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Auricular Chondritis Caused by Metal Ear Tagging in C57BL/6 Mice

Safety Research Laboratories, Shiseido Research Center, Yokohama, Japan

Although it has been shown that auricular chondritis in rats is caused by the use of metal identification ear tags, the pathogenesis remains unclear. Based on the hypothesis that the auricular chondritis is caused by metal ions released from metal identification ear tags, we investigated the pathogenesis in male C57BL/6 mice tagged with metal identification ear tags. Twenty-six weeks after the attachment of the ear tags, visible increases in the thickness of the auricle were observed, and the concentrations of copper and iron in the tagged ears were significantly increased (P < .05) in the tagged ears compared with the untagged ears. There was up-regulation of metallothionein (MT)-I and MT-II mRNA in the tagged ears, and this was confirmed by immunohistologic staining of the destroyed cartilage. Histopathologically, there were observed severe chondritis with extensive granulomatous inflammation, newly formed cartilage nodules, and osseous metaplasia accompanied by cellular infiltrates, such as CD4 T lymphocyte, macrophages, neutrophils, and mast cells, and expression of Th1 cytokines, such as interferon-gamma, tumor necrosis factor-alpha, and interleukin-2 in the tagged ear. Based on these results, we concluded that the release of copper and iron ions from the metal ear tags played a major role in the onset of auricular chondritis. Subsequent cellular interactions, such as CD4 T cells, macrophages, fibroblasts, and mast cells, mediated by cytokines, such as tumor necrosis factor-alpha and interferon-gamma, caused an autoimmune response that may have led to the progression of auricular chondritis as an autoimmune disease.

Key words: Auricular chondritis; CD4; copper; iron; macrophage; metal ear tag; metallothionein; mice.

Request reprints from M. Kitagaki, Safety Research Laboratory, Quality Assurance Center, Shiseido Research Center, 2-12-1 Fukuura, Knazawa-ku, Yokohama-shi, 236-8643 (Japan). E-mail: masato.kitagaki{at}to.shiseido.co.jp