Arsenic-mediated hyperpigmentation in skin via NF-kappa B/endothelin-1 signaling in an originally developed hairless mouse model
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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.
KeywordsArsenic Model mouse Hyperpigmentation Endothelin-1 NF-kB
This study was supported in part by Grants-in-Aid for Scientific Research (A) (15H01743 and 15H02588), (B) (16H02962, 24390157 and 24406002) and (C) (No. 25460178, 25340052, 16K10152, 16K08343), Grant-in-Aid for Challenging Exploratory Research (26670525), Grant-in-Aid for Scientific Research on Innovative Areas (24108001 and 16H01639), COE Project for Private Universities (Nutritional Health Science Research Center; No. S1201007) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Kurita Water and Environment Foundation, the Japan Health Foundation, the Mitsui & Co., Ltd. Environment Fund, Foundation from Center for Advanced Medical and Clinical Research Nagoya University Hospital, The Mitsubishi Foundation, The Research Foundation for Health Sciences (The KENKO-KAGAKU Zaidan), Ichihara International Scholarship Foundation, The Cosmetology Research Foundation, Kao Melanin Workshop, AEON Environmental Foundation, the Sumitomo Foundation, the Salt Acience Research Foundation and Nagono Medical Foundation.
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Conflict of interest
The authors declare that they have no conflict of interest.
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