Chronic Exposure to Lead Chromate Causes Centrosome Abnormalities and Aneuploidy in Human Lung Cells

Abstract

Hexavalent chromium [Cr(VI)] compounds are established human lung carcinogens. The carcinogenicity of Cr(VI) is related to its solubility, with the most potent carcinogens being the insoluble particulate Cr(VI) compounds. However, it remains unknown why particulate Cr(VI) is more carcinogenic than soluble Cr(VI). One possible explanation is that particulates may provide more chronic exposures to chromate over time. We found that aneuploid cells increased in a concentration-and time-dependent manner after chronic exposure to lead chromate. Specifically, a 24-hour lead chromate exposure induced no aneugenic effect, whereas a 120-hour exposure to 0.5 and 1 Mg/cm 2 lead chromate induced 55% and 60% aneuploid metaphases, respectively. We also found that many of these aneuploid cells were able to continue to grow and form colonies. Centrosome defects are known to induce aneuploidy; therefore, we investigated the effects of chronic lead chromate exposure on centrosomes. We found that centrosome amplification in interphase and mitotic cells increased in a concentration-and time-dependent manner with 0.5 and 1 Mg/cm 2 lead chromate for 120 hours, inducing aberrant centrosomes in 18% and 21% of interphase cells and 32% and 69% of mitotic cells, respectively; however, lead oxide did not induce centrosome amplification in interphase or mitotic cells. There was also an increase in aberrant mitosis after chronic exposure to lead chromate with the emergence of disorganized anaphase and mitotic catastrophe. These data suggest that one possible mechanism for lead chromate-induced carcinogenesis is through centrosome dysfunction, leading to the induction of aneuploidy. (Cancer Res 2006; 66(8): 4041-8)

Homologous recombination repair protects against particulate chromate-induced chromosome instability in Chinese hamster cells

“…Cr(VI) is a well-established human lung carcinogen and previous studies show that Cr(VI) chromium is most potent in particulate form. Particulate Cr(VI) induces DNA strand breaks, Cr-DNA adducts, Cr-DNA crosslinks and mutation to 6-thioguanine resistance in diploid human fibroblasts [8,[14][15][16][17]12,35,36], however how these lesions are repaired and their relationship to Cr(VI)-induced CIN are uncertain.…”

Centrosome Abnormality and Human Lung Cancer

“…Finally, the two centrosomes form the poles of the bipolar mitotic spindle. Holmes et al (2006) showed that chronic exposure to lead chromate causes centrosome abnormalities and aneuploidy using WTHBF-6 cells, a cell line derived from normal human bronchial fibroblasts. Hexavalent chromium compounds [Cr(VI)] are human lung carcinogens (Le´onard & Lauwerys, 1980), and "particulate" Cr(VI) compounds are one of the most potent forms.…”

Deficient repair of particulate hexavalent chromium-induced DNA double strand breaks leads to neoplastic transformation

“…One or more of these species induces DNA double strand breaks, which are sensed directly by gamma-H2A.X and the MRN complex, which binds DNA, unwinds the ends and recruits ATM, ultimately leading to repair (5-7). Failure to repair these breaks leads to neoplastic transformation, possibly through the generation of chromosome instability, which has also been observed after particulate Cr(VI) exposure (32,33). …”