Showing papers on "Sister chromatid exchange published in 2016"

Loss of RMI2 Increases Genome Instability and Causes a Bloom-Like Syndrome.

Abstract: Bloom syndrome is a recessive human genetic disorder with features of genome instability, growth deficiency and predisposition to cancer. The only known causative gene is the BLM helicase that is a member of a protein complex along with topoisomerase III alpha, RMI1 and 2, which maintains replication fork stability and dissolves double Holliday junctions to prevent genome instability. Here we report the identification of a second gene, RMI2, that is deleted in affected siblings with Bloom-like features. Cells from homozygous individuals exhibit elevated rates of sister chromatid exchange, anaphase DNA bridges and micronuclei. Similar genome and chromosome instability phenotypes are observed in independently derived RMI2 knockout cells. In both patient and knockout cell lines reduced localisation of BLM to ultra fine DNA bridges and FANCD2 at foci linking bridges are observed. Overall, loss of RMI2 produces a partially active BLM complex with mild features of Bloom syndrome.

High density of REC8 constrains sister chromatid axes and prevents illegitimate synaptonemal complex formation

Abstract: During meiosis, cohesin complexes mediate sister chromatid cohesion (SCC), synaptonemal complex (SC) assembly and synapsis Here, using super-resolution microscopy, we imaged sister chromatid axes in mouse meiocytes that have normal or reduced levels of cohesin complexes, assessing the relationship between localization of cohesin complexes, SCC and SC formation We show that REC8 foci are separated from each other by a distance smaller than 15% of the total chromosome axis length in wild-type meiocytes Reduced levels of cohesin complexes result in a local separation of sister chromatid axial elements (LSAEs), as well as illegitimate SC formation at these sites REC8 but not RAD21 or RAD21L cohesin complexes flank sites of LSAEs, whereas RAD21 and RAD21L appear predominantly along the separated sister-chromatid axes Based on these observations and a quantitative distribution analysis of REC8 along sister chromatid axes, we propose that the high density of randomly distributed REC8 cohesin complexes promotes SCC and prevents illegitimate SC formation

PARP Inhibitors in Clinical Use Induce Genomic Instability in Normal Human Cells.

Abstract: Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA repair pathways to be targeted by specific inhibitors for clinical benefit. Tumors harboring genetic defects in homologous recombination (HR), a DNA double-strand break (DSB) repair pathway, are hypersensitive to PARP inhibitors (PARPi). Early phase clinical trials with PARPi have been promising in patients with advanced BRCA1 or BRCA2-associated breast, ovary and prostate cancer and have led to limited approval for treatment of BRCA-deficient ovary cancer. Unlike HR-defective cells, HR-proficient cells manifest very low cytotoxicity when exposed to PARPi, although they mount a DNA damage response. However, the genotoxic effects on normal human cells when agents including PARPi disturb proficient cellular repair processes have not been substantially investigated. We quantified cytogenetic alterations of human cells, including primary lymphoid cells and non-tumorigenic and tumorigenic epithelial cell lines, exposed to PARPi at clinically relevant doses by both sister chromatid exchange (SCE) assays and chromosome spreading. As expected, both olaparib and veliparib effectively inhibited poly-ADP-ribosylation (PAR), and caused marked hypersensitivity in HR-deficient cells. Significant dose-dependent increases in SCEs were observed in normal and non-tumorigenic cells with minimal residual PAR activity. Clinically relevant doses of the FDA-approved olaparib led to a marked increase of SCEs (5-10-fold) and chromatid aberrations (2-6-fold). Furthermore, olaparib potentiated SCE induction by cisplatin in normal human cells. Our data have important implications for therapies with regard to sustained genotoxicity to normal cells. Genomic instability arising from PARPi warrants consideration, especially if these agents will be used in people with early stage cancers, in prevention strategies or for non-oncologic indications.

Bromodeoxyuridine does not contribute to sister chromatid exchange events in normal or Bloom syndrome cells.

Abstract: Sister chromatid exchanges (SCEs) are considered sensitive indicators of genome instability. Detection of SCEs typically requires cells to incorporate bromodeoxyuridine (BrdU) during two rounds of DNA synthesis. Previous studies have suggested that SCEs are induced by DNA replication over BrdU-substituted DNA and that BrdU incorporation alone could be responsible for the high number of SCE events observed in cells from patients with Bloom syndrome (BS), a rare genetic disorder characterized by marked genome instability and high SCE frequency. Here we show using Strand-seq, a single cell DNA template strand sequencing technique, that the presence of variable BrdU concentrations in the cell culture medium and in DNA template strands has no effect on SCE frequency in either normal or BS cells. We conclude that BrdU does not induce SCEs and that SCEs detected in either normal or BS cells reflect DNA repair events that occur spontaneously.

Sister chromatid exchange assay as a predictor of tumor chemoresponse.

Abstract: Sister Chromatid Exchanges (SCEs) are known to enhance as a consequence of exposure to various mutagenic agents and appear to indicate DNA damaging effects and/or subsequent repair by homologous recombination (HR). DNA damage plays an interesting role in the majority of mechanisms underlying the effects of antitumor drugs, since the genetic activity of the plethora of these agents is due to their ability to damage the DNA. The DNA-effects of antitumor agents towards normal cells (genotoxicity) are great drawbacks of antitumor therapy and are connected to important adverse health effects in cancer patients undergoing chemotherapy. On the other hand, failure of chemotherapy in many cases is due to the DNA repair ability which cancer, like normal cells, also possess. As both DNA repair and genotoxic exposure are expected to vary among patients, correlating SCEs frequencies with only individual repair capacity may be feasible to predict. Cancer risk has not been observed to be associated with high SCEs levels. Since the administration of effective antitumor drugs with limited adverse effects is of great importance in the success of anticancer therapy, a lot of interest has been directed toward the development of methods and approaches that would enable the correct selection of appropriate drugs prior to the initiation of therapy on an individual basis. To this effect, more than 30 years ago, an investigation of the ability of the in vitro and the in vivo SCEs-assay to predict the in vitro and in vivo sensitivity of tumor cells to newly synthesized drugs or to those already in use began. In this short review a critical appraisal of the SCEs-assay as an important biomarker used for predicting cancer chemo-response as well as a summary of the key findings from several studies published within the last 20 years in this field is performed.

Multiple Rad52-Mediated Homology-Directed Repair Mechanisms Are Required to Prevent Telomere Attrition-Induced Senescence in Saccharomyces cerevisiae.

Abstract: Most human somatic cells express insufficient levels of telomerase, which can result in telomere shortening and eventually senescence, both of which are hallmarks of ageing. Homology-directed repair (HDR) is important for maintaining proper telomere function in yeast and mammals. In Saccharomyces cerevisiae, Rad52 is required for almost all HDR mechanisms, and telomerase-null cells senesce faster in the absence of Rad52. However, its role in preventing accelerated senescence has been unclear. In this study, we make use of rad52 separation-of-function mutants to find that multiple Rad52-mediated HDR mechanisms are required to delay senescence, including break-induced replication and sister chromatid recombination. In addition, we show that misregulation of histone 3 lysine 56 acetylation, which is known to be defective in sister chromatid recombination, also causes accelerated senescence. We propose a model where Rad52 is needed to repair telomere attrition-induced replication stress.

A high rate of telomeric sister chromatid exchange occurs in chronic lymphocytic leukaemia B-cells.

Abstract: Cancer cells protect their telomere ends from erosion through reactivation of telomerase or by using the Alternative Lengthening of Telomere (ALT) mechanism that depends on homologous recombination. Chronic lymphocytic leukaemia (CLL) B cells are characterized by almost no telomerase activity, shelterin deregulation and telomere fusions. To characterize telomeric maintenance mechanisms in B-CLL patients, we measured their telomere length, telomerase expression and the main hallmarks of the ALT activity i.e. C-circle concentration, an extra-chromosomal telomere repeat (ECTR), and the level of telomeric sister chromatid exchange (T-SCE) rate. Patients showed relative homogenous telomere length although almost no TERT transcript and nearly no C-circle were evidenced. Nevertheless, compared with normal B cells, B-CLL cells showed an increase in T-SCE rate that was correlated with a strong down-regulation of the topoisomerase III alpha (TOP3A) expression, involved in the dissolution of Holliday Junctions (HJ), together with an increased expression of SLX1A, SLX4, MUS81 and GEN1, involved in the resolution of HJ. Altogether, our results suggest that the telomere maintenance mechanism of B-CLL cells do not preferentially use telomerase or ALT. Rather, the rupture of the dissolvasome/resolvasome balance may increase telomere shuffling that could homogenize telomere length, slowing telomere erosion in this disease.

Evaluation of potential genotoxic/cytotoxic effects induced by epoxiconazole and fenpropimorph-based fungicide in bovine lymphocytes in vitro.

Abstract: Potential genotoxic/cytotoxic effects of the epoxiconazole/fenpropimorph-based fungicide were investigated using single cell gel electrophoresis and cytogenetic assays: chromosomal aberrations, sister chromatid exchanges, micronuclei and fluorescence in situ hybridization in cultured bovine lymphocytes. No statistically significant elevations of DNA damage and increases in cytogenetic endpoints were seen. However, evident cytotoxic effect presented as a decrease in mitotic and proliferation indices were recorded after exposure of bovine lymphocytes to the fungicide for 24 and 48 h at concentrations ranging from 3 to 15 µg mL(-1) (P < 0.05, P < 0.01, P < 0.001). Similarly, for 24 h an inhibition in the cytokinesis block proliferation index (CBPI) was obtained after exposure to the fungicide at concentrations ranging from 1.5 to 15 µg mL(-1) (P < 0.01, P < 0.001) in each donor.

Similar Sister Chromatid Arrangement in Mono- and Holocentric Plant Chromosomes

Abstract: Due to the X-shape formation at somatic metaphase, the arrangement of the sister chromatids is obvious in monocentric chromosomes. In contrast, the sister chromatids of holocentric chromosomes cannot be distinguished even at mitotic metaphase. To clarify their organization, we differentially labelled the sister chromatids of holocentric Luzula and monocentric rye chromosomes by incorporating the base analogue EdU during replication. Using super-resolution structured illumination microscopy (SIM) and 3D rendering, we found that holocentric sister chromatids attach to each other at their contact surfaces similar to those of monocentrics in prometaphase. We found that sister chromatid exchanges (SCEs) are distributed homogeneously along the whole holocentric chromosomes of Luzula, and that their occurrence is increased compared to monocentric rye chromosomes. The SCE frequency of supernumerary B chromosomes, present additionally to the essential A chromosome complement of rye, does not differ from that of A chromosomes. Based on these results, models of the sister chromatid arrangement in mono- and holocentric plant chromosomes are presented.

Evaluation of DNA damage induced by norcantharidin in human cultured lymphocytes

Abstract: Norcantharidin (NCTD) is currently used in the treatment of several cancers such as leukemia, melanoma and hepatoma. The mechanism of action of NCTD is suggested to involve induction of apoptosis of cancer cells via production of reactive oxygen species. In this study, the genotoxic effect of different concentrations of NCTD (1, 10 and 20 μm) in human lymphocytes was investigated using sister chromatid exchanges (SCEs) and chromosomal aberrations (CAs) assays. The results revealed that NCTD significantly increased the rate of SCEs (p 0.05). In addition, no significant differences were detected in the mitotic index or proliferative index at examined doses (up to 20 μm). In conclusion, NCTD is genotoxic to human cultured lymphocytes as measured by SCE assay.

Chaetophractus villosus as a sentinel organism: Baseline values of mitotic index, chromosome aberrations and sister chromatid exchanges.

Abstract: Sentinel species are useful tools for studying the deleterious effects of xenobiotics on wildlife. The large hairy armadillo (Chaetophractus villosus) is the most abundant and widely distributed mammal in Argentina. It is a long-lived, omnivorous, burrowing species, with fairly restricted home ranges. To evaluate the level of spontaneous genetic damage in this mammal, we determined the baseline values of several genotoxicity biomarkers. The study included 20 C. villosus adults of both sexes from eight pristine localities within its geographic distribution range. Genotoxicity analysis was performed on 72-h lymphocyte cultures, using mitomycin C as positive control. We obtained the baseline values of mitotic index (MI=10.52±0.30 metaphases/total cells, n=20), chromosome aberrations (CA=0.13±0.22, n=20), sister chromatid exchanges (SCE)=6.55±0.26, n=6) and replication index (RI=1.66, n=6). MI and CA did not show significant differences (P>0.05) among localities or between sexes. No significant differences in MI, CA, SCE, and RI (P>0.05) were found between values from the pristine localities and historical data. There were significant differences in CA, SCE, and RI (P<0.05) between lymphocyte cultures from pristine localities and those exposed to mitomycin C. We propose the large hairy armadillo as a sentinel organism for environmental biomonitoring of genotoxic chemicals due to its abundance, easy manipulation, well-known biology, the fact that it is usually exposed to different mixtures and concentrations of environmental contaminants, and the baseline values of genetic damage characterized by MI, CA, SCE and RI as biomarkers.

Assessment of genotoxicity of Lannate-90® and its plant and animal metabolites in human lymphocyte cultures

Abstract: This study evaluated direct and metabolic genotoxic effects caused by Lannate-90®, a methomyl-based formulation (90 % active ingredient), in human lymphocyte cultures using sister chromatid exchange assay (SCE). Two processes were used for the plant promutagens evaluation: in vivo activation, applying the insecticide systemically in plants for 4 h and subsequently adding plant metabolites containing extracts to lymphocyte cultures; and in vitro activation, where the insecticide was incubated with Vicia faba S10 mix plus human lymphocyte culture. Direct treatment with the insecticide significantly increased SCE frequency in human lymphocytes (250-750 mgL-1), with cellular death observed at 1000 mgL-1 concentration. Using the extracts of Vicia faba treated with Lannate-90® to treat human lymphocytes, a dose-response relationship was observed. In lymphocyte cultures treated directly with the insecticide for 2 h, a negative response was obtained. When S10 mix was added, SCE frequency did not change significantly. Meanwhile, a mixture of S9 mammalian metabolic mix and Lannate-90® increased the SCE frequency, with an observed concentration-dependent response. Although Lannate-90® induced cellular death at the highest concentrations, it did not cause a delay in cell proliferation in any of the treatments, confirming its genotoxic action. This study is one of the first to evaluate and compare the direct effect of Lannate-90® in two bioassays, animal and vegetal, and the effect of plant and animal metabolism on its genotoxic potential.

Assessment of in vitro genotoxic and cytotoxic effects of flurbiprofen on human cultured lymphocytes.

Abstract: Flurbiprofen is non-steroidal anti-inflammatory drug which is commonly used for its analgesic, antipyretic, and anti-inflammatory effects. The purpose of the study was to explore the genotoxic and cytotoxic effects of flurbiprofen in human cultured lymphocytes by sister chromatid exchange, chromosome aberration, and cytokinesis-blocked micronucleus tests. 10, 20, 30, and 40 μg/mL concentrations of flurbiprofen (solvent is DMSO) were used to treatment of human cultured lymphocytes at two different treatment periods (24 and 48 h). Flurbiprofen had no significant genotoxic effect in any of these tests. But exposing to flurbiprofen for 24 and 48 h led to significant decrease on proliferation index, mitotic index, and nuclear division index (NDI). Also, all decreases were concentration-dependent (except NDI at 24 h treatment period). Consequently, the findings of this research showed that flurbiprofen had cytotoxic effects in human blood lymphocytes.

Genotoxic effects of the carbamate insecticide Pirimor-50® in Vicia faba root tip meristems and human lymphocyte culture after direct application and treatment with its metabolic extracts

Abstract: The aim of the study was to evaluate genotoxic effects of Pirimor-50®, a pirimicarb-based formulation (50 % active ingredient), in human lymphocyte cultures and Vicia faba root meristems. Furthermore, the objective was to examine a combined influence of insecticide treatment with mammalian microsomal S9 and vegetal S10 metabolic fractions or S10 mix metabolic transformation extracts (after Vicia faba primary roots treatment with Pirimor-50®). We used sister chromatid exchange assay-SCE and measured cell cycle progression and proliferation (proportion of M1-M3 metaphases and replication index ratio-RI). Two processes were used for plant promutagen activation: in vivo activation-Pirimor-50® was applied for 4 h to the plant and then S10 mix was added to lymphocytes; and, in vitro activation-lymphocytes were treated with Pirimor-50® and S10 or S9 for 2 h. Direct treatment induced significantly higher SCE frequencies in meristems at 0.01 mg mL-1. In lymphocytes, significantly higher SCE was at 1 mg mL-1 with decrease in RI and M1-M3 metaphase proportions at 0.5 mg mL-1 and cell division stop at 2.5 mg mL1. S10 mix lymphocyte treatment showed significantly elevated SCE values at 2-2.5 mg mL-1, with cell death at 3 mg mL-1. Lymphocyte treatment with Pirimor-50® together with S9 or S10 showed slightly elevated SCE frequency but had a significant influence on RI decrease, with lowest values in S9 treatment. Since no data are available on the genotoxicity of Pirimor-50®, this study is one of the first to evaluate and compare its direct effect in two bioassays, animal and vegetal, and also the effect of plant and animal metabolism on its genotoxic potential.

Anticarcinogenic and antimutagenic activity of Alstonia scholaris on the albino mice bone marrow cells and peripheral human lymphocyte culture against methyl methane sulfonate induced genotoxicity.

Abstract: Background: The use of medicinal plants in modern medicine for the prevention and treatment of cancer is an important aspect. For this reason, it is important to identify antitumor promoting agents present in medicinal plants commonly used by the human population. Materials and Methods: We used in vivo and in vitro methods using chromosomal aberrations (CAs), sister chromatid exchange (SCE) and replication index (RI) as markers, exposed by methyl methanesulfonate (MMS) as well as alcoholic extract of Alstonia scholaris in five increasing concentrations (200, 250, 300, 350 and 400 mg/kg body weight for in vivo and 150, 200, 250 and 300 μg/ml of culture) and of three different durations of 24, 48 and 72 h in the presence as well absence of S 9 mix. Results: Extracts of Alstonia reduces the total aberrant cells ranges from 10.0% to 41.84% and frequencies of aberration in the aberrant cells ranges from 220 to 124 against 290 aberrations causes due to MMS in vivo . Similarly in the in vitro , it reduces CAs (39.62%, 32.83%, and 38.48%) and (45.31%, 44.46%, and 38.34%) at 24, 48, and 72 h of exposure respectively; in the absence as well as presence of liver S 9 fraction. It also reduces SCE from 7.70 to 4.20 per cell and enhances RI from 1.45 to 1.64. Conclusion: Extracts of Alstonia significantly reduces the number of aberrant cells and frequency of aberration per cell at each concentration and duration of exposure in vivo ; and CAs and SCE in vitro and enhances RI.

Sister chromatid exchange test in river buffalo lymphocytes treated in vitro with furocoumarin extracts.

Abstract: Furocoumarin extracts from Psoralea morisiana, the endemic Sardinian legume species, were tested for their mutagenic potential on river buffalo blood cells. The results obtained performing the sister chromatid exchange (SCE) test in blood cultures of five river buffalo calves (exposure to furocoumarins for 72h) and five cows (exposure to furocoumarins for 3h, in the absence and presence of S9 metabolic activator) are reported. Significant differences in mean values of SCEs were observed in cells of calves compared to control cells (unexposed), but no differences in SCE mean values were found between treated and untreated cells of cows in the presence or absence of S9. SCE mean values were much higher in cells of cows (exposed and control) than in cells of calves. Indeed, in calf cells, SCE mean values/cell (±SD) were 6.66±2.45 in the control and 7.63±3.01, 9.03±3.90, 9.53±3.60 and 9.99±3.41 in treated cells at 50, 100, 200 and 400 µg/ml of furocoumarin extracts, respectively. In cow cells, grown in presence of S9, SCE mean values/cell were 11.49±4.78 and 11.65±5.19 in treated cells at 100 and 200 µg/ml of furocoumarins and 11.66±5.45 in the control. In cow cells grown in absence of S9, SCE mean values were 11.81±6.14 in the control and 12.35±7.09 and 12.01±5.43, respectively, in the presence of 100 and 200 µg/ml of furocoumarins. Despite their higher SCE values in the absence of S9, no statistically significant differences were found when these values were compared with those shown in presence of S9, suggesting no mutagenic action of furocoumarins in cows, at the doses used in this study.

Effects of infliximab on sister chromatid exchanges and chromosomal aberration in patients with rheumatoid arthritis

Abstract: The aim of this study was to evaluate in a 24-weeks the effect of anti-TNF-alpha, infliximab, on cytogenetic biomarkers in peripheral lymphocytes of patients with rheumatoid arthritis (RA). A total of 40 patients with RA met the criteria to be treated with methotrexate (15 mg/week) were evaluated. Twenty patients, randomly selected, were treated with infliximab in addition to methotrexate (group I), whereas the other 20 patients continued with only methotrexate treatment (group M). Twenty healthy volunteers matched for age, gender and smoking habits served as control group (group C). At baseline, sister chromatid exchange rate was 7.20 ± 2.21 in group I, 7.40 ± 1.60 in group M and 4.97 ± 1.32 in group C (P < 0.01 vs group I and M). After 24-weeks, sister chromatid exchange rate was 7.87 ± 2.54 in group I and 7.81 ± 1.95 in group M (P = ns). High frequency cells count was 4.9 % and 4.7 % in the groups I and M, respectively, at the end of the study (P = ns). The basal chromosomal aberration frequency was 4.90 % in group I and 5.20 % in groups M; after 24-weeks, this was 5.10 % in group I and 5.10 % in groups M (P = ns). Infliximab treatment, for 24 weeks, did not increase the cytogenetic biomarkers in patients with RA. Our data show that the use of infliximab has not a genotoxic effect in patients with RA.

The Effect of Bromodeoxyuridine on Spontaneous Sister Chromatid Exchange Frequency in Rabbit (Oryctolagus cuniculus) and Coypu (Myocastor coypu) Chromosomes.

Abstract: The sister chromatid exchange test is regarded as a highly sensitive cytogenetic assay. It measures chromosome sensitivity to particular damage factors and provides information on control and repair mechanism performance. It is instrumental in the early identification of the effects of noxious factors present in the habitat. This investigation was aimed at identifying sister chromatid exchange sites in coypu and rabbit chromosomes, as well as determining the spontaneity of the process by applying different BrdU doses. The chromosomes were obtained from an in vitro culture of blood lymphocytes, supplemented with 4 different BrdU doses: 0.25/0.5/1.0/2.5 μg/ml in order to identify spontaneous sister chromatid exchanges in both animal species. The chromosomes were stained according to the FPG method. Spontaneous SCEs were observed in coypu at a concentration of 1.0 μg/ml, and in rabbits at 0.5 μg/ml. The mean SCE/cell incidence was 1.41±1.15 in coypu, and 2.69±2.14 in rabbits. Differences in SCE incidence were identified between the analysed animal species and the applied BrdU doses.

In vitro Effects of Epigallocatechin Gallate on Sister Chromatid Exchange in the Lymphocytes Exposed to Glyphosate

Abstract: Green tea (GT), one of the most widely consumed beverage in the world, has been consumed by Eastern Asian people as a medicinal beverage to promote health and stabilize body and soul. The commonly known effects of GT are anti-diabetic activity, the lowering of plasma cholesterol and triglyceride levels and anti-oxidant activity. The 4 major catechins in GT are epigallocatechin gallate (EGCG), epicatechin gallate (ECG), epicatechin (EC) and epigallocatechin (EGC). In addition to commonly known effects of GT above, EGCG have anti-inflammatory and antiviral activities and prevent cardiovascular diseases, neurological problems and 글라이포세이트 노출로 인한 DNA손상에 대한 녹차의 예방적 효과

Study of Some Cytogenetic Parameters in Azoospermia and Severe-Oligospermia Patient

Abstract: The aim of this study is to determined micronuclei index, sister chromatid exchange %, in infertile men (azospermai and severe-oligospermia) and compared with fertile men. Thirty patients (20 with azoospermia and 10 with severe oligospermia) and 15 control were studied in this project, The results show significant increase in micronuclei index, sister chromatid exchange %, in patients group

In vitro and in vivo effects of melatonin on sister chromatid exchange in human blood lymphocytes exposed to hypoxia

Abstract: Objective: Many studies have shown that melatonin (MLT) has an anti-genotoxic effect in various tissues and cell lines. The aim of this study was to investigate the anti-genotoxic effect of MLT on normal human peripheral lymphocytes by assessing sister chromatid exchange (SCE) in vitro and in vivo. Materials and methods: Cells were treated with 50 and 200 μM of MLT. The human volunteers (n = 20) for the in vivo study were administered a single dose of 3 mg MLT daily for 2 weeks. After sufficient time for its clearance, 1.5 mg of MLT daily was then administered to the same volunteers at same the period. Results: Our results demonstrated the anti-genotoxic effect of MLT in human blood lymphocyte in vitro and in vivo. In vitro, hypoxia increased the SCE frequency compared to the control and both doses of MLT significantly decreased the SCE frequency in the hypoxic cells (p < 0.001). In vivo, oral administration of 3 mg MLT significantly increased the frequency of SCE, yet a small increase of SCE by h...

Absence of toxicity and genotoxicity in an extract of Rubus coriifolius.

Abstract: Rubus coriifolius Focke is a wild plant from the Rosaceae family. It grows in both Guatemala and Mexico. The polar extract of the aerial parts of this plant has antibacterial, anti-inflammatory, and anti-protozoal activities. These properties may explain the traditional use of this plant. In vivo and in vitro assays were used to assess the genotoxic and toxic effects of an ethanol extract of the aerial parts of R. coriifolius. Three groups of rats were orally administered the R. coriifolius extract diluted in ethanol (5%) at doses of 1.89 mg/kg body weight (low dose), 4.72 mg/kg body weight (medium dose), and 9.44 mg/kg body weight (high dose) for 3 weeks. Genotoxic/cytotoxic effects induced by the R. coriifolius ethanol extract were evaluated in vivo by a micronuclei (MN) test in rat's bone marrow cells and in vitro by MN and sister chromatid exchange (SCE) in human lymphocyte cultures. In vivo genotoxicity analyses revealed that the average number of micronucleated polychromatic erythrocytes and the polychromatic erythrocyte/red blood cell ratio at all doses were not significantly different from those of the negative control. In vitro genotoxicity analyses showed that MN, SCE, and proliferative index frequencies in a human lymphocyte cell culture were not significantly different from those of the negative control. These results demonstrate that the ethanol extract of R. coriifolius aerial parts is not toxic or mutagenic (in vitro and in vivo) and does not affect cell proliferation at the concentrations analyzed.

Role of DNA repair in mutagenesis by 7-bromomethylbenz(a)anthracer (mutagen sensitivity/mutation induction/sister chromatid exchange/t

Abstract: The role of DNA repair in mutagenesis was stud- ied in normal, repair-proficient Chinese hamster ovary cells and in two mutant strains that are deficient in excision repair. By using the mutagen 7-bromomethylbenz(a)anthracene (7-BrMeBA) and the technique of alkaline elution of DNA, the mutants were found to be defective at or before the incision step of excision repair. Dose-responses were determined for cell killing, mutation induc- tion at three loci, and sister chromatid exchanges over a survival range of 1.0-0.1 after 7-BrMeBA treatment. The mutants were 5-fold more sensitive to killing than were the normal cells, but the degree of hypersensitivity to mutation induction varied depending on the mutant strain, the genetic marker, and the dose of mutagen. In each instance, the dose-response curve for mutations was es- sentially linear in the repair-deficient cells. In the normal cells, however, the curves for induced resistance to thioguanine and azaadenine were complex and were curvilinear with increasing slope at low doses. This behavior may be attributable to saturation of the excision repair system. No difference was seen in the ef- ficiency of inducing ouabain-resistant mutations in the repair-de- ficient cells compared to the normal cells, indicating a qualitatively different behavior of this marker. These results are consistent with excision repair of 7-BrMeBA damage being error-free in Chinese hamster ovary cells. Sister chromatid exchange, another manifestation of DNA damage, also.was induced with greater ef- ficiency in the repair-deficient cells.

Genoprotective Effect of Melatonin Against to the Genotoxicity of Glyphosate on Human Blood Lymphocytes

Abstract: Glyphosate is widely used nonselective herbicide for both agricultural and non-agricultural purpose. The chemical name of glyphosate is ‘N-(Phosphonomethyl) glycine’. It was discovered to be an herbicide by Monsanto chemist John Franz in 1970. Many previous studies about the safety of glyphosate formulation have concluded that there is little toxicity to humans. Past review concluded that there is no 글라이포세이트의 유전자 독성에 대한 멜라토닌의 유전자 보호 효과

Inhibition of malignant transformation in vitro by inhibitors of poly(ADP-ribose) synthesis (3-aminobenzamide/alkylating agents/ultraviolet light/x-rays/DNA breaks)

Abstract: Malignant transformation in vitro of hamster embryo cells and mouse C3H 10T1/2 cells by x-rays, ultraviolet light, and chemical carcinogens was inhibited by benzamide and by 3-aminobenzamide at concentrations that are specific for inhibition of poly(ADP-ribose) formation. These com- pounds slow the ligation stage of repair of x-ray and alkylation damage but not of ultraviolet light damage. At high concentra- tions they also inhibited de novo synthesis of DNA purines and DNA methylation by S-adenosylmethionine. The suppression of transformation by the benzamides is in striking contrast to their reported effectiveness in enhancing sister chromatid ex- change, mutagenesis, and killing in cells exposed to alkylating agents. Our results suggest that mechanisms regulating malig- nant transformation are different from those regulating DNA repair, sister chromatid exchange, and mutagenesis and may be associated with changes in gene regulation and expression caused by alterations in poly(ADP-ribosyl)ation.

Cytochrome P-450 metabolic activit extraembryonic tissue lineages of n (benzo(a)pyrene/mammalian development/sister chromatid exchange)

Abstract: Mouse morulae, blastocysts, and embryonic and extraembryonic tissue layers were examined for benzo(a)- pyrene metabolism by cytochrome P-450, using the sister chro- matid exchange assay. Benzo(a)pyrene exposure in vitro in- creased sister chromatid exchanges in blastocysts of all geneti- cally responsive mice examined (BALB/cDub, C3H/AnfCum, and outbred Dub:(ICR) strains) but not blastocysts of the non- responsive AKR/J strain. Benzo(a)pyrene treatment of re- sponsive 71/2- and 81/2-day (postimplantation-stage) embryos, either intact or as separate tissue layers, increased sister chro- matid exchanges in tissues of both embryonic and extraem- bryonic lineages-i.e., in the embryo proper, in isolated em- bryonic ectoderm, and in yolk sac, chorion, extraembryonic ectoderm, and extraembryonic endoderm layers. These results indicate that cytochrome P-450 is active in most or all tissues of the early mammalian embryo. It could metabolize xenobiotic molecules reaching the conceptus near the onset of morpho- genesis and organogenesis, or it could have another as yet un- defined role in normal development.

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