title: In vivo tungsten exposure alters B-cell development and increases DNA damage in murine bone marrow.
abstract: 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.
authors.affiliation: Division of Experimental Medicine, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
authors.forename: Alexander D R
authors.initials: AD
authors.lastname: Kelly
authors.forename: Maryse
authors.initials: M
authors.lastname: Lemaire
authors.forename: Yoon Kow
authors.initials: YK
authors.lastname: Young
authors.forename: Jules H
authors.initials: JH
authors.lastname: Eustache
authors.forename: Cynthia
authors.initials: C
authors.lastname: Guilbert
authors.forename: Manuel Flores
authors.initials: MF
authors.lastname: Molina
authors.forename: Koren K
authors.initials: KK
authors.lastname: Mann
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000648:ultrastructure; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects*; D019070:Cell Lineage; D020552:Comet Assay; D004249:DNA Damage; D005434:Flow Cytometry; D008297:Male; D051379:Mice; D014414:Tungsten / Q000633:toxicity*
chemical_list: D014414:Tungsten