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Arch Toxicol. 2017 Nov;91(11):3507-3516. doi: 10.1007/s00204-017-1975-0. Epub 2017 May 3.

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

Yajima I1,2,3, Kumasaka MY1,2,3, Iida M1,2,3, Oshino R1,3, Tanihata H1, Al Hossain A1,3,4, Ohgami N1,2,3, Kato M5,6,7.

Author information

1
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
2
Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Aichi, 487-8501, Japan.
3
Voluntary Body for International Health Care in Universities, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
4
Directorate General of Health Services, Ministry of Health and Family Welfare, Government of People's Republic of Bangladesh, Dhaka, Bangladesh.
5
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan. katomasa@med.nagoya-u.ac.jp.
6
Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Aichi, 487-8501, Japan. katomasa@med.nagoya-u.ac.jp.
7
Voluntary Body for International Health Care in Universities, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan. katomasa@med.nagoya-u.ac.jp.

Abstract

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.

KEYWORDS:

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

PMID:
28470405
DOI:
10.1007/s00204-017-1975-0
[Indexed for MEDLINE]

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