Nongenotoxic (NGTX) carcinogens induce cancer via other mechanisms than direct DNA damage. A recognized mode of action for NGTX carcinogens is induction of oxidative stress, a state in which the... Show moreNongenotoxic (NGTX) carcinogens induce cancer via other mechanisms than direct DNA damage. A recognized mode of action for NGTX carcinogens is induction of oxidative stress, a state in which the amount of oxidants in a cell exceeds its antioxidant capacity, leading to regenerative proliferation. Currently, carcinogenicity assessment of environmental chemicals primarily relies on genetic toxicity end points. Since NGTX carcinogens lack genotoxic potential, these chemicals may remain undetected in such evaluations. To enhance the predictivity of test strategies for carcinogenicity assessment, a shift toward mechanism-based approaches is required. Here, we present an adverse outcome pathway (AOP) network for chemically induced oxidative stress leading to (NGTX) carcinogenesis. To develop this AOP network, we first investigated the role of oxidative stress in the various cancer hallmarks. Next, possible mechanisms for chemical induction of oxidative stress and the biological effects of oxidative damage to macromolecules were considered. This resulted in an AOP network, of which associated uncertainties were explored. Ultimately, development of AOP networks relevant for carcinogenesis in humans will aid the transition to a mechanism-based, human relevant carcinogenicity assessment that involves a substantially lower number of laboratory animals. Show less
Trivalent antimony is a known genotoxic agent classified as a possible human carcinogen by the International Agency for Research on Cancer (IARC) and as an animal carcinogen by the German MAK... Show moreTrivalent antimony is a known genotoxic agent classified as a possible human carcinogen by the International Agency for Research on Cancer (IARC) and as an animal carcinogen by the German MAK Commission. Nevertheless, the underlying mechanism for its genotoxicity remains elusive. Because of the similarities between antimony and arsenic, the inhibition of DNA repair has been a promising hypothesis. Investigations on the removal of DNA lesions now revealed a damage specific impairment of nucleotide excision repair (NER). After irradiation of A549 human lung carcinoma cells with UVC, a higher number of cyclobutane pyrimidine dimers (CPD) remained in the presence of SbCl3, whereas processing of the 6-4 photoproducts (6-4PP) and benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts was not impaired. Nevertheless, cell viability was reduced in a more than additive mode after combined treatment of SbCl3 with UVC as well as with BPDE. In search of the molecular targets, a decrease in gene expression and protein level of XPE was found, which is known to be indispensable for the recognition of CPD. Moreover, trivalent antimony was shown to interact with the zinc finger domain of XPA, another NER protein, since SbCl3 mediated a concentration dependent release of zinc from a peptide consistent with this domain. In the cellular system, association of XPA to and dissociation from damaged DNA was diminished in the presence of SbCl3. These results show for the first time that trivalent antimony interferes with proteins involved in nucleotide excision repair and partly impairs this pathway, pointing to an indirect mechanism in the genotoxicity of trivalent antimony. Show less
Water-soluble and particulate cadmium compounds are carcinogenic to humans. While direct interactions with DNA are unlikely to account for carcinogenicity, induction of oxidative DNA damage and... Show moreWater-soluble and particulate cadmium compounds are carcinogenic to humans. While direct interactions with DNA are unlikely to account for carcinogenicity, induction of oxidative DNA damage and interference with DNA repair processes might be more relevant underlying modes of action (recently summarized, for example, in Joseph, P. (2009) Tox. Appl. Pharmacol. 238, 271-279). The present study aimed to compare genotoxic effects of particulate CdO and soluble CdCl2 in cultured human cells (A549, VH10hTert). Both cadmium compounds increased the baseline level of oxidative DNA damage. Even more pronounced, both cadmium Compounds inhibited the nucleotide excision repair (NER) of BPDE-induced bulky DNA adducts and UVC-induced photolesions in a dose-dependent manner at noncytotoxic concentrations. Thereby, the uptake of cadmium in the nuclei strongly correlated with the repair inhibition of bulky DNA adducts, indicating that independent of the cadmium compound applied Cd2+ is the common species responsible for the observed repair inhibition. Regarding the underlying molecular mechanisms in human cells, CdCl2 (as shown before by Meplan, C., Mann, K., and Hainaut, P. (1999) J. Biol. Chem. 274, 3 1663-31670) and CdO altered the conformation of the zinc binding domain of the tumor Suppressor protein p53. In further Studies applying only CdCl2, cadmium decreased the total nuclear protein level of XPC, which is believed to be the principle initiator of global genome NER. This led to diminished association of XPC to sites of local UVC damage, resulting in decreased recruitment of further NER proteins. Additionally, CdCl2 strongly disturbed the disassembly of XPC and XPA. In Summary, our data indicate a general nucleotide excision repair inhibition by cadmium compounds, which is most likely caused by a diminished assembly and disassembly of the NER machinery. These data reveal new insights into the mechanisms involved in cadmium carcinogenesis and provide further evidence that DNA repair inhibition may be one predominant mechanism in cadmium induced carcinogenicity. Show less
