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Toxicologic Pathology
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Comparison of Endothelial Cell Proliferation in Normal Liver and Adipose Tissue in B6C3F1 Mice, F344 Rats, and Humans

Takamasa Ohnishi, Lora L. Arnold, Nicol M. Clark, James L. Wisecarver and Samuel M. Cohen

Department of Pathology and Microbiology and the UNMC/Eppley Cancer Center, University of Nebraska Medical Center, 983135 Nebraska Medical Center, Omaha, NE 68198-3135

Correspondence: Address correspondence to: Samuel M Cohen, University of Nebraska, Medical Center, 983135 Nebraska Medical Center, Omaha, NE 68198-3135; e-mail:scohen{at}unmc.edu

Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) and dual PPAR{alpha} and {gamma} agonists have been developed for use in the treatment of diabetes and hyperlipidemias. Vascular tumors were increased in mice treated with some PPAR agonists, but not in rats. Spontaneous hemangiosarcomas are common in several strains of mice, uncommon in rats, and rarely occur in humans. The objective of this study was to determine the endothelial cell proliferation rate in liver and adipose tissue of B6C3F1 mice, F344 rats, and humans to aid in investigations of the genesis and development of hemangiosarcoma formation, and to determine the relevance of the increased endothelial cell proliferation rate in drug-treated rodents in assessing the risk of these drugs in humans. We determined the endothelial cell labeling index (LI) in untreated mice, rats, and humans, in normal liver, brown fat (rats and mice only) and white fat by dual immunohistochemistry of CD31 and Ki-67. The LI, highest in mice and lowest in humans, was statistically significantly greater in the mouse compared to the human and rat. The increased rate of spontaneous or PPAR agonist-induced hemangiosarcoma formation in mice may be related to the higher background endothelial cell proliferation rate compared to rats and humans.

Key Words: Endothelial cell • proliferation • PPAR{gamma} • hemangiosarcoma

Abbreviations: PPAR{gamma}, peroxisome proliferators-activated receptor gamma • LI, labeling index • PBF, phosphate-buffered formalin • HE, hematoxylin and eosin • DAB, 3, 3'-diaminobenzidine tetrahydrochloride

Toxicologic Pathology, Vol. 35, No. 7, 904-909 (2007)
DOI: 10.1080/01926230701748081
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