D DNAprotein crosslinks

DNA-protein crosslinks are known to be produced by exposure to Cr(VI) in vitro and in vivo.29,32 Several groups of human subjects who were exposed to Cr(VI) occupational^576973 74 or lived in Cr-contaminated areas75 have been examined for the presence of DNA-protein crosslinks in peripheral blood lymphocytes. The levels of DNA-protein crosslinks were found to be elevated in all exposed groups and the dose-response curve showed a good sensitivity at low to medium exposures.57,69 The saturation of lymphocyte DNA-protein crosslinks was estimated to occur at 7-8 |J.g/l Cr in erythrocytes.57 Stainless steel welders from Germany,69 73 mild steel welders from the U.S.74 and chrome platers from Bulgaria57 all exhibited increased levels of DNA-protein crosslinks without confounding effects of smoking. Studies on control and exposed populations have also determined that DNA-protein crosslinks are not affected by body weight, age, race or gender.57,75,75a The ability of the DNA-protein crosslink-based biomarker to detect low level human exposures to Cr is probably related to the inefficient repair of these lesions in human lymphocytes.32,76 Giving that the majority of human lymphocytes have a lifespan of several years,76a the inability of these cells to remove DNA-protein crosslinks could lead to the accumulation of these lesions during chronic exposure even to low levels of Cr(VI). The mutagenic potential of DNA-protein crosslinks has never been tested directly but the size-dependence of mutagenesis by other ternary Cr-DNA adducts could be indicative of their high genotoxic activity.32,41

A major problem hampering the use of DNA-protein crosslink measurements in biomonitoring is the inability of current methodology to unambiguously establish the chemical nature of the crosslinks. Since the level of DNAprotein crosslinks showed an association with Cr exposure in several studies, it is clear that this biomarker is sensitive to the presence of Cr. The high-temperature version of the K-SDS assay significantly limited other possible crosslinking agents,32,77 which is illustrated by the absence of an association between smoking and the levels of these adducts. Even inhalation exposure to high levels of formaldehyde has not led to increased DNA-protein crosslinking in lymphocytes of furniture factory workers.57 A better understanding of the nature of background DNA-protein crosslinks should lead to the development of experimental strategies for the specific determination of Cr-derived lesions. Formation of crosslink-producing malondialdehyde during lipid peroxidation reactions has been suggested to be one of the potential mechanisms for the induction of DNA-protein crosslinks in unexposed individuals.78 The pattern of crosslinked proteins generated by exposure to malondialdehyde and Cr(VI) is expected to be different, therefore, immunoprecipitation is a promising approach to increase Cr specificity of crosslink determinations.

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