinogenic potential of the clinical PPs and that the rodent liver effects have been set aside as probable laboratory curiosities, as well as continuing uncertainty regarding the safety of the nonpharmaceutical PPs.
Hepatocellular hypertrophy and cell proliferation in Sprague–Dawley rats following dietary exposure to ammonium perfluorooctanoate occurs through increased activation of the xenosensor nuclear receptors PPARα and CAR/PXR
It is suggested that the hepatomegaly and tumours observed after chronic dietary exposure of S-D rats to APFO likely are due to a proliferative response to combined activation of PPARα and CAR/PXR.
The PPARα-dependent rodent liver tumor response is not relevant to humans: addressing misconceptions
PPARα activators are unlikely to induce liver tumors in humans due to biological differences in the response of KEs downstream of PPARα activation and absence of alteration in growth pathways, hepatocyte proliferation, and tumors in the livers of species that are more appropriate human surrogates than mice and rats at overlapping dose levels.
PPARα Agonist-Induced Rodent Tumors: Modes of Action and Human Relevance
An in-depth analysis of the state of the science on several topics critical to evaluating the relationship between the MOA for PPARα agonists and the human relevance of related animal tumors produces a range of outcomes, depending partly on the quality and quantity of MOA data available from laboratory animals and related information from human data sources.


Mechanisms for the pancreatic oncogenic effects of the peroxisome proliferator Wyeth-14,643.
Chronic exposure to WY causes liver alterations such as cholestasis, which may increase plasma concentrations of CCK, and the absence of any early pancreas changes in the subchronic study is consistent with the in vitro data which demonstrated that WY is not a CCK(A) agonist or a trypsin inhibitor.
Effect of the peroxisome proliferator, ammonium perfluorooctanoate (C8), on hepatic aromatase activity in adult male Crl:CD BR (CD) rats.
The results of this study suggest that the increased serum concentration of estradiol produced by C8 in rats is at least partly due to a direct effect on the liver to increase synthesis ofEstradiol through induction of aromatase cytochrome P450 in the endoplasmic reticulum.
Effects of ammonium perfluorooctanoate on Leydig cell function: in vitro, in vivo, and ex vivo studies.
The hypothesis that C8 produces an increase in estradiol by inducing cytochrome P450 XIX (aromatase), which converts testosterone to Estradiol, and that the elevated estradio levels ultimately produce Leydig cell hyperplasia and adenoma formation is investigated.
The Direct Effect of Hepatic Peroxisome Proliferators on Rat Leydig Cell Function in Vitro1
Peroxisome proliferators, as a class of compounds, directly modify the steroidogenic function of Leydig cells in vitro, and this suggests that compounds which directly affectLeydig cell function in vitromay also induce Leydigs cell tumors in vivo.
Induction of Leydig cell adenomas by ammonium perfluorooctanoate: a possible endocrine-related mechanism.
Malignant tumors in rats fed nafenopin, a hepatic peroxisome proliferator.
  • J. Reddy, M. Rao
  • Medicine, Biology
    Journal of the National Cancer Institute
  • 1977
Nafenopin (2-methyl-2-[P-(1,2,3,4-tetrahydro-1-naphthyl)phenoxy] propionic acid; Su-13,437), a potent hypolipidemic hepatic peroxisome proliferator, was fed to male F344 rats at a dietary concentration of o.1% and was transplantable successfully through 6 generations.
Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) in rats.
A strong correlation was observed between the relative hepatocarcinogenicity of DEHP and Wy-14,643 and the ability to induce a persistent increase in replicative DNA synthesis, emphasizing the possible importance of cell replication in the mechanism of PP-induced hepatOCarcinogenesis.
Rodent Leydig cell tumorigenesis: a review of the physiology, pathology, mechanisms, and relevance to humans.
This review attempts to fill deficiencies in the literature on Leydig cell tumors by comparing the cytology and ontogeny of the LC, as well as the endocrine and paracrine regulation of both normal and tumorigenic LCs, and the pathology of LCTs in rodents and humans is compared.
Induction of coagulation effects by Wyeth-14,643 in Crl:CD BR rats.
New data suggest that deaths in the WY-treated group in the initial study were due to a vitamin K deficiency, and the role of increased serum estradiol, its effects on blood coagulation, and enhanced hepatic cell proliferation in the vitamin K-dependent coagulated processes warrant further investigation.