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

  • Organ Toxicity and Mechanisms
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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.

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References

  • 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):1485–1489

    Article  CAS  Google Scholar 

  • 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):162–167

    Article  CAS  Google Scholar 

  • Arsura M, Cavin LG (2005) Nuclear factor-κB and liver carcinogenesis. Cancer Lett 229(2):157–169

    Article  CAS  Google Scholar 

  • 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):303–307

    Article  CAS  Google Scholar 

  • 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):469–473

    Article  CAS  Google Scholar 

  • 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):47–60

    Article  CAS  Google Scholar 

  • 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):3849–3854

    Article  CAS  Google Scholar 

  • 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):1–49

    Article  CAS  Google Scholar 

  • 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):83–119

    Article  CAS  Google Scholar 

  • Dayan AD (2007) Risk assessment of triclosan [Irgasan®] in human breast milk. Food Chem Toxicol 45(1):125–129

    Article  CAS  Google Scholar 

  • 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):787–798

    Article  CAS  Google Scholar 

  • 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):147–171

    Article  CAS  Google Scholar 

  • 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 4:867–877

    Article  CAS  Google Scholar 

  • 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):609–623

    CAS  PubMed  Google Scholar 

  • Fernández MA, Albor C, Ingelmo-Torres M et al (2006) Caveolin-1 is essential for liver regeneration. Science 313(5793):1628–1632

    Article  Google Scholar 

  • 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–i108

    Article  CAS  Google Scholar 

  • 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):1664–1672

    Article  CAS  Google Scholar 

  • 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):219–227

    Article  CAS  Google Scholar 

  • 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):105–117

    Article  CAS  Google Scholar 

  • 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):1789–1792

    CAS  PubMed  Google Scholar 

  • Hurst CH, Waxman DJ (2003) Activation of PPARα and PPARγ by environmental phthalate monoesters. Toxicol Sci 74(2):297–308

    Article  CAS  Google Scholar 

  • Karin M (2006) Nuclear factor-κB in cancer development and progression. Nature 441(7092):431–436

    Article  CAS  Google Scholar 

  • 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):655–780

    Article  CAS  Google Scholar 

  • 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):571–580

    Article  CAS  Google Scholar 

  • 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):983–996

    Article  CAS  Google Scholar 

  • McMullen PD, Bhattacharya S, Woods CG et al (2014) A map of the PPARα transcription regulatory network for primary human hepatocytes. Chem Biol Interact 209:14–24

    Article  CAS  Google Scholar 

  • 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)

  • Olaniyan LWB, Mkwetshana N, Okoh AI (2016) Triclosan in water, implications for human and environmental health. SpringerPlus 5(1):1639

    Article  CAS  Google Scholar 

  • 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):14–22

    Article  CAS  Google Scholar 

  • 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):e6796

    Article  Google Scholar 

  • 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):422–484

    Article  CAS  Google Scholar 

  • Shearer BG, Hoekstra WJ (2003) Recent advances in peroxisome proliferator-activated receptor science. Curr Med Chem 10(4):267–280

    Article  CAS  Google Scholar 

  • 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):108–117

    Article  CAS  Google Scholar 

  • 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):1531–1538

    Article  Google Scholar 

  • 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):17–28

    Article  CAS  Google Scholar 

  • 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):1297–1311

    Article  CAS  Google Scholar 

  • 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):17200–17205

    Article  CAS  Google Scholar 

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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.

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Authors and Affiliations

  1. Division of Biochemical Toxicology, National Center for Toxicological Research (NCTR), U.S Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA

    Yangshun Tang, Michelle M. Vanlandingham, Yuanfeng Wu, Frederick A. Beland & Jia-Long Fang

  2. Toxicologic Pathology Associates, Inc., National Center for Toxicological Research (NCTR), U.S Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA

    Greg R. Olson

Authors
  1. Yangshun Tang
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  2. Michelle M. Vanlandingham
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  3. Yuanfeng Wu
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  4. Frederick A. Beland
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  5. Greg R. Olson
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  6. Jia-Long Fang
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Correspondence to Jia-Long Fang.

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The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration.

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Tang, Y., M. Vanlandingham, M., Wu, Y. et al. Role of peroxisome proliferator-activated receptor alpha (PPARα) and PPARα-mediated species differences in triclosan-induced liver toxicity. Arch Toxicol 92, 3391–3402 (2018). https://doi.org/10.1007/s00204-018-2308-7

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  • DOI: https://doi.org/10.1007/s00204-018-2308-7

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