Histopathology of the urinary bladders of cynomolgus monkeys treated with PPAR agonists

Jerry F. Hardisty, Daniel C. Anderson, Scott Brodie, J. Mark Cline, Fletcher F. Hahn, Holly Kolenda-Roberts, Subodh M Lele, Linda J. Lowenstine

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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 PPARγ and dual α/γ 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.

Original languageEnglish (US)
Pages (from-to)769-776
Number of pages8
JournalToxicologic Pathology
Volume36
Issue number6
DOIs
StatePublished - Oct 1 2008

Fingerprint

Peroxisome Proliferator-Activated Receptors
Macaca fascicularis
Urinary Bladder
Rodentia
Environmental Health
Pathology
Medical problems
Hypertrophy
Hyperplasia
Tumors
Health
Biological Science Disciplines
Diabetes Complications
Terminology
Vacuoles
Hyperlipidemias
Type 2 Diabetes Mellitus
Action Potentials
Haplorhini
Toxicity

Keywords

  • Cynomolgus monkey
  • Diagnostic criteria
  • Hyperplasia
  • PPAR agonists
  • Urinary bladder
  • Vacuolation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Toxicology
  • Cell Biology

Cite this

Hardisty, J. F., Anderson, D. C., Brodie, S., Cline, J. M., Hahn, F. F., Kolenda-Roberts, H., ... Lowenstine, L. J. (2008). Histopathology of the urinary bladders of cynomolgus monkeys treated with PPAR agonists. Toxicologic Pathology, 36(6), 769-776. https://doi.org/10.1177/0192623308323624

Histopathology of the urinary bladders of cynomolgus monkeys treated with PPAR agonists. / Hardisty, Jerry F.; Anderson, Daniel C.; Brodie, Scott; Cline, J. Mark; Hahn, Fletcher F.; Kolenda-Roberts, Holly; Lele, Subodh M; Lowenstine, Linda J.

In: Toxicologic Pathology, Vol. 36, No. 6, 01.10.2008, p. 769-776.

Research output: Contribution to journalArticle

Hardisty, JF, Anderson, DC, Brodie, S, Cline, JM, Hahn, FF, Kolenda-Roberts, H, Lele, SM & Lowenstine, LJ 2008, 'Histopathology of the urinary bladders of cynomolgus monkeys treated with PPAR agonists', Toxicologic Pathology, vol. 36, no. 6, pp. 769-776. https://doi.org/10.1177/0192623308323624
Hardisty JF, Anderson DC, Brodie S, Cline JM, Hahn FF, Kolenda-Roberts H et al. Histopathology of the urinary bladders of cynomolgus monkeys treated with PPAR agonists. Toxicologic Pathology. 2008 Oct 1;36(6):769-776. https://doi.org/10.1177/0192623308323624
Hardisty, Jerry F. ; Anderson, Daniel C. ; Brodie, Scott ; Cline, J. Mark ; Hahn, Fletcher F. ; Kolenda-Roberts, Holly ; Lele, Subodh M ; Lowenstine, Linda J. / Histopathology of the urinary bladders of cynomolgus monkeys treated with PPAR agonists. In: Toxicologic Pathology. 2008 ; Vol. 36, No. 6. pp. 769-776.
@article{4d406de8580d48578d202bd82e844164,
title = "Histopathology of the urinary bladders of cynomolgus monkeys treated with PPAR agonists",
abstract = "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 PPARγ and dual α/γ 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.",
keywords = "Cynomolgus monkey, Diagnostic criteria, Hyperplasia, PPAR agonists, Urinary bladder, Vacuolation",
author = "Hardisty, {Jerry F.} and Anderson, {Daniel C.} and Scott Brodie and Cline, {J. Mark} and Hahn, {Fletcher F.} and Holly Kolenda-Roberts and Lele, {Subodh M} and Lowenstine, {Linda J.}",
year = "2008",
month = "10",
day = "1",
doi = "10.1177/0192623308323624",
language = "English (US)",
volume = "36",
pages = "769--776",
journal = "Toxicologic Pathology",
issn = "0192-6233",
publisher = "SAGE Publications Inc.",
number = "6",

}

TY - JOUR

T1 - Histopathology of the urinary bladders of cynomolgus monkeys treated with PPAR agonists

AU - Hardisty, Jerry F.

AU - Anderson, Daniel C.

AU - Brodie, Scott

AU - Cline, J. Mark

AU - Hahn, Fletcher F.

AU - Kolenda-Roberts, Holly

AU - Lele, Subodh M

AU - Lowenstine, Linda J.

PY - 2008/10/1

Y1 - 2008/10/1

N2 - 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 PPARγ and dual α/γ 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.

AB - 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 PPARγ and dual α/γ 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.

KW - Cynomolgus monkey

KW - Diagnostic criteria

KW - Hyperplasia

KW - PPAR agonists

KW - Urinary bladder

KW - Vacuolation

UR - http://www.scopus.com/inward/record.url?scp=54949096932&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=54949096932&partnerID=8YFLogxK

U2 - 10.1177/0192623308323624

DO - 10.1177/0192623308323624

M3 - Article

VL - 36

SP - 769

EP - 776

JO - Toxicologic Pathology

JF - Toxicologic Pathology

SN - 0192-6233

IS - 6

ER -