Arsenic-mediated hyperpigmentation in skin via NF-kappa B/endothelin-1 signaling in an originally developed hairless mouse model

Ichiro Yajima, Mayuko Y. Kumasaka, Machiko Iida, Reina Oshino, Hiroko Tanihata, Aeorangajeb Al Hossain, Nobutaka Ohgami, Masashi Kato

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Chronic exposure to arsenic is associated with various diseases in humans. Skin hyperpigmentation is the most sensitive objective symptom for patients with arsenicosis. However, there is very limited information about the mechanism of arsenic-mediated skin hyperpigmentation in vivo. In this study, hairless homozygous mice (Hr/Hr-mice) that drank water containing 3 and 30 µM arsenic for 2 months developed skin hyperpigmentation with increased levels of arsenic and number of melanocytes in the skin. Since it is possible for humans to be exposed to 3 µM of arsenic in well drinking water, our results suggest that the Hr/Hr-mice could be a novel model sensitively reflecting arsenic-mediated skin hyperpigmentation. We then analyzed the mechanism of arsenic-mediated skin hyperpigmentation. The epidermis of Hr/Hr-mice and human HaCaT skin keratinocytes exposed to arsenic for 2 and 4 months, respectively, showed 5.4–21.5-fold increased levels of endothelin-1 (ET-1) expression via NF-kappa B activation. Coexposure of primary normal human epithelial melanocytes to arsenic and ET-1 activated their proliferation and melanin synthesis with increased levels of MITF-M and ET-1 receptor expression. Our results suggest that interaction between keratinocytes and melanocytes in the skin through ET-1 and its receptor contributes to arsenic-mediated skin pigmentation, a hallmark of arsenicosis.

Original languageEnglish
Pages (from-to)3507-3516
Number of pages10
JournalArchives of Toxicology
Issue number11
Publication statusPublished - 2017 Nov 1
Externally publishedYes


  • Arsenic
  • Endothelin-1
  • Hyperpigmentation
  • Model mouse
  • NF-kB

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis


Dive into the research topics of 'Arsenic-mediated hyperpigmentation in skin via NF-kappa B/endothelin-1 signaling in an originally developed hairless mouse model'. Together they form a unique fingerprint.

Cite this