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The Molecular Genetics OF DNA Methylation in Colorectal Cancer
Published in Leonard H. Augenlicht, Cell and Molecular Biology of Colon Cancer, 2019
5-azaCR and 5-azaCdR may be transformed by mechanisms not including DNA methylation. For example, 5-azaCR is clastogenic, inducing chromosomal breaks and rearrangements,59 and treatment of normal human cells by 5-azaCR causes decondensation of centromeric heterochromatin with subsequent chromatid interchanges.60 A possible direct chromosomal role of 5-azaCR on transformation is suggested by studies of the hamster cell line CHEF/18. In every case, 5-azaCR-induced transformation of those cells is associated with an abnormality of hamster chromosome 3.61 Point mutation by 5-azaCR is also possible but seems less likely, because the measured frequency of point mutation is several orders of magnitude lower than the transformation frequency.62
Nonclinical Safety Evaluation of Drugs
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Thomas M. Monticello, Jeanine L. Bussiere
Variations of the “abbreviated” or “miniaturized” or “mini-Ames” assay are commonly utilized, owing to very small compound requirements, as an early screening to detect compounds that are mutagens (i.e., cause DNA damage), since a positive result indicates that the chemical may also act as a carcinogen (Ames et al. 1973). These mutagenicity tests use multiple strains of Salmonella typhimurium engineered to be histidine deficient (his−), necessitating histidine in the culture media for growth. The bacteria are plated and, over time, only those that have mutated back to his+ survive; revertants indicate that the molecule is Ames positive. An additional genotoxicity test, often conducted during lead optimization, is an in vitro clastogenicity assay (Fenech 2000). A positive clastogen is an agent that can cause structural damage to the chromosome or induces aneugenic aberrations, resulting in the loss or gain of chromosomes. In general, a genotoxic molecule would not be a good candidate to move forward into drug development because of the increased risk of the molecule being a carcinogen in humans.
Identification and Use of Biomarkers in Preclinical Toxicologic Safety Assessment
Published in Anthony P. DeCaprio, Toxicologic Biomarkers, 2006
Donna M. Dambach, Jean-Charles Gautier
There are several non-GLP (good laboratory practice) mutagenicity assays that have been used in this capacity, such as three assays that are derived from the standard GLP Ames the plate-based miniaturized and abbreviated Ames assay; the non-plate-based Ames II assay; and an assay that is based on inducing the DNA repair apparatus, the SOS chromotest (40–43). Each of these assays have been reported to have greater than 85% concordance with the standard GLP Ames, thus these assays can be utilized as surrogates for Ames testing to identify potential mutagenicity issues during lead optimization. Furthermore, data generated from these assays can be coupled with in silico computational mutagenicity SAR databases, such as DEREK for Windows (Lhasa Limited, Leeds, U.K.), so that SAR testing can be performed to identify the offending chemophore with the goal of removing the mutagenic potential while maintaining efficacy (44–46). A similar approach has been adopted to examine the clastogenic potential of compounds via utilization of either the in vitro chromosome aberration or in vitro micronucleus assays (47), the latter of which has been reported to have 80% or more concordance with the in vivo erythrocyte micronucleus assay (48,49). In addition to detection of potential clastogens, the in vitro micronucleus assay will also detect mutagens and aneugens (50). Thus, these assays for genotoxicity that exhibit good concordance to regulatory standard assays are examples of bridging biomarkers for these endpoints. As a result, these assays can be applied much earlier in the discovery process so that compounds can be optimized away from the potential issue of genotoxicity, resulting in greater compound success and far greater cost savings.
Cadmium exposure and DNA damage (genotoxicity): a systematic review and meta-analysis
Published in Critical Reviews in Toxicology, 2022
Raju Nagaraju, Ravibabu Kalahasthi, Rakesh Balachandar, Bhavani Shankara Bagepally
Further, Cd exposure induces DNA damage through the DNA metal interaction, oxidative stress, and inhibition of the DNA repair process, epigenetic mechanisms of gene expression control, and interference with cell proliferation (cell cycle checkpoints), differentiation, and apoptosis (Waisberg et al. 2003; Bertin and Averbeck 2006; Viau et al. 2008; Pereira et al. 2013). According to the studies, Cd exposure can potentially be a co-mutagen in vitro and mutagen in vivo system (Hartwig et al. 2002). Furthermore, Cd exposure affects zinc finger proteins, which increases tumor promoters even at low concentrations (Xu et al. 2017). Cd exposure alone acts as a strong mutagen and clastogen at physiological concentration, and this is potentially alarming and could influence the current standards and permissible limits in occupational settings (Ostoich et al. 2020). This results in a probability of developing cancer and other diseases associated with genomic instability (Filipič 2012). Considering the above review of the literature and based on the severity of Cd effects at physiological levels, we compared the effects of occupational Cd exposure on biomarkers of genotoxicity among exposed and unexposed groups in the current study.
Toxicity, preparation methods and applications of silver nanoparticles: an update
Published in Toxicology Mechanisms and Methods, 2022
Anuj Choudhary, Sanjiv Singh, V. Ravichandiran
Widely used test to check out the chromosomal abnormalities by silver nanoparticles. A specific term is used for an agent that causes chromosome abnormalities is clastogen. Chromosomal abnormalities (C.A.) are classified into two categories first is structural and second numerical. Structural abnormalities are further subdivided into four types – deletion, duplication, inversion, translocation. Numerical C.A. is also subdivided into two types – aneuploidy and euploidy. Chromosomal abnormalities depend upon the duration of exposure and amount of silver nanoparticles. To determine chromosomal loss chromosome aberration test can be performed in an invitro and in-vivo way. The procedure of chromosomal aberration involves blockage of cell cycles of cultured mammalian cells with silver nanoparticles at the stage when chromosomes line up on the central plane of the cell i.e., metaphase. The arrested metaphase stage cell is then transferred to the stained with 4–5% Giemsa in phosphate buffer ph around 6.8 for ¼ of the hour. To analyze chromosomal abnormalities with its category then microscope study performed (Galloway et al. 1987).
Exploring graphene-based materials’ genotoxicity: inputs of a screening method
Published in Nanotoxicology, 2021
Salma Achawi, Ludovic Huot, Fabrice Nesslany, Jérémie Pourchez, Sophie Simar, Valérie Forest, Bruno Feneon
Briefly, aneugenicity, clastogenicity or mutagenicity are major genotoxicity mechanisms. For aneugenicity, genotoxicants act primarily on non-DNA targets (microtubule, centrosome or kinetochore (More et al. 2021)) or cause damage to the mitosis apparatus, leading to improper chromosome segregation (Parry et al. 1996, 2002). For clastogenicity, structural chromosome aberrations such as chromatid/chromosome breaks occur (Bignold 2009). Clastogenic agents can covalently bind to DNA or enzymes, leading to chromosome breakage. Mutagenicity corresponds to the induction of DNA mutations (Kumar et al. 2018), either by direct interaction with DNA or chromatin or by indirect mechanisms, such as through generation of reactive oxygen species or inflammation (DeMarini 2019). Genotoxicity is associated to serious health effects, the first one being cancer (Phillips and Arlt 2009): some genotoxic agents can indeed cause mutations that can eventually lead to malign tumor. Hence, most carcinogenic chemicals are genotoxic (Hayashi 1992), which make the measurement of this endpoint critical for hazard assessment.