Extracellular signal-regulated kinases 1/2 and Akt contribute to triclosan-stimulated proliferation of JB6 Cl 41-5a cells

Arch Toxicol. 2015 Aug;89(8):1297-311. doi: 10.1007/s00204-014-1308-5. Epub 2014 Jul 18.

Abstract

Triclosan is a broad spectrum anti-bacterial agent widely used in many personal care products, household items, medical devices, and clinical settings. Human exposure to triclosan is mainly through oral and dermal routes. In previous studies, we found that sub-chronic dermal exposure of B6C3F1 mice to triclosan induced epidermal hyperplasia and focal necrosis; however, the mechanisms for these responses remain elusive. In this study, using mouse epidermis-derived JB6 Cl 41-5a cells, we found that triclosan stimulated cell growth in a concentration- and time-dependent manner. Enhanced cell proliferation was demonstrated by a substantial increase in the percentage of BrdU-positive cells, an elevation in the protein levels of cyclin D1 and cyclin A, and a reduction in the protein level of p27(Kip1). Western blotting analysis revealed that triclosan induced the activation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), p38, and Akt. Pre-treatment of the cells with PD184352, an inhibitor of the upstream kinase MEK1/2, or with wortmannin, an inhibitor of phosphoinositide 3-kinase, blocked triclosan-mediated phosphorylation of ERK1/2 and Akt, respectively, and substantially suppressed triclosan-stimulated cell proliferation, whereas the JNK inhibitor SP600125 or the p38 inhibitor SB203580 had little to no effect on triclosan-stimulated cell proliferation. The phosphorylation activation of ERK1/2 and Akt was further confirmed on the skin of mice dermally administered triclosan. These data suggest that the activation of ERK1/2 and Akt is involved in triclosan-stimulated proliferation of JB6 Cl 41-5a cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Infective Agents, Local / toxicity*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Culture Techniques
  • Cell Line
  • Cell Proliferation / drug effects*
  • Comet Assay
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Female
  • Mice, Inbred Strains
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Time Factors
  • Triclosan / toxicity*

Substances

  • Anti-Infective Agents, Local
  • Enzyme Inhibitors
  • Triclosan
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3