Lead chromate-induced chromosome instability is caused by centrosome amplification in human lung cells

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Hexavalent chromium (Cr(VI)) compounds are well established human lung carcinogens with solubility playing an important role in its carcinogenicity. Particulate or ‘insoluble’ Cr(VI) compounds are considered the most potent carcinogens, however, their carcinogenic mechanism remains unknown. We investigated the hypothesis that the carcinogenicity of particulate Cr(VI) is due to more chronic exposures. We found that a 24 h exposure to lead chromate does not cause aneuploidy, but more chronic exposures induced both a concentration- and time-dependent increase in aneuploidy with a 120 h exposure to 0.5 and 1 μg/cm² lead chromate inducing 55% and 60% aneuploid metaphases. Many of these aneuploid cells were able to continue to grow and form colonies. We investigated centrosome amplification as one possible mechanism for lead chromate-induced aneuploidy and found that centrosome amplification in both interphase and mitotic cells increased in a concentration- and time-dependent manner after chronic exposure to lead chromate. Specifically, a 120 h exposure to 0.5 and 1 μg/cm² lead chromate induced centrosome amplification in 18 and 21% of interphase cells and 32 and 69% of mitotic cells, respectively. There was also an increase in aberrant mitotic figures after chronic exposure to lead chromate with the emergence of disorganized anaphase and mitotic catastrophe. These data indicate that the induction of centrosome amplification and chromosome instability manifested as aneuploidy may be a key mechanism in lead chromate-induced carcinogenesis. This work was supported by NIEHS grant ES10838 (J.P.W.).