Division of Experimental Medicine, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
Toxicol Sci. 2013 Feb;131(2):434-46. doi: 10.1093/toxsci/kfs324. Epub 2012 Nov 14.
High environmental tungsten levels were identified near the site of a childhood pre-B acute lymphoblastic leukemia cluster; however, a causal link between tungsten and leukemogenesis has not been established. The major site of tungsten deposition is bone, the site of B-cell development. In addition, our in vitro data suggest that developing B lymphocytes are susceptible to tungsten-induced DNA damage and growth inhibition. To extend these results, we assessed whether tungsten exposure altered B-cell development and induced DNA damage in vivo. Wild-type mice were exposed to tungsten in their drinking water for up to 16 weeks. Tungsten concentration in bone was analyzed by inductively coupled plasma mass spectrometry and correlated with B-cell development and DNA damage within the bone marrow. Tungsten exposure resulted in a rapid deposition within the bone following 1 week, and tungsten continued to accumulate thereafter albeit at a decreased rate. Flow cytometric analyses revealed a transient increase in mature IgD(+) B cells in the first 8 weeks of treatment, in animals of the highest and intermediate exposure groups. Following 16 weeks of exposure, all tungsten groups had a significantly greater percentage of cells in the late pro-/large pre-B developmental stages. DNA damage was increased in both whole marrow and isolated B cells, most notably at the lowest tungsten concentration tested. These findings confirm an immunological effect of tungsten exposure and suggest that tungsten could act as a tumor promoter, providing leukemic "hits" in multiple forms to developing B lymphocytes within the bone marrow.
高环境钨水平在儿童前 B 急性淋巴细胞白血病集群的地点附近被确定；然而，钨与白血病发生之间的因果关系尚未建立。钨的主要沉积部位是骨骼，也是 B 细胞发育的部位。此外，我们的体外数据表明，正在发育的 B 淋巴细胞容易受到钨诱导的 DNA 损伤和生长抑制。为了扩展这些结果，我们评估了钨暴露是否会改变体内 B 细胞发育并诱导 DNA 损伤。野生型小鼠在饮用水中暴露于钨长达 16 周。通过电感耦合等离子体质谱法分析骨中的钨浓度，并将其与骨髓中的 B 细胞发育和 DNA 损伤相关联。钨暴露后，1 周内迅速在骨骼中沉积，此后钨继续积累，尽管积累速度降低。流式细胞术分析显示，在治疗的前 8 周内，高暴露组和中暴露组的成熟 IgD(+) B 细胞数量短暂增加。暴露 16 周后，所有钨组的晚期前 B 发育阶段的细胞比例均显著增加。整个骨髓和分离的 B 细胞中的 DNA 损伤均增加，在测试的最低钨浓度下最为明显。这些发现证实了钨暴露的免疫作用，并表明钨可能作为肿瘤促进剂，为骨髓中的发育中的 B 淋巴细胞提供多种形式的白血病“打击”。
