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


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.


Triclosan PPARα Liver toxicity Peroxisome Cell proliferation 



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.


  1. Adolfsson-Erici M, Pettersson M, Parkkonen J, Sturve J (2002) Triclosan, a commonly used bactericide found in human milk and in the aquatic environment in Sweden. Chemosphere 46(9–10):1485–1489CrossRefGoogle Scholar
  2. Allmyr M, Harden F, Toms L-ML et al (2008) The influence of age and gender on triclosan concentrations in Australian human blood serum. Sci Total Environ 393(1):162–167CrossRefGoogle Scholar
  3. Arsura M, Cavin LG (2005) Nuclear factor-κB and liver carcinogenesis. Cancer Lett 229(2):157–169CrossRefGoogle Scholar
  4. Calafat AM, Ye X, Wong L-Y, Reidy JA, Needham LL (2008) Urinary concentrations of triclosan in the U.S. population: 2003–2004. Environ Health Perspect 116(3):303–307CrossRefGoogle Scholar
  5. Cattley RC, Marsman DS, Popp JA (1991) Age-related susceptibility to the carcinogenic effect of the peroxisome proliferator WY-14,643 in rat liver. Carcinogenesis 12(3):469–473CrossRefGoogle Scholar
  6. Cattley RC, DeLuca J, Elcombe C et al (1998) Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol 27(1 Pt 1):47–60CrossRefGoogle Scholar
  7. Cheung C, Akiyama TE, Ward JM et al (2004) Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor α. Cancer Res 64(11):3849–3854CrossRefGoogle Scholar
  8. Corton JC, Cunningham ML, Hummer BT et al (2014) Mode of action framework analysis for receptor-mediated toxicity: the peroxisome proliferator-activated receptor alpha (PPARα) as a case study. Crit Rev Toxicol 44(1):1–49CrossRefGoogle Scholar
  9. Corton JC, Peters JM, Klaunig JE (2018) The PPARα-dependent rodent liver tumor response is not relevant to humans: addressing misconceptions. Arch Toxicol 92(1):83–119CrossRefGoogle Scholar
  10. Dayan AD (2007) Risk assessment of triclosan [Irgasan®] in human breast milk. Food Chem Toxicol 45(1):125–129CrossRefGoogle Scholar
  11. Elcombe CR, Elcombe BM, Foster JR et al (2010) 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. Arch Toxicol 84(10):787–798CrossRefGoogle Scholar
  12. Fang J-L, Stingley RL, Beland FA, Harrouk W, Lumpkins DL, Howard P (2010) Occurrence, efficacy, metabolism, and toxicity of triclosan. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 28(3):147–171CrossRefGoogle Scholar
  13. Fang J-L, Vanlandingham MM, Juliar BE, Olson GR, Patton RE, Beland FA (2015) Dose–response assessment of the dermal toxicity of triclosan in B6C3F1 mice. Toxicol Res 4:867–877CrossRefGoogle Scholar
  14. Fang J-L, Vanlandingham MM, Gamboa da Costa G, Beland FA (2016) Absorption and metabolism of triclosan after application to the skin of B6C3F1 mice. Environ Toxicol 31(5):609–623PubMedGoogle Scholar
  15. Fernández MA, Albor C, Ingelmo-Torres M et al (2006) Caveolin-1 is essential for liver regeneration. Science 313(5793):1628–1632CrossRefGoogle Scholar
  16. Grivennikov SI, Karin M (2011) Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann Rheum Dis 70(Suppl 1):i104–i108CrossRefGoogle Scholar
  17. Guyton KZ, Chiu WA, Bateson TF et al (2009) A reexamination of the PPAR-α activation mode of action as a basis for assessing human cancer risks of environmental contaminants. Environ Health Perspect 117(11):1664–1672CrossRefGoogle Scholar
  18. Hays T, Rusyn I, Burns AM et al (2005) Role of peroxisome proliferator-activated receptor-α (PPARα) in bezafibrate-induced hepatocarcinogenesis and cholestasis. Carcinogenesis 26(1):219–227CrossRefGoogle Scholar
  19. Hovander L, Malmberg T, Athanasiadou M et al (2002) Identification of hydroxylated PCB metabolites and other phenolic halogenated pollutants in human blood plasma. Arch Environ Contam Toxicol 42(1):105–117CrossRefGoogle Scholar
  20. Huber W, Kraupp-Grasl B, Esterbauer H, Schulte-Hermann R (1991) Role of oxidative stress in age dependent hepatocarcinogenesis by the peroxisome proliferator nafenopin in the rat. Cancer Res 51(7):1789–1792PubMedGoogle Scholar
  21. Hurst CH, Waxman DJ (2003) Activation of PPARα and PPARγ by environmental phthalate monoesters. Toxicol Sci 74(2):297–308CrossRefGoogle Scholar
  22. Karin M (2006) Nuclear factor-κB in cancer development and progression. Nature 441(7092):431–436CrossRefGoogle Scholar
  23. Klaunig JE, Babich MA, Baetcke KP et al (2003) PPARα agonist-induced rodent tumors: modes of action and human relevance. Crit Rev Toxicol 33(6):655–780CrossRefGoogle Scholar
  24. Lefebvre P, Chinetti G, Fruchart J-C, Staels B (2006) Sorting out the roles of PPARα in energy metabolism and vascular homeostasis. J Clin Invest 116(3):571–580CrossRefGoogle Scholar
  25. Liu A, Krausz KW, Fang Z-Z, Brocker C, Qu A, Gonzalez FJ (2014) Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity. Arch Toxicol 88(4):983–996CrossRefGoogle Scholar
  26. McMullen PD, Bhattacharya S, Woods CG et al (2014) A map of the PPARα transcription regulatory network for primary human hepatocytes. Chem Biol Interact 209:14–24CrossRefGoogle Scholar
  27. Molitor E, Persohn E, Thomas H (1992) The effect of FAT 80′023/Q (Irgasan DP 300) on selected biochemical and morphological liver parameters following subchronic dietary administration to male and female mice. Ciba-Geigy Limited Laboratory report no. CB 91/18 (cited by The Soap And Detergent Association (2009) Triclosan: comments on carcinogenicity studies and other relevant data, submitted to California Environmental Protection Agency)Google Scholar
  28. Olaniyan LWB, Mkwetshana N, Okoh AI (2016) Triclosan in water, implications for human and environmental health. SpringerPlus 5(1):1639CrossRefGoogle Scholar
  29. Palmer CNA, Hsu M-H, Griffin KJ, Raucy JL, Johnson EF (1998) Peroxisome proliferator activated receptor-α expression in human liver. Mol Pharmacol 53(1):14–22CrossRefGoogle Scholar
  30. Rakhshandehroo M, Hooiveld G, Müller M, Kersten S (2009) Comparative analysis of gene regulation by the transcription factor PPARα between mouse and human. PLoS One 4(8):e6796CrossRefGoogle Scholar
  31. Rodricks JV, Swenberg JA, Borzelleca JF, Maronpot RR, Shipp AM (2010) Triclosan: a critical review of the experimental data and development of margins of safety for consumer products. Crit Rev Toxicol 40(5):422–484CrossRefGoogle Scholar
  32. Shearer BG, Hoekstra WJ (2003) Recent advances in peroxisome proliferator-activated receptor science. Curr Med Chem 10(4):267–280CrossRefGoogle Scholar
  33. Takacs ML, Abbott BD (2007) Activation of mouse and human peroxisome proliferator-activated receptors (α, β/δ, γ) by perfluorooctanoic acid and perfluorooctane sulfonate. Toxicol Sci 95(1):108–117CrossRefGoogle Scholar
  34. van Raalte DH, Li M, Pritchard PH, Wasan KM (2004) Peroxisome proliferator-activated receptor (PPAR)-α: a pharmacological target with a promising future. Pharm Res 21(9):1531–1538CrossRefGoogle Scholar
  35. Wu Y, Wu Q, Beland FA, Ge P, Manjanatha MG, Fang J-L (2014) Differential effects of triclosan on the activation of mouse and human peroxisome proliferator-activated receptor alpha. Toxicol Lett 231(1):17–28CrossRefGoogle Scholar
  36. Wu Y, Beland FA, Chen S, Fang J-L (2015) Extracellular signal-regulated kinases 1/2 and Akt contribute to triclosan-stimulated proliferation of JB6 Cl 41-5a cells. Arch Toxicol 89(8):1297–1311CrossRefGoogle Scholar
  37. Yueh M-F, Taniguchi K, Chen S et al (2014) The commonly used antimicrobial additive triclosan is a liver tumor promoter. Proc Natl Acad Sci USA 111(48):17200–17205CrossRefGoogle Scholar

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

Personalised recommendations