Prenatal exposure of mice to tungstate is associated with decreased transcriptome-expression of the putative tumor suppressor gene, DMBT1: implications for childhood leukemia.

Abstract

Background. Two concurrent, childhood leukemia clusters have been identified in the southwestern United States at Fallon, Nevada, and Sierra Vista, Arizona. Additionally, Fallon, Nevada has also experienced concurrent contamination by atmospheric tungsten particles. The etiology of leukemia is not known. Hypothesized risk factors for leukemia are environmental exposure, genetic predisposition, and viral infection. Additionally, strong evidence supports a prenatal origin. Our objective is to generate testable hypotheses towards elucidating the probable, multi-factorial etiology of leukemia by identifying the exposures unique to Fallon, Nevada, and held in common with Sierra Vista, Arizona, then exposing C57BL/6 mice, while in utero, to these chemicals to ascertain their leukemogenic potential. Utilizing advances in medical geology to analyze tree rings, surface dust, lichens and atmospheric particulate matter, we have identified tungsten and arsenic as potentially relevant to leukemogenesis. Methods. We utilized microarray (Affymetrix 430A 2.0 mouse) and real-time RTPCR of Dmbt1 transcriptome-expression in spleen tissue collected from four-week-old C57BL/6 mouse pups (N = 6–8/group/gender) exposed, while in utero, to tungstate, arsenite, tungstate/arsenite and longitudinal controls at 20% of the normalized exposure a human mother would receive during gestation at mean environmental concentrations. Results. Prenatal exposure to tungstate is associated with a 37 + 1.2-fold (p = 0.012) decrease in DMBT1 transcriptome-expression in mice expressing DMBT1 at high levels. Additionally, prenatal exposure to tungstate/arsenite significantly altered a cytokine–cytokine receptor interaction pathway associated with lymphocyte activation and a network associated with hematological/immunological disease. Conclusion. Because DMBT1 protein products are known to aggregate viruses and possibly regulate immune response, additional research is warranted to determine the potential that prenatal exposure to tungstate or tungstate/ arsenite has to increase susceptibility to viruses and to induce leukemogenesis.