Abstract
Hexavalent chromium (Cr[VI]) is associated with occupational lung cancer and poses a significant public health concern. When exposed to Cr[VI], cells rapidly internalize this compound and metabolize it to Cr[III]. Byproducts of Cr[VI] metabolism include unstable Cr[V] and Cr[IV] intermediates that are believed to be directly responsible for the genotoxicity and carcinogenicity caused by Cr[VI] exposure; however, the carcinogenic potential of the Cr intermediates and the mechanisms of Cr-induced carcinogenesis remain to be further defined. Utilizing synthetic Cr[IV] and Cr[V] compounds, we demonstrate here that Cr[IV] or Cr[V] exposure induces DNA double-strand breaks; however, of the two compounds, mammalian cells only respond to Cr[V]-induced DNA damage. Exposure to Cr[V], but not Cr[IV], results in initiation of cell cycle checkpoints and activates the ATM kinase, a critical regulator of the DNA damage response. Furthermore, cells exposed to Cr[IV] have significantly increased mutation frequencies in the HPRT gene compared to cells exposed to Cr[V], indicating that Cr[IV] possesses a higher mutagenic potential than Cr[V]. We also find that MLH1, a critical mismatch repair (MMR) protein, is required for activation of the G2/M cell cycle checkpoint in response to Cr[VI] exposure and to limit Cr-induced mutagenesis. Our results provide evidence for Cr[IV] as the ultimate mutagenic intermediate produced during Cr[VI] metabolism and indicate that functional MMR is crucial in the cellular response to chromium exposure.
Highlights
Chromium compounds exist in nature almost exclusively in the trivalent (Cr [III]) or hexavalent (Cr [VI]) state, with the relatively non-reactive Cr[III] being predominant
Our results provide evidence for Cr[IV] as the ultimate mutagenic intermediate produced during Cr[VI] metabolism and indicate that functional mismatch repair (MMR) is crucial in the cellular response to chromium exposure
To further investigate if DNA damage response induced by exposure to Cr[IV] is altered, we examined if the ataxia-telangiectasia mutated (ATM) kinase, a DNA damage regulator previously reported to be stimulated by Cr[VI], became activated after exposure to chromium intermediates
Summary
Chromium compounds exist in nature almost exclusively in the trivalent (Cr [III]) or hexavalent (Cr [VI]) state, with the relatively non-reactive Cr[III] being predominant. Cr[III] is an essential nutrient required for proper insulin function and is harmless even at moderately high levels. Cr[VI] compounds are common industrial waste products, many of which are water soluble and can readily pollute the environment through direct release into lakes and streams. These compounds are released into the air, exposing workers to high levels of Cr[VI]. Cr[VI] compounds are known human carcinogens, and workers exposed to these compounds exhibit high incidences of nasal, esophageal, and lung cancers.
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