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Histopathology of the Urinary Bladders of Cynomolgus Monkeys Treated with PPAR Agonists

¹ Experimental Pathology Laboratories, Inc., Research Triangle Park, North Carolina, USA
² Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
³ Schering-Plough Research Institute, Lafayette, New Jersey, USA
⁴ Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
⁵ Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA
⁶ University of Nebraska Medical Center, Omaha, Nebraska, USA
⁷ University of California, Davis, California, USA

Correspondence: Holly M. Kolenda-Roberts, EPL, Inc., P.O. Box 12766, Research Triangle Park, NC 27709, USA; e-mail:hroberts{at}epl-inc.com.

Peroxisome proliferator-activated receptors (PPAR) are involved in the pathogenesis of insulin resistance, diabetes, hyperlipidemias, and related complications. Consequently, a mechanistic understanding of PPAR subtypes and their activation provides promising therapeutic targets for the management of type 2 diabetes mellitus and the metabolic syndrome. Available data from rodent carcinogenicity studies, however, demonstrate that PPAR agonists can be tumorigenic in one or more species of rodents at multiple sites. Sufficient data are not yet available to explain the mode(s) of action for most of these tumor types. There has been information presented by FDA that indicates there are urothelial changes in the monkey (and possibly the dog) in addition to the rat. Outstanding questions exist regarding potency, species differences, safety margins, and other issues.

In 2005, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) PPAR Agonist Project Committee was established to advance research on the modes of action and potential human relevance of emerging rodent tumor data. Additionally, the HESI PPAR Agonist Project Committee authorized a Pathology Working Group (PWG) to examine the urinary bladder from cynomolgus monkeys. The focus of this PWG was to establish consistent diagnostic criteria for urothelial changes and to assess the potential relationship of these changes to treatment. Specific diagnostic criteria and nomenclature were recommended for the diagnosis of urothelial granules, vacuolation, hypertrophy, and hyperplasia in studies conducted with PPAR and dual / agonists in cynomolgus monkeys, which will assist investigators performing toxicity studies to provide data in a consistent manner between studies and laboratories. In this review of selected tissues, treatment with PPAR agonists was not associated with urothelial hypertrophy or hyperplasia, but there was an increased incidence in the size and frequency of vacuoles within the superficial urothelial and adjacent intermediate cell layers.

Key Words: PPAR agonists • urinary bladder • cynomolgus monkey • vacuolation • hyperplasia • diagnostic criteria

This version was published on October 1, 2008

Toxicologic Pathology, Vol. 36, No. 6, 769-776 (2008)
DOI: 10.1177/0192623308323624


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