Chantarawong Wipa, Takeda Kazuhisa, Sangartit Weerapon, Yoshizawa Miki, Pradermwong Kantimanee, Shibahara Shigeki
Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan; Inter Departmental Multidisciplinary Graduate Program in Bioscience, Faculty of Science, Kasetsart University, Bangkok, Thailand.
Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan.
Biochem Biophys Res Commun. 2014 Nov 28;454(4):594-9. doi: 10.1016/j.bbrc.2014.10.141. Epub 2014 Nov 4.
Dietary intake of cadmium is inevitable, causing age-related increase in cadmium accumulation in many organs, including hair, choroid and retinal pigment epithelium (RPE). Cadmium has been implicated in the pathogenesis of hearing loss and macular degeneration. The functions of cochlea and retina are maintained by melanocytes and RPE, respectively, and the differentiation of these pigment cells is regulated by microphthalmia-associated transcription factor (MITF). In the present study, we explored the potential toxicity of cadmium in the cochlea and retina by using cultured human melanocytes and human RPE cell lines. MITF consists of multiple isoforms, including melanocyte-specific MITF-M and widely expressed MITF-H. Levels of MITF-M protein and its mRNA in human epidermal melanocytes and HMV-II melanoma cells were decreased significantly by cadmium. In parallel with the MITF reduction, mRNA levels of tyrosinase, the key enzyme of melanin biosynthesis that is regulated by MITF-M, were also decreased. In RPE cells, however, the levels of total MITF protein, constituting mainly MITF-H, were not decreased by cadmium. We thus identify MITF-M as the molecular target of cadmium toxicity in melanocytes, thereby accounting for the increased risk of disability from melanocyte malfunction, such as hearing and vision loss among people with elevated cadmium exposure.
膳食中镉的摄入不可避免，会导致包括头发、脉络膜和视网膜色素上皮（RPE）在内的许多器官中镉积累随年龄增长而增加。镉与听力损失和黄斑变性的发病机制有关。耳蜗和视网膜的功能分别由黑素细胞和RPE维持，这些色素细胞的分化由小眼相关转录因子（MITF）调节。在本研究中，我们使用培养的人黑素细胞和人RPE细胞系探讨了镉在耳蜗和视网膜中的潜在毒性。MITF由多种异构体组成，包括黑素细胞特异性的MITF-M和广泛表达的MITF-H。镉显著降低了人表皮黑素细胞和HMV-II黑色素瘤细胞中MITF-M蛋白及其mRNA的水平。与MITF减少同时，受MITF-M调节的黑色素生物合成关键酶酪氨酸酶的mRNA水平也降低。然而，在RPE细胞中，主要由MITF-H组成的总MITF蛋白水平并未因镉而降低。因此，我们确定MITF-M是黑素细胞中镉毒性的分子靶点，从而解释了镉暴露增加人群中因黑素细胞功能障碍导致残疾风险增加的原因，如听力和视力丧失。
