Level Of Genotoxic Damage Research Articles

Genotoxic markers in patients with diabetes mellitus (Literature review)

This paper considers studies aimed at identifying markers of genotoxicity (chromosomal aberrations, micronuclei, and DNA damage assessed by the DNA comet assay) in patients with both gestational diabetes mellitus (GDM) and diabetes type 1 and 2 (T1DM and T2DM, respectively), as well as possible changes in the levels of these genotoxic markers under the influence of medicines and nutritions. Patients with T2DM are characterized by an increased level of genotoxicity markers. The results of genotoxicity markers in patients with T1DM and GDM studies are contradictory, however, they indicate the presence of an increased genotoxic load rather than its absence. The levels of genotoxic damage in diabetic patients may be reduced by physical exercises, diet, and/or hypoglycemic drugs. Metformin, Afobazole and Noopept are recommended for experimental and clinical studies as possible drug candidates that reduce the levels of genotoxic biomarkers in diabetic patients.

Genotoxic damage evaluation in agricultural workers by exposure to pesticides in Vicente Guerrero-Tlaxcala, Mexico

Pesticides are one of the main inputs in agricultural activities; however, their exposure has been linked to the generation of various health effects. Today, many studies show the ability of pesticides to induce genotoxic damage. The aim of this study was to evaluate the level of genotoxic damage of agricultural workers from Vicente Guerrero-Tlaxcala community, Mexico, exposed to pesticides. The study was composed by 50 agricultural workers from the Vicente Guerrero community and 16 non-exposed individuals. To assess genotoxic damage, the micronucleus (MN) test was applied to exfoliated buccal cell samples by analyzing their frequency and that of other nuclear abnormalities. The agricultural workers showed a frequency of micronucleated cells (P<0,05) and nuclear outbreaks (P<0,05) higher than the control group. The types of pesticides most referred to by the producers were herbicides, belonging to the chemical groups chlorophenoxy and triazine. The exposure time is more than 6 years in more than half of the workers, while the use of personal protective equipment is low. The detected anomalies did not show statistical associations with age, diseases, alcohol, and tobacco consumption. The study revealed that the significant increase in the frequency of MN observed in the exposed group is induced by exposure to pesticides. The application of biomarkers of genotoxicity represents a useful tool to estimate the genetic risk of a population when exposed to a complex mixture of chemicals.

Risk of genotoxic damage in schoolchildren exposed to organochloride pesticides

This study identified and determined organochloride pesticide (OCs) concentrations in hair samples from children at two elementary schools: one exposed to fumigations in agricultural fields, the other unexposed. Three concentrations of OCs levels in the hair were compared (high, medium, low), and total nuclear abnormalities in buccal cells were determined: micronuclei (MNi), condensed chromatin, karyorrhexis, pyknosis, binucleate cells, karyolysis, lobed nuclei, and apoptosis. No significant differences were found for the presence of MNi between the schoolchildren from the exposed and unexposed schools, but the prevalence of OCs in both schools was over 50%, as well as the frequencies of MNi in the children were over 58%. Findings show a significant difference between the frequency of MNi in the total sample of schoolchildren (exposed school + unexposed school) in relation to the concentration of OCs detected in their hair. The children from exposed school that showed the higher concentrations of OCs in hair had higher levels of genotoxic damage in the buccal cells; compared against children with lower concentrations of OCs. The most frequent nuclear abnormalities in the exposed children were lobed nuclei (79.4%), binucleate cells (66.66%), apoptosis (65.07), and MNi (58.7%). We determined the prevalence ratio (PR) and prevalence odds ratio (POR) for the presence of MNi in buccal cells in relation to the OCs concentrations in the hair samples. Both ratios were high for MNi [PR 3.93, 95% confidence interval (CI) 1.97–7.84, p = 0.0003; and POR 7.97, 95% CI 2.62–24.28, p = 0.0003], indicating a 7.97 times greater risk that the exposed children will present > 0.2% of MNi when OCs concentrations exceed 0.447 μg/g. These indicators may be useful biomarkers of genotoxic damage in children exposed to persistent, highly-toxic compounds. Results suggest the potential risk to which those schoolchildren are exposed on a daily basis due to fumigations in nearby agricultural fields.

Influence of Carnicor, Venofer, and Sevelamer on the levels of genotoxic damage in end-stage renal disease patients.

End-stage renal disease (ESRD) patients present high levels of phosphorus and calcium products in serum, which contribute to the development of vascular calcification and cardiovascular disease, and to low iron stores and carnitine deficiency. For these reasons, ESRD patients are generally supplemented with different medicines. Some of the most common treatments include the use of Carnicor, Venofer, and Sevelamer drugs. Carnicor is used as a source of L-carnitine, acting as antioxidant and neuroprotector. Venofer is used to reduce the deficit of iron. Sevelamer is used to treat hyperphosphatemia. To determine the potential harmful genotoxic effects of these drugs, a group of 214 patients included in a hemodialysis program with different intakes of Carnicor, Venofer, and Sevelamer were evaluated. The levels of basal and oxidative DNA damage, as well as chromosomal damage, were measured in all individuals using the comet and the micronucleus assays, respectively. Our results indicate that Carnicor administration was associated with low but significant increases in the frequency of basal DNA damage and micronuclei. Environ. Mol. Mutagen. 59:302-311, 2018. © 2018 Wiley Periodicals, Inc.

Mammalian Cell DNA Damage and Repair Kinetics of Monohaloacetic Acid Drinking Water Disinfection By-Products

Haloacetic acids (HAAs) are the second most common class of chlorinated water disinfection by-products (DBPs). The single cell gel electrophoresis genotoxicity assay using Chinese hamster ovary (CHO) cells was modified to include liquid holding recovery time to measure genomic DNA damage and repair kinetics of three monoHAAs: chloroacetic acid (CAA), bromoacetic acid (BAA), and iodoacetic acid (IAA). The rank order of genotoxic potency was IAA > BAA >> CAA from previous research. The concentration of each HAA was chosen to generate approximately the same level of genotoxic damage. No cytotoxicity was expressed during the 24 h liquid holding period. Nuclei from CHO cells treated with BAA showed the lowest rate of DNA repair (t(50) = 296 min) compared to that of CAA or IAA (t(50) = 134 and 84 min, respectively). The different rates of genomic repair expressed by IAA or CAA versus BAA suggest that different distributions of DNA lesions are induced. The use of DNA repair coupled with genomic technologies may lead to the understanding of the biological and genetic mechanisms involved in toxic responses induced by DBPs.

DNA damage studies in untreated and treated leprosy patients

The alkaline single cell gel electrophoresis assay was performed on peripheral blood lymphocytes of lepromatous and tubercloid leprosy patients (untreated and those undergoing treatment) in order to ascertain whether differential damage to DNA occurs. The study group included 28 male and 2 female patients and 15 healthy males who were matched for age and socio-economic status. The results revealed DNA damage in all patients, with a mean DNA migration length of 29.88 +/- 3.39 microm and 38% of their cells damaged when compared with the respective values obtained in healthy controls (1.28 +/- 0.40 microm, 5%). Multiple regression analysis for effects of confounding factors revealed antibiotic treatment in patients and alcohol consumption in controls as the only variables influencing DNA damage. In lepromatous and tubercloid patients, both untreated and those undergoing treatment, DNA damage increased significantly from that observed in control individuals, with greater increased damage in lepromatous patients. An increase in treatment time increased DNA damage linearly. Furthermore, an arbitrary classification of damaged cells (categories I-IV) was made based on observed tail lengths in leprosy patients (5.00-225.00 microm). The number of damaged cells in untreated patients was lower than in those undergoing treatment; the latter also had more cells with greater DNA migration lengths. There were no category III or IV cells in the control group. The results of the study therefore reveal that patients undergoing therapy had significantly greater DNA damage than untreated patients, indicating bacterial infection and drug therapy as the causal factors, since lepromatous-type disease is the more severe form with the patients having lower resistance to Mycobacterium leprae and requiring heavier and prolonged dosage of antibiotics. The study also corroborates that the assay offers an opportunity for correlating levels of therapy-induced DNA damage with administered dose and for modulating the dose-schedule so as to achieve lower levels of genotoxic damage.

Genetic polymorphism of XRCC1 and lung cancer risk among African–Americans and Caucasians

Reduced DNA repair capacity may influence susceptibility to lung cancer. XRCC1 plays an important role in base excision repair and in rejoining DNA strand breaks. In the XRCC1 gene, two common polymorphisms induce amino acid changes in codon 194 and codon 399 and correlate with levels of genotoxic damage. We examined the relation between these two polymorphisms and susceptibility to lung cancer among 334 incident cases and 704 population controls of African–American and Caucasian ethnicity in Los Angeles County, California. African–American and Caucasian subjects smoking 20+ cigarettes/day and carrying at least one copy of the codon 194 variant allele were at somewhat decreased risk of lung cancer (African–Americans OR=0.2, 95% CI 0.1–0.9; Caucasians OR=0.5, 95% CI 0.2–1.1). Similarly, for the codon 399 polymorphism, there was some evidence of a decreased risk for the homozygous variant genotype among heavier smokers (African–Americans OR=0.3, 95% CI 0.0–2.9; Caucasians OR=0.4, 95% CI 0.2–1.0). These results suggest that genetic variation in XRCC1 might contribute to lung cancer and may interact with the amount smoked.

Influence of GSTT1 genotype on sister chromatid exchange induction by styrene-7,8-oxide in cultured human lymphocytes.

The genetic polymorphisms of glutathione S-transferases (GSTs), which are involved in the metabolic inactivation of various toxicants, have been suggested to be an important source of variation in individual response to genotoxic carcinogens. We have previously shown that donor GSTM1 genotype does not influence the induction of sister chromatid exchanges (SCEs) in cultured human lymphocytes by styrene-7,8-oxide (SO), a metabolite of styrene. Here, we expanded the study to GSTT1 polymorphism. SCEs were analyzed from 72-hr whole-blood lymphocyte cultures of five GSTT1 positive (at least one undeleted allele) and five GSTT1 null (gene homozygously deleted) donors, all GSTM1 positive, after a 48-hr treatment with 50 microM and 150 microM SO. SO clearly increased SCEs in cultures of all donors. The mean number of SCEs/cell induced by SO (individual mean SCEs from acetone-treated control cultures subtracted) was 1.7 (50 microM) and 1.4 (150 microM) times greater among the GSTT1 null individuals (4.83 at 50 microM, 18.98 at 150 microM) compared with the GSTT1 positive individuals (2.78 at 50 microM, 13.74 at 150 microM), the differences being statistically significant (P=0.006 and P=0.022, respectively). These findings show that the lack of the GSTT1 gene increases the genotoxic effects of SO in human whole-blood lymphocyte cultures, suggesting that GSTT1 is involved in the detoxification of SO in humans. Although glutathione conjugation is considered a minor metabolic pathway for SO in vivo, the high GSTT1 activity in erythrocytes may be important locally and might affect the level of genotoxic damage observed in peripheral lymphocytes of styrene-exposed reinforced plastics workers. The GSTT1 polymorphism could also influence the urinary excretion of SO-specific mercapturic acids.