Chronic Exposure to Zinc Chromate Induces Centrosome Amplification and Spindle Assembly Checkpoint Bypass in Human Lung Fibroblasts

Abstract

Hexavalent chromium (Cr(VI)) compounds are known human lung carcinogens. Solubility plays an important role in its carcinogenicity with the particulate or insoluble form being the most potent. Of the particulate Cr(VI) compounds, zinc chromate appears to be the most potent carcinogen, however, very few studies have investigated its carcinogenic mechanism. In this study, we investigated the ability of chronic exposure to zinc chromate to induce numerical chromosome instability. We found no increase in aneuploidy after a 24 hour exposure to zinc chromate, but with more chronic exposures, zinc chromate induced concentration- and time-dependent increases in aneuploidy in the form of hypodiploidy, hyperdiploidy and tetraploidy. Zinc chromate also induced centrosome amplification in a concentration- and time-dependent manner in both interphase and mitotic cells after chronic exposure, producing cells with centriolar defects. Further, chronic exposure to zinc chromate induced concentration- and time-dependent increases in spindle assembly checkpoint bypass with increases in centromere spreading, premature centromere division and premature anaphase. Lastly, we found that chronic exposure to zinc chromate induced a G2 arrest. All together, these data indicate that zinc chromate can induce chromosome instability after prolonged exposures.

Centrosome Abnormality and Human Lung Cancer

“…They suggested that one possible mechanism for lead chromate-induced carcinogenesis is through centrosome dysfunction, leading to the induction of aneuploidy. The same group (Holmes et al, 2010) also showed that chronic exposure to zinc chromate, another particulate Cr(VI) compound, induces centrosome amplification and spindle checkpoint bypass using human lung fibroblasts. Arsenic is another environmental toxicant, and the biological effects of arsenic have been studied.…”

Aneuploidy as an early mechanistic event in metal carcinogenesis

“…Disruption of the SAC by Cr(VI) particles was manifested by the formation of chromosome spreads showing centromere spreading, premature centromere division, and premature anaphase [34,35]. In addition, levels of Mad2 expression were decreased indicating that the SAC was satisfied and the cells were allowed to proceed to anaphase [35].…”

“…Centrosome amplification is a third potential mechanism for Cr(VI)-induced aneuploidy [33,34,39]. Zinc chromate, in particular, was shown to induce a prolonged G2 arrest along with an increase in centriolar defects [34]; this suggests multiple mechanisms for chromium-induced centrosome amplification such as multiple rounds of centrosome duplication during the prolonged G2 arrest, centriole splitting and acentriolar centrosome formation.…”

“…Zinc chromate, in particular, was shown to induce a prolonged G2 arrest along with an increase in centriolar defects [34]; this suggests multiple mechanisms for chromium-induced centrosome amplification such as multiple rounds of centrosome duplication during the prolonged G2 arrest, centriole splitting and acentriolar centrosome formation. Supporting a role for centrosome amplification in Cr(VI)-induced numerical chromosome instability, Xie et al 2007 [39] showed that cells neoplastically transformed by lead chromate exhibited increased levels of aneuploidy and centrosome amplification.…”

Environmental Hazard in the Aetiology of Somatic and Germ Cell Aneuploidy

“…The mechanisms of zinc chromate carcinogenesis are still poorly understood. Recently, an article was published [Holmes et al, 2010] investigating the ability of chronic exposure to zinc chromate to induce numerical chromosome instability in human lung fibroblasts in vitro. It was found that exposures longer than 24 h induced concentration-and timedependent increases in hypoploid, hyperploid and polyploid cells.…”