Chronic Exposure to Particulate Chromate Induces Spindle Assembly Checkpoint Bypass in Human Lung Cells
- 6 October 2006
- journal article
- Published by American Chemical Society (ACS) in Chemical Research in Toxicology
- Vol. 19 (11), 1492-1498
- https://doi.org/10.1021/tx0601410
Abstract
One of the hallmarks of lung cancer is chromosome instability (CIN), particularly a tetraploid phenotype, which is normally prevented by the spindle assembly checkpoint. Hexavalent chromium [Cr(VI)] is an established human lung carcinogen, and Cr(VI) induces tumors at lung bifurcation sites where Cr(VI) particles impact and persist. However, the effects of Cr(VI) on the spindle assembly checkpoint are unknown and little is known about prolonged exposure to particulate Cr(VI). Accordingly, we investigated particulate Cr(VI)-induced bypass of the spindle assembly checkpoint after several days of exposure in WHTBF-6 cells. We found that lead chromate indeed induces spindle assembly checkpoint bypass in human lung cells, as 72, 96, and 120 h treatments with 0.5 or 1 μg/cm2 lead chromate induced significant increases in the percentage of cells with aberrant mitotic figures. For example, treatment with 1 μg/cm2 lead chromate for 96 h induced 11, 12.3, and 14% of cells with premature anaphase, centromere spreading and premature centromere division, respectively. In addition, we found a disruption of mitosis with more cells accumulating in anaphase; cells treated for 96 h increased from 18% in controls to 31% in cells treated with lead chromate. To confirm involvement of the spindle assembly checkpoint, Mad2 expression was used as a marker. Mad2 expression was decreased in cells exposed to chronic treatments of lead chromate, consistent with disruption of the checkpoint. We also found concentration- and time-dependent increases in tetraploid cells, which continued to grow and form colonies. When cells were treated with chronic lead alone there was no increase in aberrant mitotic cells or polyploidy; however, chronic exposure to a soluble Cr(VI) showed an increase in aberrant mitotic cells and polyploidy. These data suggest that lead chromate does induce CIN and may be one mechanism in the development of Cr(VI)-induced lung cancer.Keywords
This publication has 10 references indexed in Scilit:
- Carcinogenic lead chromate induces DNA double-strand breaks in human lung cellsMutation Research - Genetic Toxicology and Environmental Mutagenesis, 2005
- Lead ions do not cause human lung cells to escape chromate-induced cytotoxicityToxicology and Applied Pharmacology, 2005
- Lead Chromate-Induced Chromosome Damage Requires Extracellular Dissolution to Liberate Chromium Ions but Does Not Require Particle Internalization or Intracellular DissolutionChemical Research in Toxicology, 2004
- Comparison of two particulate hexavalent chromium compounds: Barium chromate is more genotoxic than lead chromate in human lung cellsEnvironmental and Molecular Mutagenesis, 2004
- Telomerase-mediated lifespan extension of human bronchial cells does not affect hexavalent chromium-induced cytotoxicity or genotoxicityMolecular and Cellular Biochemistry, 2004
- Barium chromate is cytotoxic and genotoxic to human lung cellsEnvironmental and Molecular Mutagenesis, 2003
- Apoptosis and P53 induction in human lung fibroblasts exposed to chromium (VI): effect of ascorbate and tocopherol.Toxicological Sciences, 2000
- Internalization of Carcinogenic Lead Chromate Particles by Cultured Normal Human Lung Epithelial Cells: Formation of Intracellular Lead-Inclusion Bodies and Induction of ApoptosisToxicology and Applied Pharmacology, 1999
- Premature centromere division: A possible manifestation of chromosome instabilityAmerican Journal of Medical Genetics, 1995
- Characteristics of chromate workers' cancers, chromium lung deposition and precancerous bronchial lesions: an autopsy studyBritish Journal of Cancer, 1994