DNA damage in cetaceans: A mini review Poirier, Miriam C.
Mutation research. Genetic toxicology and environmental mutagenesis,
October-November 2021, 2021-10-00, Letnik:
870-871
Journal Article
Recenzirano
•DNA damage is an important biomarker of cancer risk.•Both non-specific and chemical-specific DNA damage were found in cetaceans.•Tumor incidences in whales are typically low (0.7–2.0 %).•Beluga ...exposed to PAHs had 7% intestinal cancers and intestinal PAH-DNA adducts.•DNA damage was found in cetaceans living in contaminated areas.
DNA damage has long been known to play an essential role in tumorigenesis induced by chemical carcinogen exposure. The preponderance of data generated during the past approximately 50 years of cancer research indicates that DNA damage and DNA adduct formation are necessary but not sufficient for tumor induction by chemical carcinogenesis. This is true for all of the species studied, including experimental animals, some animals in the wild, and humans. Cetaceans, which include whales, dolphins and porpoises, are a challenge to evaluate because tissues are difficult to obtain, and cancer rates, with a single exception, are low (0.7–2.0 %). However, both non-specific (chromosomal aberrations, DNA strand breaks, 8-hydroxy-2’-deoxyguanosine, mitochondrial DNA damage), and chemical-specific (aromatic DNA adducts, and carcinogenic polycyclic aromatic hydrocarbon PAH-DNA adducts) DNA damage have been found in cetaceans. For some types of DNA damage, cetaceans may carry a burden similar to that seen in many other species, including humans, but linking DNA damage to cancer rates in cetaceans has been largely impossible. The one exception is a population of beluga whales in the St. Lawrence Estuary (SLE) in Quebec, Canada, where correlations have been found between long-term PAH exposure, PAH-DNA adducts in small intestinal crypt cells, and a high rate (7%) of gastrointestinal cancers. Taken together, the current literature demonstrates that cetaceans may carry a burden of many types of DNA damage and, given the example of the SLE beluga, cetaceans may sustain a potential susceptibility to pollution-induced tumorigenesis. Knowledge of DNA damage and cancer rates in whales is critically important for understanding and predicting the health of marine life, human life, and the aquatic environment of our planet.
Chemical carcinogenesis involves a complex series of events, the earliest of which typically include DNA damage and the fixation of DNA mutations. Sophisticated new techniques have been developed to ...quantify DNA damage and to correlate the amount of damage with cancer risk. Approaches such as these are underway in Linxian, China, where food contains high levels of DNA-damaging, carcinogenic polycyclic aromatic hydrocarbons (PAHs), and where there is high mortality from oesophageal cancer. Gaining better insight into the mechanisms by which PAH exposure might increase oesophageal cancer risk could lead to new strategies for cancer prevention.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
For more than 200 years human cancer induction has been known to be associated with a large variety of chemical exposures. Most exposures to chemical carcinogens occur as a result of occupation, ...pollution in the ambient environment, lifestyle choices, or pharmaceutical use. Scientific investigations have revealed that the majority of cancer causing chemicals, or chemical carcinogens, act through "genotoxic" or DNA damaging mechanisms, which involve covalent binding of the chemical to DNA (DNA adduct formation). Cancer-inducing exposures are typically frequent and/or chronic over years, and the accumulation of DNA damage or DNA adduct formation is considered to be a necessary requirement for tumor induction. Studies in animal models have indicated that the ability to reduce DNA damage will also result in reduction of tumor risk, leading to the hypothesis that individuals having the highest levels of DNA adducts may have an increased cancer risk, compared to individuals with the lowest levels of DNA adducts. Here we have reviewed twelve investigations showing 2- to 9-fold increased Relative Risks (RR) or Odds Ratios (OR) for cancer in (the 25% of) individuals having the highest DNA adduct levels, compared to (the 25% of) matched individuals with the lowest DNA adducts. These studies also provided preliminary evidence that multiple types of DNA adducts combined, or DNA adducts combined with other risk factors (such as infection or inflammation), may be associated with more than 10-fold higher cancer risks (RR = 34-60), compared to those found with a single carcinogen. Taken together the data suggest that a reduction in human DNA adduct level is likely to produce a reduction in human cancer risk.
Remembering Radim J. Šrám DeMarini, David M.; Poirier, Miriam C.; Waters, Michael D. ...
Environmental and molecular mutagenesis,
February 2023, 2023-Feb, 2023-02-00, 20230201, Letnik:
64, Številka:
2
Journal Article
The lack of anticancer agents that overcome innate/acquired drug resistance is the single biggest barrier to achieving a durable complete response to cancer therapy. To address this issue, a new drug ...family was developed for intracellular delivery of the bioactive aminothiol WR1065 by conjugating it to discrete thiol-PEG polymers: 4-star-PEG-S-S-WR1065 (4SP65) delivers four WR1065s/molecule and m-PEG
-S-S-WR1065 (1LP65) delivers one. Infrequently, WR1065 has exhibited anticancer effects when delivered via the FDA-approved cytoprotectant amifostine, which provides one WR1065/molecule extracellularly. The relative anticancer effectiveness of 4SP65, 1LP65, and amifostine was evaluated in a panel of 15 human cancer cell lines derived from seven tissues. Additional experiments assessed the capacity of 4SP65 co-treatments to potentiate the anticancer effectiveness and overcome drug resistance to cisplatin, a chemotherapeutic, or gefitinib, a tyrosine kinase inhibitor (TKI) targeting oncogenic
mutations. The CyQUANT
-NF proliferation assay was used to assess cell viability after 48-h drug treatments, with the National Cancer Institute COMPARE methodology employed to characterize dose-response metrics. In normal human epithelial cells, 4SP65 or 1LP65 enhanced or inhibited cell growth but was not cytotoxic. In cancer cell lines, 4SP65 and 1LP65 induced dose-dependent cytostasis and cytolysis achieving 99% cell death at drug concentrations of 11.2 ± 1.2 µM and 126 ± 15.8 µM, respectively. Amifostine had limited cytostatic effects in 11/14 cancer cell lines and no cytolytic effects. Binary pairs of 4SP65 plus cisplatin or gefitinib increased the efficacy of each partner drug and surmounted resistance to cytolysis by cisplatin and gefitinib in relevant cancer cell lines. 4SP65 and 1LP65 were significantly more effective against
-mutant than
-wild-type cell lines, consistent with WR1065-mediated reactivation of mutant p53. Thus, 4SP65 and 1LP65 represent a unique prodrug family for innovative applications as broad-spectrum anticancer agents that target p53 and synergize with a chemotherapeutic and an EGFR-TKI to prevent or overcome drug resistance.
Polycyclic aromatic hydrocarbons (PAHs) are combustion products of organic materials, mixtures of which contain multiple known and probable human carcinogens. PAHs occur in indoor and outdoor air, as ...well as in char-broiled meats and fish. Human exposure to PAHs occurs by inhalation, ingestion and topical absorption, and subsequently formed metabolites are either rendered hydrophilic and excreted, or bioactivated and bound to cellular macromolecules. The formation of PAH-DNA adducts (DNA binding products), considered a necessary step in PAH-initiated carcinogenesis, has been widely studied in experimental models and has been documented in human tissues. This review describes immunohistochemistry (IHC) studies, which reveal localization of PAH-DNA adducts in human tissues, and semi-quantify PAH-DNA adduct levels using the Automated Cellular Imaging System (ACIS). These studies have shown that PAH-DNA adducts concentrate in: basal and supra-basal epithelium of the esophagus, cervix and vulva; glandular epithelium of the prostate; and cytotrophoblast cells and syncitiotrophoblast knots of the placenta. The IHC photomicrographs reveal the ubiquitous nature of PAH-DNA adduct formation in human tissues as well as PAH-DNA adduct accumulation in specific, vulnerable, cell types. This semi-quantative method for PAH-DNA adduct measurement could potentially see widespread use in molecular epidemiology studies.
Antiretroviral drugs have proved useful in the clinical management of HIV-infected persons, though there are concerns about the effects of exposure to these DNA-reactive drugs. We investigated the ...potential of the plant model Allium cepa root tip assay to demonstrate the cytogenotoxicity of zidovudine and nevirapine and as a replace-reduce-refine programme amenable to resource-poor research settings. Cells mitotic index were determined in squashed root cells from Allium cepa bulbs exposed to zidovudine or nevirapine for 48 hr. The concentration of zidovudine and nevirapine inhibiting 50% root growth after 96 hr exposure was 65.0 µM and 92.5 µM respectively. Root length of all antiretroviral-exposed roots after 96 hr exposure was significantly shorter than the unexposed roots while additional root growth during a subsequent 48 hr recovery period in the absence of drug was not significantly different. By ANOVA, there was a significant association between percentage of cells in mitosis and zidovudine dose (p=0.004), but not nevirapine dose (p=0.68). Chromosomal aberrations such as sticky chromosomes, chromatin bridges, multipolar mitoses and binucleated cells were observed in root cells exposed to zidovudine and nevirapine for 48 hr. The most notable chromosomal aberration was drug-related increases in sticky chromosomes. Overall, the study showed inhibition in root length growth, changes in the mitotic index, and the induction of chromosomal aberrations in Allium bulbs treated for 96 hr or 48 hr with zidovudine and nevirapine. The study reveals generalized cytogenotoxic damage induced by exposure to zidovudine and nevirapine, and further show that the two compounds differ in their effects on mitosis and the types of chromosomal aberrations induced.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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