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The Human Cancer Situation
Published in Samuel C. Morris, Cancer Risk Assessment, 2020
Repair of genetic damage in a cell and suppression of its results are natural processes. Some people have defective or reduced repair mechanisms, making them more susceptible to the effect of spontaneous mutations and to environmental carcinogens. A frequently cited example of this is xeroderma pigmentosum, an inherited inability to repair DNA damage caused by the UVB band in sunlight. This makes its victims highly susceptible to skin cancer. Since repair processes are inherited, there is bound to be a range of sensitivity to mutagens within the population. This variety in sensitivity is similar in some ways to the distribution in sensitivity to acute toxic agents, and provides the basis of applying a class of models (e.g., the probit model) to cancer assessment which were originally used to predict effects of toxic chemicals and which assume an underlying distribution of susceptability in the population.
Risk of Low-Level Exposure to Radiation-Biological Basis
Published in Lawrence T. Dauer, Bae P. Chu, Pat B. Zanzonico, Dose, Benefit, and Risk in Medical Imaging, 2018
Tatjana Paunesku, Gayle E. Woloschak
Also, cell cycle differences may hypothetically provide an explanation of a lowered threshold for the “adaptive response” to low-dose radiation in p53+/− animals. Lower expression of p53 in heterozygote mice should correspond to decreased activation of p21 protein upon radiation, which, in turn, allows progression of the S phase of the cell cycle. While this may lead to the accumulation of DNA damage, its quantity is low enough that it could be handled by homologous recombination balancing the damage introduced by unrestrained S phase progression. In p53 wild-type cells, on the other hand, relatively minor DNA damage can lead to an excessive p21 activation response, resulting in collapsed DNA replication forks. These, in turn, may attract the Xeroderma Pigmentosum A protein leading to a DNA double-strand break as in progeria, for example [61].
Chemical Carcinogenesis in Skin: Causation, Mechanism, and Role of Oncogenes
Published in Rhoda G. M. Wang, James B. Knaak, Howard I. Maibach, Health Risk Assessment, 2017
The bay region dihydrodiol epoxides react spontaneously with nucleophilic groups of cellular macromolecules forming covalent bonds, a reaction thought to be essential for the neoplastic transformation of the target cell. In view of the irreversibility of tumor formation, at least in the initiation step, the close correlation between mutagenic and carcinogenic efficacy, and the high incidence of cancers in patients with defective DNA repair (e.g., in xeroderma pigmentosum), DNA (mainly the hydroxyl and amino groups of the nucleobases) is generally assumed to be the critical target molecule for ultimate carcinogens. In general, the DNA binding of carcinogens possesses a high degree of specificity, for example, the ultimate carcinogenic metabolite of BP has been shown to bind exclusively to the 2-amino group of guanine residues in epidermal DNA, whereas the metabolites of N-acetoxy-2-acetylaminofluorene prefers the C-8 position of guanine.5
Insights into the mechanisms of arsenic-selenium interactions and the associated toxicity in plants, animals, and humans: A critical review
Published in Critical Reviews in Environmental Science and Technology, 2021
Waqar Ali, Hua Zhang, Muhammad Junaid, Kang Mao, Nan Xu, Chuanyu Chang, Atta Rasool, Muhammad Wajahat Aslam, Jamshed Ali, Zhugen Yang
Low concentrations of Se compounds can also inhibit the Zn finger protein that binds to DNA, leading to the release of Zn from the motif of the Zn finger (Woo Youn, Fiala, & Soon Sohn, 2001). The cellular pathways are mostly dependent on Zn finger proteins, so redox responses are essential for the regulation of Zn finger proteins (Blessing et al., 2004; Zeng et al., 2005). The inequality overdose or deficiency in Se compounds inhibits or decreases genomic stability (Blessing et al., 2004; Zeng et al., 2005). Zinc finger proteins are also susceptible to intracellular targets for AsIII at a preliminary low micromolar level of all AsIII compounds triggered, and Zn is released from the Zn finger protein domains and develops a disease known as xeroderma pigmentosum (XPA) (Zeng et al., 2005). Based on previous findings, MMAV and DMAV are more reactive than AsIII (Blessing et al., 2004; Hartwig et al., 2003; Zeng et al., 2005). During the upholding genomic stability process, Zn finger proteins are usually required in almost every intracellular reaction; therefore, the inactivation or inhibition of these proteins may enhance genomic instability (Hamilton, 2004).
Overview of biological mechanisms of human carcinogens
Published in Journal of Toxicology and Environmental Health, Part B, 2019
Nicholas Birkett, Mustafa Al-Zoughool, Michael Bird, Robert A. Baan, Jan Zielinski, Daniel Krewski
High-energy UVR (e.g. UVB/C) interacts directly with DNA to produce damage. UVA interacts mainly with endogenous or exogenous photosensitizers, which release ROS and RNS that lead to DNA damage. A common effect is production of cyclobutane dimers between adjacent pyrimidine bases. UVR is mutagenic in in vitro and in vivo tests across a wide range of species. Mutations usually are targeted at two adjacent pyrimidines. The most common mutations are tandem CC→VR which is mutagenic in in vitro and in vivo tests such as rare genetic condition Xeroderma pigmentosum, which is defective in the NER pathway. Tandem CC→VR mutations are associated with more extensive DNA damage and an increased cancer risk. This DNA damage leads to genomic instability, including chromatid breakage and elevated levels of sister chromatid exchange. Alterations of gene expression profiles were noted with use of cDNA micro-arrays. Solar-simulated UV (but not UVA and UVB) produced significant immunosuppression in humans. A bystander effect was also described.