Altered B lymphocytes Due to Tungstate Exposure

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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.