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Archives of Toxicology

, Volume 92, Issue 11, pp 3391–3402 | Cite as

Role of peroxisome proliferator-activated receptor alpha (PPARα) and PPARα-mediated species differences in triclosan-induced liver toxicity

  • Yangshun Tang
  • Michelle M. Vanlandingham
  • Yuanfeng Wu
  • Frederick A. Beland
  • Greg R. Olson
  • Jia-Long FangEmail author
Organ Toxicity and Mechanisms
  • 283 Downloads

Abstract

Triclosan, a widely used broad spectrum anti-bacterial agent, is hepatotoxic in rodents and exhibits differential effects on mouse and human peroxisome proliferator-activated receptor alpha (PPARα) in vitro; however, the mechanism underlying triclosan-induced liver toxicity has not been elucidated. This study examined the role of mouse and human PPARα in triclosan-induced liver toxicity by comparing the effects between wild-type and PPARα-humanized mice. Female mice of each genotype received dermal applications of 0, 58, or 125 mg triclosan/kg body weight daily for 13 weeks. Following the treatment, triclosan caused an increase in liver weight and relative liver weight only in wild-type mice. The expression levels of PPARα target genes cytochrome P450 4A and acyl-coenzyme A oxidase 1 were increased in livers of both wild-type and PPARα-humanized mice, indicating that triclosan activated PPARα. Triclosan also elevated the expression levels of peroxisomal membrane protein PMP70 and catalase in the livers of both genotypes, suggesting that triclosan promoted the production of hepatocyte peroxisomes. There was an enhanced expression of cyclin D1, c-myc, proliferating cell nuclear antigen, and Ki67, and a higher percentage of BrdU-labeled hepatocytes in wild-type mice, but not in PPARα-humanized mice, demonstrating triclosan-activated PPARα had differential effects on the hepatocyte proliferation. These findings imply that the differential effects of triclosan-activated PPARα on cell proliferation may play a role in the species differences in triclosan-induced liver toxicity.

Keywords

Triclosan PPARα Liver toxicity Peroxisome Cell proliferation 

Notes

Funding

This research was partially supported by funding from the Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Yangshun Tang was supported by an appointment to the Postgraduate Research Program in the Division of Biochemical Toxicology at the National Center for Toxicological Research administered by Oak Ridge Institute for Science Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

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Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2018

Authors and Affiliations

  1. 1.Division of Biochemical ToxicologyNational Center for Toxicological Research (NCTR), U.S Food and Drug AdministrationJeffersonUSA
  2. 2.Toxicologic Pathology Associates, Inc., National Center for Toxicological Research (NCTR), U.S Food and Drug AdministrationJeffersonUSA

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