Altered B lymphocytes Due to Tungstate Exposure

在元素周期表上，钨在钼（Mo）和铬的正下方用字母“W”表示。W在现代技术中的应用越来越多。钨重量轻，但柔韧性强。钨现在被用于制造许多商品，包括灯泡、电脑、弹药、建筑设备和医疗设备，如辐射屏蔽和动脉支架。钨和其他几种金属一起被开采，第二大的钨矿是在加拿大发现的。钨使用量的增加意味着更多的钨被开采，环境污染也在增加。我的研究小组和其他人已经证明，钨可以改变免疫反应。钨主要在骨骼中积累，因此，可以预测会改变造血所依赖的骨髓微环境。在与博士合作。Scott Bohle和Fackson Mwale，我们已经描述了钨在骨骼中积累的形式为磷钨酸盐。此外，我们已经描述了钨改变B淋巴细胞的发育，B淋巴细胞是在骨髓中产生抗体的免疫细胞。在之前的NSERC资助下，我们对preB淋巴细胞进行了RNA测序，这是钨暴露小鼠中积累的分化阶段。我们确定了由钨调节的DNA损伤反应/修复途径的组成部分。这在B细胞发育过程中尤为重要，因为这一过程涉及到DNA的断裂和修复以产生抗体。我们的数据表明，钨可能会增强DNA损伤，尽管它不会单独造成DNA损伤。我们假设这是由于修复减少，即用于产生抗体的相同修复过程。我们提出了几组互补的实验来确定钨对DNA修复机制的影响，在组织培养系统和小鼠中。我们将比较多种含钨化合物，因为它们可能不会以相同的方式改变DNA损伤反应。成熟的B细胞在被激活后也会发生同样的DNA断裂和修复。这个过程使抗体适应它要对抗的特定外来入侵者。我们的初步数据表明，钨也可能损害这种反应（称为类开关重组）。因此，我们建议通过对接触过或未接触过钨的小鼠进行免疫来研究这一问题。通过这些实验，我们将确定这种金属如何与免疫系统相互作用，特别是B淋巴细胞反应。环境中钨的增加可能对生态系统产生深远的影响。这些数据将提供有关钨的相对毒性的基本信息。特别是，监管机构可以利用这些信息来确定钨暴露造成的危害风险。

Tungsten is represented by the letter "W" on the periodic table right below molybdenum (Mo) and chromium. W is increasing used in modern technology. Tungsten is light-weight, yet flexible and strong. Tungsten is now used in the manufacture of many goods including light bulbs, computers, ammunitions, construction equipment, and medical devices, such as radiation shields and arterial stents. Tungsten is mined along with several other metals, and the second largest tungsten mining operation is found in Canada. The increased usage of tungsten means that more is mined and that environmental contamination is increasing. My research group and others have shown that tungsten alters the immune response. Tungsten accumulates primarily in the bone and thus, could be predicted to alter the bone marrow microenvironment on which hematopoiesis is dependent. In collaboration with Drs. Scott Bohle and Fackson Mwale, we have described the form of tungsten that accumulates within the bone as a phosphotungstate. In addition, we have described that tungsten alters the development of B lymphocytes, the immune cells that produce antibody, within the bone marrow. With our previous NSERC funding, we performed RNA Sequencing on preB lymphocytes, the stage of differentiation which accumulates in tungsten-exposed mice. We identified components of the DNA damage response/repair pathways, which were modulated by tungsten. This is particularly important in B cell development, as this process involves regulated breaking and repairing DNA to generate antibodies. Our data suggest that tungsten may enhance DNA damage, although doesn't cause DNA damage alone. We hypothesize that this is due to decreased repair, namely the same repair processes used to generate antibody. We propose several complimentary sets of experiments to define the effects of tungsten on DNA repair mechanisms in defined tissue culture systems and in mice. We will compare multiple tungsten-containing compounds as they may not all alter DNA damage responses in the same manner. The same breaking and repair of DNA occurs in mature B cells after they are activated. This process tailors the antibody towards the particular foreign invader that it will fight. Our preliminary data indicate tungsten may also impair this response (called class switch recombination). So, we propose experiments to investigate this by immunizing mice that have or have not been exposed to tungsten. Through these experiments, we will define how this metal interacts with the immune system, specifically B lymphocyte responses. Increased environmental tungsten may have profound effects on ecosystems. These data will provide essential information regarding the relative toxicity of tungsten. In particular, regulatory agencies could use this information to determine risk of harm due to tungsten exposure.