Altered B lymphocytes Due to Tungstate Exposure

钨酸盐暴露导致 B 淋巴细胞发生改变

• 批准号: RGPIN-2020-05899
• 负责人: Mann, Koren
• 金额: $ 2.62万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761827
• 关键词: Altered; lymphocytes; Due; Tungstate; Exposure

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.

钨在元素周期表中以字母“W”表示，位于钼（Mo）和铬的正下方。W在现代技术中的使用越来越多。钨是重量轻，但灵活和强大。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，如辐射屏蔽和动脉支架。钨与其他几种金属一起沿着开采，加拿大是第二大钨开采地。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会改变免疫反应。 钨主要积聚在骨骼中，因此可以预测会改变造血所依赖的骨髓微环境。在与Scott Bohle和Fackson Mwale博士的合作中，我们描述了钨在骨内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淋巴细胞是骨髓中产生抗体的免疫细胞。在我们之前的NSERC资助下，我们对前B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。我们确定了由钨调制的DNA损伤反应/修复途径的组成部分。这在B细胞发育中特别重要，因为该过程涉及受调节的DNA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，尽管不会单独引起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。我们提出了几套免费的实验，以确定钨对DNA修复机制的影响，在定义的组织培养系统和小鼠。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。这一过程使抗体适应它将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，我们建议通过免疫小鼠来研究这一点，这些小鼠有或没有接触过钨。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重要信息。特别是，监管机构可以使用这些信息来确定钨暴露造成的危害风险。