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Research Article

The commonly used antimicrobial additive triclosan is a liver tumor promoter

Mei-Fei Yueh, Koji Taniguchi, Shujuan Chen, Ronald M. Evans, Bruce D. Hammock, Michael Karin, and Robert H. Tukey
  1. aLaboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, and
  2. bLaboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093;
  3. cGene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037; and
  4. dDepartment of Entomology and Nematology and Comprehensive Cancer Center, University of California Davis Cancer Center, University of California, Davis, CA 95616

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PNAS first published November 17, 2014; https://doi.org/10.1073/pnas.1419119111
Mei-Fei Yueh
aLaboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, and
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Koji Taniguchi
bLaboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093;
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Shujuan Chen
aLaboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, and
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Ronald M. Evans
cGene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037; and
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Bruce D. Hammock
dDepartment of Entomology and Nematology and Comprehensive Cancer Center, University of California Davis Cancer Center, University of California, Davis, CA 95616
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  • For correspondence: rtukey@ucsd.edu bdhammock@ucdavis.edu
Michael Karin
bLaboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093;
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Robert H. Tukey
aLaboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, and
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  • For correspondence: rtukey@ucsd.edu bdhammock@ucdavis.edu
  1. Contributed by Bruce D. Hammock, October 8, 2014 (sent for review June 17, 2014; reviewed by Christopher A. Bradfield and Margaret O. James)

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Significance

Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a broad-spectrum antimicrobial agent that has become one of the most common additives used in consumer products. As a result, TCS has significantly affected the environment and has been frequently detected in human body fluids. Through a long-term feeding study, we found that TCS enhances hepatocyte proliferation, fibrogenesis, and oxidative stress, which, we believe, can be the driving force for developing advanced liver disease in mice. Indeed, TCS strongly enhances hepatocarcinogenesis after diethylnitrosamine initiation, accelerating hepatocellular carcinoma (HCC) development. Although animal studies require higher chemical concentrations than predicted for human exposure, this study demonstrates that TCS acts as a HCC tumor promoter and that the mechanism of TCS-induced mouse liver pathology may be relevant to humans.

Abstract

Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a synthetic, broad-spectrum antibacterial chemical used in a wide range of consumer products including soaps, cosmetics, therapeutics, and plastics. The general population is exposed to TCS because of its prevalence in a variety of daily care products as well as through waterborne contamination. TCS is linked to a multitude of health and environmental effects, ranging from endocrine disruption and impaired muscle contraction to effects on aquatic ecosystems. We discovered that TCS was capable of stimulating liver cell proliferation and fibrotic responses, accompanied by signs of oxidative stress. Through a reporter screening assay with an array of nuclear xenobiotic receptors (XenoRs), we found that TCS activates the nuclear receptor constitutive androstane receptor (CAR) and, contrary to previous reports, has no significant effect on mouse peroxisome proliferation activating receptor α (PPARα). Using the procarcinogen diethylnitrosamine (DEN) to initiate tumorigenesis in mice, we discovered that TCS substantially accelerates hepatocellular carcinoma (HCC) development, acting as a liver tumor promoter. TCS-treated mice exhibited a large increase in tumor multiplicity, size, and incidence compared with control mice. TCS-mediated liver regeneration and fibrosis preceded HCC development and may constitute the primary tumor-promoting mechanism through which TCS acts. These findings strongly suggest there are adverse health effects in mice with long-term TCS exposure, especially on enhancing liver fibrogenesis and tumorigenesis, and the relevance of TCS liver toxicity to humans should be evaluated.

  • triclosan
  • liver fibrosis
  • tumor promoter
  • hepatocellular carcinoma

Footnotes

  • ↵1To whom correspondence may be addressed. Email: rtukey{at}ucsd.edu or bdhammock{at}ucdavis.edu.
  • Author contributions: M.-F.Y., K.T., S.C., and R.H.T. designed research; M.-F.Y., K.T., and S.C. performed research; M.-F.Y., K.T., S.C., R.M.E., B.D.H., M.K., and R.H.T. contributed new reagents/analytic tools; M.-F.Y. analyzed data; and M.-F.Y., M.K., and R.H.T. wrote the paper.

  • Reviewers: C.A.B., University of Wisconsin–Madison; and M.O.J., University of Florida.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1419119111/-/DCSupplemental.

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Triclosan promotes liver fibrosis and tumor growth
Mei-Fei Yueh, Koji Taniguchi, Shujuan Chen, Ronald M. Evans, Bruce D. Hammock, Michael Karin, Robert H. Tukey
Proceedings of the National Academy of Sciences Nov 2014, 201419119; DOI: 10.1073/pnas.1419119111

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Triclosan promotes liver fibrosis and tumor growth
Mei-Fei Yueh, Koji Taniguchi, Shujuan Chen, Ronald M. Evans, Bruce D. Hammock, Michael Karin, Robert H. Tukey
Proceedings of the National Academy of Sciences Nov 2014, 201419119; DOI: 10.1073/pnas.1419119111
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