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Human physiology, hazards and health risks
Published in Stephen Battersby, Clay's Handbook of Environmental Health, 2023
Revati Phalkey, Naima Bradley, Alec Dobney, Virginia Murray, John O’Hagan, Mutahir Ahmad, Darren Addison, Tracy Gooding, Timothy W Gant, Emma L Marczylo, Caryn L Cox
Similar spermatozoa microsatellite mutations were reported in mice exposed to ambient air near two integrated steel mills and a major highway compared to high-efficiency air particulate (HEPA) filtered ambient air, suggesting that air pollution may also affect germline stability [43]. There are caveats to be added here; (a) a microsatellite instability in the sperm does not indicate an adverse outcome either for the cell or the whole organism, and (b) the dose of ionising radiation used was very high compared to environmental exposures. Thus, although this work provides a potential causal pathway, the data are not likely to be consequential for the Sellafield worker cohort due to the high ionising radiation exposures used [44]. When considered together, these studies indicate the profound difficulty in undertaking this type of work where the generational time in humans is 25 years. Even for mice with a shorter generational time the numbers of animals required becomes prohibitive, and expensive, and the results can be challenging to translate to the human situation.
Chronic Arsenic Exposure to Drinking Water
Published in M. Manzurul Hassan, Arsenic in Groundwater, 2018
Cancer cells are characterized by an unstable genome, and genomes of certain cells are susceptible in accumulating DNA damage at an accelerated rate, developing a wide range of genetic abnormalities, and ultimately becoming cancerous. Genomic instability can be CIN (chromosome instability) and MIN (microsatellite instability) (Bhattacharjee et al., 2013c; Hudler, 2012). CIN is associated with mitotic errors such as chromosomal rearrangements or segregational anomalies and is most commonly observed in human cancer, while MIN is associated with DNA level instability seen in tumors (Bhattacharjee et al., 2013c) (Figure 4.5). As a nonmutagenic human carcinogen, arsenic has very strong clastogenic properties that can lead to its carcinogenic potential (Bustaffa et al., 2014; Collotta et al., 2013; Engström et al., 2011). The most prominent example of genetic variation influencing arsenic metabolism capacity is the 10q24.32 locus, which harbors the As3MT (arsenite methyltransferase enzyme) gene. Genetic variants have shown consistent association with arsenic metabolism capacity. Studies have reported associations between 10q24.32 metabolism-related SNP and skin lesion risk (Agusa et al., 2011).
Carcinogens and cancer
Published in Chris Winder, Neill Stacey, Occupational Toxicology, 2004
Critical regulators of genomic integrity, as exemplified by mismatch repair genes, have also been implicated as tumour-suppressor genes. The microsatellite instability genes, MLH1 and MSH2, are important to maintenance of genomic integrity by repairing mismatched base pairs that arise with a stable frequency during DNA replication (Kolodner and Marsischky 1999). Without such genes, repairs are not made and mutations are introduced into newly synthesised DNA. Alternatively, the stress of mismatch structure may fragment the DNA. Both of these possibilities can lead to cell growth or death.
An immune cell infiltration landscape classification to predict prognosis and immunotherapy effect in oral squamous cell carcinoma
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2023
The ICI scores were not only associated with prognosis but also a novel biomarker for immunotherapy independent of TMB. Current studies suggest that multiple biomarkers may be used to predict the efficacy of immunotherapy (Gavrielatou et al. 2020). Wang et al. found that CD8+ T and CD4+ T cells were significantly increased, and the aggregation of CT-LA-4+ T cells in the microenvironment of 4-nitroquinoline 1-oxide induced oral cancer mouse models after the use of PD-1 blocking antibodies. PD-1 inhibits the induced activation associated with IFN -γ and STAT1, suggesting that T cell activation mediates the immunoprotective effect against PD-1. The findings demonstrated that CTLA-4 might be utilized as a biomarker to predict the efficacy and the CTLA-4 inhibitors can improve anti-PD-1 regulation, thus evaluating the effectiveness of immunotherapy (Wang et al. 2017). Furthermore, some defects, mutations, and physiological and pathological states in vivo can also be used as biomarkers to predict the efficacy of immunotherapy. Microsatellite Instability (MSI) and Mismatch Repair Defect (MMRD), for example, are hypermutated phenotypes. The high immunogenicity of tumors with MSI and MMRD characteristics has been used as a predictive biomarker of ICI’s efficacy and demonstrated in clinical trials against PD-1 (Chalmers et al. 2017).
Toxic and carcinogenic effects of hexavalent chromium in mammalian cells in vivo and in vitro: a recent update
Published in Journal of Environmental Science and Health, Part C, 2022
Shehnaz Islam, Sreejata Kamila, Ansuman Chattopadhyay
Most of the chromate cancer occurs due to microsatellite instability of DNA mismatch repair (MMR) proteins.4, 142–144 DNA hypermethylation responsible for the repression of MLH1 protein (one of MMR protein) was observed in chromate exposed worker.144,145 In the presence of antioxidant ascorbate (Asc), Cr (VI) rapidly reduced to Cr (III) and forms Asc-Cr-DNA crosslink, which activates the MMR system and induces p53 independent cellular apoptosis.142,143 Recruiting gamma H2AX foci by MMR after Cr-DNA adduct formation induces DNA double-strand breaks and p53-mediated apoptosis.4, 143 Loss or deficiency of MMR protein are the major reasons behind chromate cancer (Figure 2).
Effect of Gene 33/Mig6/ERRFI1 on hexavalent chromium-induced transformation of human bronchial epithelial cells depends on the length of exposure
Published in Journal of Environmental Science and Health, Part C, 2022
Cen Li, Dina Edeni, Sarah Platkin, Raymond Liu, Jiangwei Li, Maheen Hossain, Mozibur Rahman, Humayun Islam, John L. Phillips, Dazhong Xu
Hexavalent chromium (Cr(VI)) compounds are classified as Group 1 carcinogens by the International Agency for Research on Cancer. Occupational contact with Cr(VI) compounds is well documented to increase the risk for lung cancer in workers in industries using these compounds, such as plating, pigment production, and chromate production.1–6 The mechanism of Cr(VI) carcinogenesis is apparently very complex and poorly understood. Cr(VI) is capable of generating strong oxidative stress during its reduction process upon entering cells, which can lead to oxidation of intracellular macromolecules.5,7–10 Intracellular Cr(VI), upon rapid reduction to trivalent chromium (Cr(III)), can form DNA adducts that elicit DNA damage in the forms of single or double-stranded DNA breaks.11,12 Despite its effect on DNA damage, Cr(VI) appears to have limited mutagenic ability.9 Thus, lung cancers caused by Cr(VI) exposure exhibit few point mutations of key oncogenes or tumor suppressor genes.5 On the other hand, Cr(VI) is known to cause chromosome instability and microsatellite instability.9,13 These are known causes of carcinogenesis and conceivably able to drive neoplastic transformation of lung epithelial cells.14,15