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Mutation Research. Genetic Toxicology... Sep 2019Drug-induced kidney injury is one of the most significant adverse events and dose limiting factor in chemotherapy as well a major cause of prospective drug attrition...
Drug-induced kidney injury is one of the most significant adverse events and dose limiting factor in chemotherapy as well a major cause of prospective drug attrition during pharmaceutical development. Moreover, kidney injury can also occur as a consequence of exposures to environmental xenobiotics such as heavy metals, fungal toxins and nanomaterials. The lack of adequate in vitro human kidney models that mimic more realistically the in vivo conditions and the absence of suitable and robust, cost-effective and predictive cell-based in vitro assays contribute to an underestimation of the kidney toxic potential of new drugs and xenobiotics. Therefore, a rapid screening system capable to detect potential nephrotoxicity at early stages of drug discovery is an urgent need. Here we provide an overview of human cell lines currently used as a surrogate in vitro kidney models in nephrotoxicity studies, including their advantages and limitations. In addition, the capacity of the single cell gel electrophoresis (SCGE)/comet assay as a potential tool in kidney toxicants screening is discussed. Despite a limited number of studies using the comet assay to evaluate the drug-induced kidney damage potential, a considerable variability in SCGE methodology (e.g. lysis, unwinding, and electrophoresis conditions) has been observed. Before the comet assay can be included in nephrotoxicity testing, a basic guideline has to be developed. To test its feasibility, additional in vitro experiments including inter-laboratory validation studies based on this guideline have to be performed.
Topics: Animals; Automation; Cell Line; Comet Assay; DNA Damage; Drug Development; Drug Evaluation, Preclinical; Forecasting; Guidelines as Topic; HEK293 Cells; Humans; Image Processing, Computer-Assisted; Kidney; Miniaturization; Nanostructures; Reproducibility of Results; Risk Assessment; Single-Cell Analysis; Th1 Cells; Toxicity Tests
PubMed: 31561894
DOI: 10.1016/j.mrgentox.2018.11.012 -
Critical Reviews in Toxicology Nov 2022Existing literature suggests an association between chronic cadmium (Cd) exposure and the induction of DNA damage and genotoxicity. However, observations from individual... (Meta-Analysis)
Meta-Analysis Review
Existing literature suggests an association between chronic cadmium (Cd) exposure and the induction of DNA damage and genotoxicity. However, observations from individual studies are inconsistent and conflicting. Therefore current systematic review aimed to pool evidence from existing literature to synthesize quantitative and qualitative corroboration on the association between markers of genotoxicity and occupational Cd exposed population. Studies that evaluated markers of DNA damage among occupationally Cd-exposed and unexposed workers were selected after a systematic literature search. The DNA damage markers included were chromosomal aberrations (chromosomal, chromatid, sister chromatid exchange), Micronucleus (MN) frequency in mono and binucleated cells (MN with condensed chromatin, lobed nucleus, nuclear buds, mitotic index, nucleoplasmatic bridges, pyknosis, and karyorrhexis), comet assay (tail intensity, tail length, tail moment, and olive tail moment), and oxidative DNA damage (8-hydroxy-deoxyguanosine). Mean differences or standardized mean differences were pooled using a random-effects model. The Cochran- test and statistic were used to monitor heterogeneity among included studies. Twenty-nine studies with 3080 occupationally Cd-exposed and 1807 unexposed workers were included in the review. Cd among the exposed group was higher in blood [4.77 μg/L (-4.94-14.48)] and urine samples [standardized mean difference 0.47 (0.10-0.85)] than in the exposed group. The Cd exposure is positively associated with higher levels of DNA damage characterized by increased frequency of MN [7.35 (-0.32-15.02)], sister chromatid exchange [20.30 (4.34-36.26)], chromosomal aberrations, and oxidative DNA damage (comet assay and 8OHdG [0.41 (0.20-0.63)]) compared to the unexposed. However, with considerable between-study heterogeneity. Chronic Cd exposure is associated with augmented DNA damage. However, more extensive longitudinal studies with adequate sample sizes are necessary to assist the current observations and promote comprehension of the Cd's role in inducing DNA damage. CRD42022348874.
Topics: Humans; Cadmium; Micronucleus Tests; Occupational Exposure; DNA Damage; Chromosome Aberrations
PubMed: 36802997
DOI: 10.1080/10408444.2023.2173557 -
International Journal of Environmental... Oct 2022Occupational exposure may involve a variety of toxic compounds. A mutagenicity analysis using the Ames test can provide valuable information regarding the toxicity of... (Review)
Review
Occupational exposure may involve a variety of toxic compounds. A mutagenicity analysis using the Ames test can provide valuable information regarding the toxicity of absorbed xenobiotics. Through a search of relevant databases, this systematic review gathers and critically discusses the published papers (excluding other types of publications) from 2001-2021 that have assessed urinary mutagenicity (Ames test with ) in an occupational exposure context. Due to the heterogeneity of the study methods, a meta-analysis could not be conducted. The characterized occupations were firefighters, traffic policemen, bus drivers, mail carriers, coke oven and charcoal workers, chemical laboratory staff, farmers, pharmacy workers, and professionals from several other industrial sectors. The genetically modified bacterial strains (histidine dependent) TA98, TA100, YG1041, YG1021, YG1024 and YG1042 have been used for the health risk assessment of individual (e.g., polycyclic aromatic hydrocarbons) and mixtures of compounds (e.g., diesel engine exhaust, fire smoke, industrial fumes/dyes) in different contexts. Although comparison of the data between studies is challenging, urinary mutagenicity can be very informative of possible associations between work-related exposure and the respective mutagenic potential. Careful interpretation of results and their direct use for occupational health risk assessment are crucial and yet complex; the use of several strains is highly recommended since individual and/or synergistic effects of complex exposure to xenobiotics can be overlooked. Future studies should improve the methods used to reach a standardized protocol for specific occupational environments to strengthen the applicability of the urinary mutagenicity assay and reduce inter- and intra-individual variability and exposure source confounders.
Topics: Humans; Mutagens; Mutagenicity Tests; Coke; Charcoal; Histidine; Vehicle Emissions; Polycyclic Aromatic Hydrocarbons; Smoke; Coloring Agents
PubMed: 36293654
DOI: 10.3390/ijerph192013074 -
Archives of Toxicology Nov 2022Studies suggest that chronic lead (Pb) exposure may induce deoxyribonucleic acid (DNA) damage. However, there is no synthesised evidence in this regard. We... (Meta-Analysis)
Meta-Analysis Review
Studies suggest that chronic lead (Pb) exposure may induce deoxyribonucleic acid (DNA) damage. However, there is no synthesised evidence in this regard. We systematically reviewed existing literature and synthesised evidence on the association between chronic Pb exposure and markers of genotoxicity. Observational studies reporting biomarkers of DNA damage among occupationally Pb-exposed and unexposed controls were systematically searched from PubMed, Scopus and Embase databases from inception to January 2022. The markers included were micronucleus frequency (MN), chromosomal aberrations, comet assay, and 8-hydroxy-deoxyguanosine. During the execution of this review, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Mean differences in the biological markers of DNA damage between Pb-exposed and control groups were pooled using the random-effects model. The heterogeneity was assessed using the Cochran-Q test and I statistic. The review included forty-five studies comparing markers of DNA damage between Pb-exposed and unexposed. The primary studies utilised buccal and/or peripheral leukocytes for evaluating the DNA damage. The pooled quantitative results revealed significantly higher DNA damage characterised by increased levels of MN and SCE frequency, chromosomal aberrations, and oxidative DNA damage (comet assay and 8-OHdG) among Pb-exposed than the unexposed. However, studies included in the review exhibited high levels of heterogeneity among the studies. Chronic Pb exposure is associated with DNA damage. However, high-quality, multicentred studies are required to strengthen present observations and further understand the Pb's role in inducing DNA damage. CRD42022286810.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Chromosome Aberrations; Comet Assay; DNA; DNA Damage; Humans; Lead; Micronucleus Tests; Occupational Exposure
PubMed: 35930012
DOI: 10.1007/s00204-022-03352-9 -
Mutation Research. Reviews in Mutation... 2020Auto-immune diseases (AUD) are characterized by an immune response to antigenic components of the host itself. The etiology of AUD is not well understood. The available... (Meta-Analysis)
Meta-Analysis
Auto-immune diseases (AUD) are characterized by an immune response to antigenic components of the host itself. The etiology of AUD is not well understood. The available evidence points to an interaction between genetic, epigenetic, environmental, infectious and life-style factors. AUD are more prevalent in women than in men; sex hormones play a crucial role in this sex bias. Micronuclei (MN) emerged as a new player in the induction of AUD, based on the capacity of DNA-sensors to detect self-DNA that leaks into the cytoplasm from disrupted MN and induce the cGAS-STING pathway triggering an innate auto-immune response and chronic inflammation. It was found that inflammation can induce MN and MN can induce inflammation, leading to a vicious inflammation-oxidative-DNA damage-MN-formation-chromothripsis cycle. MN originating from sex chromosome-loss may induce inflammation and AUD. We performed a systematic review of studies reporting MN in patients with systemic or organ-specific AUD. A meta-analysis was performed on lymphocyte MN in diabetes mellitus (10 studies, 457 patients/290 controls) and Behcet's disease (3 studies, 100 patients/70 controls) and for buccal MN in diabetes mellitus (11 studies, 507 patients/427 controls). A statistically significant increase in patients compared to controls was found in the meta-analyses providing an indication of an association between MN and AUD. A 36%-higher mean-MRi in buccal cells (3.8+/-0.7) was found compared to lymphocytes (2.8+/-0.7)(P = 0.01). The meta-MRi in lymphocytes and buccal cells (1.7 and 3.0 respectively) suggest that buccal cells may be more sensitive. To assess their relative sensitivity, studies with measurements from the same subjects would be desirable. It is important that future studies (i) investigate, in well-designed powered studies, the prospective association of MN-formation with AUD and (ii) explore the molecular mechanisms by which chromosome shattering in MN and the release of chromatin fragments from MN lead to the formation of auto-antibodies.
Topics: Autoimmune Diseases; Chromothripsis; Female; Humans; Inflammation; Lymphocytes; Male; Micronuclei, Chromosome-Defective; Micronucleus Tests
PubMed: 33339583
DOI: 10.1016/j.mrrev.2020.108335 -
Biomedical Papers of the Medical... Mar 2024Oxidative DNA damage markers (8OHdG, comet assay, gammaH2AX) are becoming widely used in clinical cardiology research. To conduct this review of DNA damage in relation... (Meta-Analysis)
Meta-Analysis Review
Oxidative DNA damage markers (8OHdG, comet assay, gammaH2AX) are becoming widely used in clinical cardiology research. To conduct this review of DNA damage in relation to hypertension in humans, we used databases (e.g. PubMed, Web of Science) to search for English-language publications up to June 30, 2022 and the terms: DNA damage, comet assay, gammaH2AX, 8OHdG, strand breaks, and arterial hypertension. Exclusion criteria were: children, absence of relevant controls, extra-arterial hypertensive issues, animal, cell lines. From a total of 79526, 15 human studies were selected. A total of 902 hypertensive patients (pts): (comet: N=418 pts; 8OHdG: N=484 pts) and 587 controls (comet: N=203; 8OHdG: N=384) were included. DNA damage was significantly higher in hypertensive pts than healthy controls (comet 26.6±11.0 vs 11.7±4.07 arbitrary units /A.U./; P<0.05 and="" 8ohdg="" 13="" 1="" 4="" 12="" vs="" 6="" 97="" 2="" 67="" ng="" mg="" creatinine="" i=""> P<0.05) confirmed with meta-analysis for both. Greater DNA damage was observed in more adverse cases (concentric cardiac hypertrophy 43.4±15.4 vs 15.6±5.5; sustained/untreated hypertension 31.4±12.1 vs 14.2±5/35.0±5.0 vs 25.0 ±5.0; non-dippers 39.2±15.5 vs 29.4±11.1 A.U.; elderly 14.9±4.5 vs 9.3±4.1 ng/mg creatinine; without carvedilol 9.1±4.2 vs 5.7±3.9; with coronary heart disease 0.5±0.1 vs 0.2±0.1 ng/mL) (P<0.05) confirmed with meta-analysis. DNA damage correlated strongly positively with serum glycosylated haemoglobin (r=0.670; P<0.05) and negatively with total antioxidant status (r=-0.670 to -0.933; P<0.05). This is the first systematic review with meta-analysis showing that oxidative DNA damage was increased in humans with arterial hypertension compared to controls.
Topics: Child; Animals; Humans; Aged; 8-Hydroxy-2'-Deoxyguanosine; Creatinine; DNA Damage; Comet Assay; Hypertension
PubMed: 37916467
DOI: 10.5507/bp.2023.044 -
Critical Reviews in Toxicology May 2022To evaluate, through a systematic review, the assessment of genotoxicity of glass ionomer cements and . A systematic review was performed with the problem,... (Review)
Review
To evaluate, through a systematic review, the assessment of genotoxicity of glass ionomer cements and . A systematic review was performed with the problem, intervention, control, and outcomes (PICOS) strategy, aiming to answer the following question: "Can glass ionomer cements induce genetic damage and ?" A systematic search was performed in the following electronic databases: PubMed (including MedLine), Web of Science, and Scopus. The quality of included studies was assessed using the Effective Public Health Practice Project (EPHPP). After the authors performed the review of all articles, a total of 13 manuscripts met all the inclusion criteria in the systematic review. Following the parameters of the EPHPP, eight articles were classified as strong or moderate quality. The other ones (five studies) were weak. Taken together our results demonstrated that, six studies reported genotoxicity of the modified glass ionomer cements tested and two studies concluded that the effect of genotoxicity was time dependent.
Topics: Glass Ionomer Cements; DNA Damage
PubMed: 36102112
DOI: 10.1080/10408444.2022.2101914 -
Mutation Research. Reviews in Mutation... 2021A systematic review and a meta-analysis were performed on 19 studies on head and neck cancer (HNC) and 21 studies on breast cancer (BC) to evaluate the application of... (Meta-Analysis)
Meta-Analysis
A systematic review and a meta-analysis were performed on 19 studies on head and neck cancer (HNC) and 21 studies on breast cancer (BC) to evaluate the application of micronucleus (MN) assay as a predictive and prognostic test for cancer risk. In these studies the MN test was applied in peripheral lymphocytes and buccal cells of patients and healthy subjects with family history of cancer. The meta-analysis on MN applied in buccal cells of HNC patients was performed on two subgroups of studies. A significant increase of MN frequency in patients compared to healthy controls was observed for the subgroup on oral cancer (243 cases/370 controls, meta-MR = 4.71 95 %CI:2.75-8.06) and HNC (204 patients/163 controls metaMR=2.28 95 %CI:2.02-2.58). A metaMR = 3.27 (95 %CI:1.41-7.59) was obtained for MN applied in peripheral lymphocytes on HNC (160 cases/160 controls). For BC, the analysis of MN in peripheral lymphocytes showed significantly higher values in patients (n = 761) than in controls (n = 788) (meta-MR1.90 95 % CI:1.44-2.49). No statistically significant increase of baseline MN was detected in studies on groups of healthy subjects with BC family history (n = 224) or with BRCA1/2 mutations (n = 101) with respect to the controls. After ex-vivo challenge with ionizing radiation, the meta-analysis revealed a slightly statistically significant increase in MN only in BC patients (n = 614) compared to controls (n = 622)(meta-MR = 1.11 95 %CI:1.02-1.21); no increase was observed in healthy subjects with BC family history carrying or not BRCA1/2 mutations. Significant difference between BC patients (n = 183) and controls (n = 165) was observed by the meta-analysis of data on MN in buccal cells (MR = 3.89 95 %CI:1.54-9.78). The MN assay in buccal cells has some perspective of clinical application in HNC.
Topics: Female; Humans; Breast Neoplasms; Head and Neck Neoplasms; Micronucleus Tests; Mouth Neoplasms
PubMed: 34083052
DOI: 10.1016/j.mrrev.2020.108358 -
Mutation Research. Reviews in Mutation... 2022Carbon black exposure causes oxidative stress, inflammation and genotoxicity. The objective of this systematic review was to assess the contributions of primary (i.e.... (Meta-Analysis)
Meta-Analysis Review
Carbon black exposure causes oxidative stress, inflammation and genotoxicity. The objective of this systematic review was to assess the contributions of primary (i.e. direct formation of DNA damage) and secondary genotoxicity (i.e., DNA lesions produced indirectly by inflammation) to the overall level of DNA damage by carbon black. The database is dominated by studies that have measured DNA damage by the comet assay. Cell culture studies indicate a genotoxic action of carbon black, which might be mediated by oxidative stress. Many in vivo studies originate from one laboratory that has investigated the genotoxic effects of Printex 90 in mice by intra-tracheal instillation. Meta-analysis and pooled analysis of these results demonstrate that Printex 90 exposure is associated with a slightly increased level of DNA strand breaks in bronchoalveolar lavage cells and lung tissue. Other types of genotoxic damage have not been investigated as thoroughly as DNA strand breaks, although there is evidence to suggest that carbon black exposure might increase the mutation frequency and cytogenetic endpoints. Stratification of studies according to concurrent inflammation and DNA damage does not indicate that carbon black exposure gives rise to secondary genotoxicity. Even substantial pulmonary inflammation is at best only associated with a weak genotoxic response in lung tissue. In conclusion, the review indicates that nanosized carbon black is a weak genotoxic agent and this effect is more likely to originate from a primary genotoxic mechanism of action, mediated by e.g., oxidative stress, than inflammation-driven (secondary) genotoxicity.
Topics: Mice; Animals; Soot; Comet Assay; DNA Damage; Nanoparticles; Inflammation; Mammals
PubMed: 36007825
DOI: 10.1016/j.mrrev.2022.108441 -
Mutation Research. Reviews in Mutation... 2023Ambient particulate matter (PM) has gained significant attention as an environmental risk factor for human health. Although the association between ambient PM and... (Meta-Analysis)
Meta-Analysis Review
Ambient particulate matter (PM) has gained significant attention as an environmental risk factor for human health. Although the association between ambient PM and micronucleus (MN) induction has been investigated, the quantitative association of PM and genomic instability is inconclusive. We conducted a systematic review and meta-analysis to study the association between PM exposure and MN endpoint. Four databases were systematically searched for studies published up to November 2022, to find papers investigating the relationship between ambient PM and MN induction. Random effect models were conducted to estimate the overall effect based on the Ratio of Means (RoM) with 95% confidence intervals (95% CIs). Subgroup analysis, funnel plot, and Egger and Begg tests, were also performed. Twenty-three studies across nine countries, including 4450 participants, were included. A meta-RoM of 2.13 for MN (95% CI 1.63-2.79) was observed for individuals exposed to ambient PM compared to non-exposed. A significant difference in the subgroup test was found for buccal cells (3.16, 95% CI 2.20-4.52) and low economy level (3.61, 95% CI 1.44-9.01). Our meta-analysis suggests the presence of an association between PM exposure and the frequency of MN and identified the kind of cells and economic status as possible effect modifiers. The use of effective methods, such as the MN assay, enables identification of early genetic damage in humans, which in turn may anticipate the risk of developing respiratory diseases, including lung cancer.
Topics: Humans; Particulate Matter; Environmental Exposure; Mouth Mucosa; Cell Nucleus; Micronucleus Tests; Air Pollutants
PubMed: 36787824
DOI: 10.1016/j.mrrev.2023.108454