Altered B lymphocytes Due to Tungstate Exposure

钨在元素周期表中用字母“W”表示，紧挨着钼(Mo)和铬。W在现代技术中的使用越来越多。钨很轻，但很灵活，很结实。钨现在用于制造许多商品，包括灯泡、计算机、弹药、建筑设备和医疗设备，如辐射防护罩和动脉支架。钨与其他几种金属一起开采，第二大钨开采作业在加拿大。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表明，钨可以改变免疫反应。钨主要聚集在骨骼中，因此可以预测会改变造血所依赖的骨髓微环境。在与Scott Bohle博士和Fackson Mwale博士的合作中，我们描述了聚集在骨骼中的钨的形式是磷钨酸盐。此外，我们已经描述了钨改变了B淋巴细胞的发育，B淋巴细胞是产生抗体的免疫细胞，在骨髓中。在我们之前的NSERC资助下，我们对Preb淋巴细胞进行了RNA测序，Preb淋巴细胞是钨暴露小鼠积累的分化阶段。我们确定了DNA损伤反应/修复途径的成分，这些成分受到钨的调节。这在B细胞发育中尤其重要，因为这一过程涉及到受调控的断裂和修复DNA以产生抗体。我们的数据表明，钨可能会增加DNA损伤，尽管不会单独造成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。我们提出了几套相辅相成的实验来确定钨对特定组织培养系统和小鼠中DNA修复机制的影响。我们将对多种含钨化合物进行比较，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细胞被激活后，DNA也会发生同样的断裂和修复。这个过程针对它要对抗的特定外来侵略者量身定做抗体。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，我们建议进行实验，通过免疫已经或没有接触过钨的小鼠来研究这一点。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会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，监管机构可以使用这些信息来确定由于接触钨而造成的伤害风险。

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.