J Pathol：证实温石棉具有很强的致癌性

温石棉(chrysotile asbestos)是一种商业使用的石棉。根据一项于2012年8月2日在线发表在Journal of Pathology期刊上的研究，温石棉能够在大鼠腹腔诱导产生恶性间皮瘤(malignant mesothelioma, MM)产生，并且这种癌变过程与铁过载(iron overload)强烈相关联。

为了研究温石棉的致癌性，来自日本名古屋大学医学研究生院的Li Jiang和同事们将生理盐水中的标准温石棉悬浮液注射进大鼠体内。这些接受温石棉注射的大鼠中的一些还被注射80 mg/kg次氮基三乙酸酯(nitrilotriacetate, NTA)以便加强铁催化的芬顿反应(Fenton reaction)。他们然后分析大鼠样品的组织学特征和免疫组化特征。

研究人员发现温石棉诱导的间皮癌变过程与铁过载密切相关。重复注射铁螯合剂NTA能够显著性地减少癌变所需的时间。他们发现大鼠腹膜大量地堆积着铁。在基于芯片的比较基因组杂交研究的92.6%病例当中，研究人员观察到人恶性间皮瘤和铁诱导的鼠类间皮癌变中最为常见的基因组变异为CDKN2A/2B/ARF肿瘤抑制基因的纯合性缺失(homozygous deletion)。铁诱导的大鼠恶性间皮瘤细胞高水平地表达中胚层特异性的转录因子Dlx5和Hand1，从而证实它们活跃地利用和摄取铁。

论文作者们写道，“总之，温石棉是一种比较强的致癌物，当它到达间皮细胞时，通过诱导体内局部铁过载而发挥作用。因此，人们采取更为合适的对策就是降低这种坏境癌症风险，从而提高人的寿命。”

本文编译自Rat study shows chrysotile asbestos is strong carcinogen

doi: 10.1002/path.4075
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Iron overload signature in chrysotile-induced malignant mesothelioma

Li Jiang1, Shinya Akatsuka1, Hirotaka Nagai1,2, Shan-Hwu Chew1, Hiroki Ohara1,2, Yasumasa Okazaki1, Yoriko Yamashita1, Yutaka Yoshikawa3, Hiroyuki Yasui3, Katsuya Ikuta4, Katsunori Sasaki5, Yutaka Kohgo4, Seishiro Hirano6, Yasushi Shinohara7, Norihiko Kohyama8, Takashi Takahashi9, Shinya Toyokuni

Exposure to asbestos is a risk for malignant mesothelioma (MM) in humans. Among the commercially used types of asbestos (chrysotile, crocidolite, and amosite), the carcinogenicity of chrysotile is not fully appreciated. Here, we show that all three asbestos types similarly induced MM in the rat peritoneal cavity and that chrysotile caused the earliest mesothelioma development with a high fraction of sarcomatoid histology. The pathogenesis of chrysotile-induced mesothelial carcinogenesis was closely associated with iron overload: repeated administration of an iron chelator, nitrilotriacetic acid, which promotes the Fenton reaction, significantly reduced the period required for carcinogenesis; massive iron deposition was found in the peritoneal organs with high serum ferritin; and homozygous deletion of the CDKN2A/2B/ARF tumour suppressor genes, the most frequent genomic alteration in human MM and in iron-induced rodent carcinogenesis, was observed in 92.6% of the cases studied with array-based comparative genomic hybridization. The induced rat MM cells revealed high expression of mesoderm-specific transcription factors, Dlx5 and Hand1, and showed an iron regulatory profile of active iron uptake and utilization. These data indicate that chrysotile is a strong carcinogen when exposed to mesothelia, acting through the induction of local iron overload. Therefore, an intervention to remove local excess iron might be a strategy to prevent MM after asbestos exposure. Copyright © 2012 Pathological Society of Great Britain and Ireland.