Showing papers on "Sister chromatid exchange published in 2005"
TL;DR: It is proposed that the increased incidence of chromosomal instability and cancer in WS relates in part to aberrant recombinations between sister chromatids at telomeres, which facilitates the activation of ALT and engenders cancer-relevant chromosomal aberrations and tumor formation.
Abstract: Werner Syndrome (WS) is characterized by premature aging, genomic instability, and cancer. The combined impact of WRN helicase deficiency and limiting telomere reserves is central to disease pathogenesis. Here, we report that cells doubly deficient for telomerase and WRN helicase show chromosomal aberrations and elevated recombination rates between telomeres of sister chromatids. Somatic reconstitution of WRN function, but not a WRN helicase-deficient mutant, abolished telomere sister chromatid exchange (T-SCE), indicating that WRN normally represses T-SCEs. Elevated T-SCE was associated with greater immortalization potential and resultant tumors maintained telomeres via the alternative lengthening of telomere (ALT) pathway. We propose that the increased incidence of chromosomal instability and cancer in WS relates in part to aberrant recombinations between sister chromatids at telomeres, which facilitates the activation of ALT and engenders cancer-relevant chromosomal aberrations and tumor formation.
190 citations
TL;DR: It is shown that in mouse embryonic stem (ES) cells, mutations in either the Bloom syndrome homologue (Blm) or the Recql5 genes result in a significant increase in the frequency of sister chromatid exchange (SCE), whereas deleting both Blm and RecQL5 lead to an even higher frequency of SCE.
Abstract: In eukaryotes, crossovers in mitotic cells can have deleterious consequences and therefore must be suppressed. Mutations in BLM give rise to Bloom syndrome, a disease that is characterized by an elevated rate of crossovers and increased cancer susceptibility. However, simple eukaryotes such as Saccharomyces cerevisiae have multiple pathways for suppressing crossovers, suggesting that mammals also have multiple pathways for controlling crossovers in their mitotic cells. We show here that in mouse embryonic stem (ES) cells, mutations in either the Bloom syndrome homologue (Blm) or the Recql5 genes result in a significant increase in the frequency of sister chromatid exchange (SCE), whereas deleting both Blm and Recql5 lead to an even higher frequency of SCE. These data indicate that Blm and Recql5 have nonredundant roles in suppressing crossovers in mouse ES cells. Furthermore, we show that mouse embryonic fibroblasts derived from Recql5 knockout mice also exhibit a significantly increased frequency of SCE compared with the corresponding wild-type control. Thus, this study identifies a previously unknown Recql5-dependent, Blm-independent pathway for suppressing crossovers during mitosis in mice.
128 citations
TL;DR: It is concluded that BRCA1 regulates RAD51 function in response to the type of DNA damage and B RCA1 suppresses SCRS, suggesting a role for this protein in sister chromatid cohesion/alignment.
Abstract: The breast/ovarian cancer susceptibility proteins BRCA1 and BRCA2 maintain genome stability, at least in part, through a functional role in DNA damage repair. They both colocalize with RAD51 at sites of DNA damage/replication and activate RAD51-mediated homologous recombination repair of DNA double-strand breaks (DSB). Whereas BRCA2 interacts directly with and regulates RAD51, the role of BRCA1 in this process is unclear. However, BRCA1 may regulate RAD51 in response to DNA damage or through its ability to interact with and regulate MRE11/RAD50/NBS1 (MRN) during the processing of DSBs into single-strand DNA (ssDNA) ends, prerequisite substrates for RAD51, or both. To test these hypotheses, we measured the effect of BRCA1 on the competition between RAD51-mediated homologous recombination (gene conversion and crossover) versus RAD51-independent homologous recombination [single-strand annealing (SSA)] for ssDNA at a site-specific chromosomal DSB within a DNA repeat, a substrate for both homologous recombination pathways. Expression of wild-type BRCA1 in BRCA1-deficient human recombination reporter cell lines promoted both gene conversion and SSA but greatly enhanced gene conversion. In addition, BRCA1 also suppressed both spontaneous gene conversion and deletion events, which can arise from either crossover or sister chromatid replication slippage (SCRS), a RAD51-independent process. BRCA1 does not seem to block crossover. From these results, we conclude that (a) BRCA1 regulates RAD51 function in response to the type of DNA damage and (b) BRCA1 suppresses SCRS, suggesting a role for this protein in sister chromatid cohesion/alignment. Loss of such control in response to estrogen-induced DNA damage after BRCA1 inactivation may be a key initial event that triggers genome instability and carcinogenesis.
102 citations
TL;DR: It is reported that a p53 deletion is sufficient to extend the life span of Rad51d-deficient embryos by up to 6 days and rescue the cell lethal phenotype and support a crucial role for mammalian RAD51D in normal development, recombination, and maintaining mammalian genome stability.
Abstract: Homologous recombination is a double-strand break repair pathway required for resistance to DNA damage and maintaining genomic integrity. In mitotically dividing vertebrate cells, the primary proteins involved in homologous recombination repair are RAD51 and the five RAD51 paralogs, RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3. In the absence of Rad51d, human and mouse cells fail to proliferate, and mice defective for Rad51d die before birth, likely as a result of genomic instability and p53 activation. Here, we report that a p53 deletion is sufficient to extend the life span of Rad51d-deficient embryos by up to 6 days and rescue the cell lethal phenotype. The Rad51d−/−Trp53−/− mouse embryo–derived fibroblasts were sensitive to DNA-damaging agents, particularly interstrand cross-links, and exhibited extensive chromosome instability including aneuploidy, chromosome fragments, deletions, and complex rearrangements. Additionally, loss of Rad51d resulted in increased centrosome fragmentation and reduced levels of radiation-induced RAD51-focus formation. Spontaneous frequencies of sister chromatid exchange were not affected by the absence of Rad51d, but sister chromatid exchange frequencies did fail to be induced upon challenge with the DNA cross-linking agent mitomycin C. These findings support a crucial role for mammalian RAD51D in normal development, recombination, and maintaining mammalian genome stability.
101 citations
TL;DR: A regulatory role of the Rev1 BRCT domain in TLS of a limited spectrum of endogenous and exogenous nucleotide damages during a defined phase of the cell cycle is indicated.
Abstract: Rev1 is a deoxycytidyl transferase associated with DNA translesion synthesis (TLS). In addition to its catalytic domain, Rev1 possesses a so-called BRCA1 C-terminal (BRCT) domain. Here, we describe cells and mice containing a targeted deletion of this domain. Rev1B/B mice are healthy, fertile and display normal somatic hypermutation. Rev1B/B cells display an elevated spontaneous frequency of intragenic deletions at Hprt. In addition, these cells were sensitized to exogenous DNA damages. Ultraviolet-C (UV-C) light induced a delayed progression through late S and G2 phases of the cell cycle and many chromatid aberrations, specifically in a subset of mutant cells, but not enhanced sister chromatid exchanges (SCE). UV-C-induced mutagenesis was reduced and mutations at thymidine–thymidine dimers were absent in Rev1B/B cells, the opposite phenotype of UV-C-exposed cells from XP-V patients, lacking TLS polymerase η. This suggests that the enhanced UV-induced mutagenesis in XP-V patients may depend on error-prone Rev1-dependent TLS. Together, these data indicate a regulatory role of the Rev1 BRCT domain in TLS of a limited spectrum of endogenous and exogenous nucleotide damages during a defined phase of the cell cycle.
87 citations
TL;DR: The study suggests that the occupational exposure to mercury did not cause a direct genotoxicity but caused significant deficiency in DNA repair, consistent with previous studies using the standard chromosome aberration assay.
Abstract: We have conducted a population study to investigate whether current occupational exposure to mercury can cause genotoxicity and can affect DNA repair efficiency. Blood samples from 25 exposed workers and 50 matched controls were investigated for the expression of genotoxicity. The data indicate that mercury exposure did not cause any significant differences between the workers and controls in the baseline levels of DNA strand breaks (as measured by the alkaline version of the single cell gel electrophoresis [SCGE] assay) or sister chromatid exchanges (SCE). However, the exposure produced elevated average DNA tails length in the SCGE assay and frequency of chromosome aberrations. In the studies, isolated lymphocytes were exposed to 6J/m2 UV-C light or 2 Gy dose of X-rays in a challenge assay and repair of the induced DNA damage was evaluated using the SCGE assay. Results from the UV-light challenge assay showed no difference between the workers and controls in the expression of DNA strand breaks after exposure followed by incubation in the absence or presence of the cellular mitogen (phytohemagglutinin, PHA). No difference in DNA strand breaks between the workers and controls was seen immediately after the X-ray challenge, either. However, significant differences were observed in cells that were incubated for 2h with and without phytohemagglutinin. Data from the X-rays challenge assay were further used to calculate indices that indicate DNA repair efficiency. Results show that the repair efficiencies for the workers (69.7% and 83.9% in un-stimulated and stimulated lymphocytes, respectively) were significantly lower than that of matched controls (85.7% and 90.4%, respectively). In addition, the repair efficiency showed a consistent and significant decrease with the duration of occupational exposure to mercury (from 75.7% for <10 years employment, to 65.1% for 11-20 years and to 64.1% for 21-35 years) associated with increase of cytogenetic damage. Our study suggests that the occupational exposure to mercury did not cause a direct genotoxicity but caused significant deficiency in DNA repair. Our observations are consistent with previous studies using the standard chromosome aberration assay to show that exposure to hazardous environmental agents can cause deficiency in DNA repair. Therefore, these affected individuals may have exposure-related increase of health risk from continued exposure and in combination with exposure to other genotoxic agents.
79 citations
TL;DR: The hypothesis that 900 MHz radiofrequency field exposure induces DNA damage in human peripheral blood leukocytes in this range of SAR does not support the hypothesis.
Abstract: Human peripheral blood leukocytes from healthy volunteers have been employed to investigate the induction of genotoxic effects following 2 h exposure to 900 MHz radiofrequency radiation The GSM signal has been studied at specific absorption rates (SAR) of 03 and 1 W/kg The exposures were carried out in a waveguide system under strictly controlled conditions of both dosimetry and temperature The same temperature conditions (370 ± 01 °C) were realized in a second waveguide, employed to perform sham exposures The induction of DNA damage was evaluated in leukocytes by applying the alkaline single cell gel electrophoresis (SCGE)/comet assay, while structural chromosome aberrations and sister chromatid exchanges were evaluated in lymphocytes stimulated with phytohemagglutinin Alterations in kinetics of cell proliferation were determined by calculating the mitotic index Positive controls were also provided by using methyl methanesulfonate (MMS) for comet assay and mitomycin-C (MMC), for chromosome aberration, or sister chromatid exchange tests No statistically significant differences were detected in exposed samples in comparison with sham exposed ones for all the parameters investigated On the contrary, the positive controls gave a statistically significant increase in DNA damage in all cases, as expected Thus the results obtained in our experimental conditions do not support the hypothesis that 900 MHz radiofrequency field exposure induces DNA damage in human peripheral blood leukocytes in this range of SAR Bioelectromagnetics 26:258–265, 2005 © 2005 Wiley-Liss, Inc
73 citations
TL;DR: Results indicate that human lymphocytes cells and plants cells (Allium cepa) have a very sensitive cellular response to the mycotoxin fumonisin B(1) as observed at the highest concentrations.
61 citations
TL;DR: Frequency of sister chromatid exchange (SCE); aberrant cells, including numerical and structural chromosomal aberrations; and chromosome aberrages were investigated in peripheral blood lymphocytes from exposed workers and controls.
61 citations
TL;DR: A novel "nested intron" reporter is developed that allows the positive selection in mammalian cells of "long tract" gene conversion events arising between sister chromatids, and shows that these events arise spontaneously in cycling cells and are strongly induced by a site-specific double-strand break caused by the restriction endonuclease, I-SceI.
58 citations
TL;DR: It is hypothesize that HR is essential for the induction of SCE in bystander cells; however, HR is unable to repair the DNA damage induced in NHEJ-deficient bystanding cells that leads to either SCE or chromosomal aberrations.
Abstract: Nagasawa, H., Peng, Y., Wilson, P. F., Lio, Y-C., Chen, D. J., Bedford, J. S. and Little, J. B. Role of Homologous Recombination in the Alpha-Particle-Induced Bystander Effect for Sister Chromatid Exchanges and Chromosomal Aberrations. Radiat. Res. 164, 141–147 (2005). The bystander effect for sister chromatid exchanges (SCEs) and chromosomal aberrations was examined in hamster cell lines deficient in either DNA-PKcs (V3 cells, deficient in nonhomologous end joining, NHEJ) or RAD51C (irs3 cells, deficient in homologous recombination, HR). Cells synchronized in G0/G1 phase were irradiated with very low fluences of α particles such that <1% of the nuclei were traversed by an α particle. Wild-type cells showed a prominent bystander response for SCE induction; an even greater effect was observed in V3 cells. On the other hand, no significant induction of SCE was observed in the irs3 RAD51C-deficient bystander cells irradiated at various stages in the cell cycle. Whereas a marked bystander effect for ...
TL;DR: RecQL 1 is identified as a predominant ATP-dependent, HJ branch migrator present in human nuclear extracts and proposed that RecQL1 is involved in the processing of Holliday junctions in human cells.
Abstract: Homologous recombination provides an effective way to repair DNA double-strand breaks (DSBs) and is required for genetic recombination. During the process of homologous recombination, a heteroduplex DNA structure, or a ‘Holliday junction’ (HJ), is formed. The movement, or branch migration, of this junction is necessary for recombination to proceed correctly. In prokaryotes, the RecQ protein or the RuvA/RuvB protein complex can promote ATP-dependent branch migration of Holliday junctions. Much less is known about the processing of Holliday junctions in eukaryotes. Here, we identify RecQL1 as a predominant ATP-dependent, HJ branch migrator present in human nuclear extracts. A reduction in the level of RecQL1 induced by RNA interference in HeLa cells leads to an increase in sister chromatid exchange. We propose that RecQL1 is involved in the processing of Holliday junctions in human cells.
TL;DR: The results suggest that animals and cell culture differ in their ability to carry out genomic rearrangements as a means of maintaining telomere integrity when telomeres become critically shortened.
Abstract: Telomerase deficiency leads to a progressive loss of telomeric DNA that eventually triggers cell apoptosis in human primary cells during prolonged growth in culture. Rare survivors can maintain telomere length through either activation of telomerase or recombination-based telomere lengthening, and thus proliferate indefinitely. We have explored the possibility that telomeres may be maintained through telomere sister chromatid exchange (T-SCE) in murine telomere reverse transcriptase-deficient (mTert-/-) splenocytes and ES cells. Because telomerase deficiency leads to gradual loss of telomeric DNA in mTert-/- splenocytes and ES cells and eventually to chromosomes with telomere signal-free ends (SFEs), we examined these cell types for evidence of sister chromatid exchange at telomeres, and observed an increase in T-SCEs only in a subset of mTert-/- splenocytes or ES cells that possessed multiple SFEs. Furthermore, T-SCEs were more often detected in ES cells than in splenocytes that harbored a similar frequency of SFEs. In mTert heterozygous (mTert+/-) ES cells or splenocytes, which are known to exhibit a decrease in average telomere length but no SFEs, no increase in T-SCE was observed. In addition to T-SCE, other genomic rearrangements (i.e., SCE) were also significantly increased in mTert-/- ES cells possessing critically short telomeres, but not in splenocytes. Our results suggest that animals and cell culture differ in their ability to carry out genomic rearrangements as a means of maintaining telomere integrity when telomeres become critically shortened.
TL;DR: Results indicate that both TF and TR have significant antimutagenic and anticlastogenic effects.
National Defense Medical Center1, University of Freiburg2, National Cheng Kung University3, China Medical University (Taiwan)4, Academia Sinica5, Heidelberg University6, University of Marburg7, University of Padua8, French Institute of Health and Medical Research9, University of California, Los Angeles10
TL;DR: Additional polymorphisms identified within the DAZ repeat regions of theDAZ genes indicate that sister chromatid exchange plays a significant role in the genesis of deletions, duplications, and polymorphisms of the Y chromosome.
TL;DR: The data suggest that the sensitivity of the wild-type cells to raltitrexed is not associated with activation of PARP-1 dependent BER, extensive uracil incorporation into DNA and persistent strand breaks, but rather with changes suggestive of DNA recombination.
TL;DR: No clear evidence that styrene exposure in workers results in detectable levels of mutagenic damage is provided, but evidence of exposure to genotoxic metabolites is demonstrated by the formation of DNA adducts and strand breaks.
Abstract: Styrene (CAS No. 100-42-5) is an important industrial chemical for which positive results have been reported in in vitro and in vivo genotoxicity assays. Styrene-exposed workers have been studied extensively over two decades for the induction of various types of genotoxic effects. The outcomes of these studies have been conflicting, and where positive responses have been reported, it has proved difficult to demonstrate clear relationships between levels of damage reported and exposure levels. In this review, we have assessed studies addressing mutagenicity (chromosome aberrations, micronuclei and gene mutations) and other endpoints (sister chromatid exchanges, DNA breaks and DNA adducts) using criteria derived from the IPCS guidelines for the conduct of human biomonitoring studies. Based on the re-evaluated outcomes, the data are not convincing that styrene induces gene mutations. The evidence for induction of clastogenicity in occupationally exposed workers is less clear, with a predominant lack of induction of micronuclei in different studies, but conflicting responses in chromosome aberration assays. The results of numerous studies on sister chromatid exchanges do not provide evidence of a clear positive response, despite these being induced in animals exposed to styrene at high concentrations. However, there is evidence that both DNA adducts and DNA single strand breaks are induced in styrene workers. These types of damage are considered indicative of exposure of the target cells and interaction with cellular DNA but do not necessarily result in heritable changes. There is evidence that the metabolism of styrene in humans is affected by genetic polymorphisms of metabolizing genes and that these polymorphisms affect the outcome of in vitro mutagenicity studies on styrene. Therefore, studies that have addressed the potential of this factor to affect in vivo responses were considered. To date, there are no consistent relationships between genetic polymorphisms and induction of genotoxicity by styrene in humans, but further work is warranted on larger samples. The analyses of individual studies, together with a consideration of dose-response relationships and the lack of a common profile of positive responses for the various endpoints in different studies, provide no clear evidence that styrene exposure in workers results in detectable levels of mutagenic damage. However, evidence of exposure to genotoxic metabolites is demonstrated by the formation of DNA adducts and strand breaks.
TL;DR: Apitol, with cymiazole hydrochloride as the active ingredient, is used in bee-keeping against the ectoparasitic mite Varroa destructor and the preparation was evaluated for genotoxicity in cultured human peripheral blood lymphocytes, suggesting that it has genotoxic potential.
Abstract: Apitol®, with cymiazole hydrochloride as the active ingredient, is used in bee-keeping against the ectoparasitic mite Varroa destructor. The preparation was evaluated for genotoxicity in cultured human peripheral blood lymphocytes. Sister chromatid exchange, the mitotic index and the cell proliferation index were determined for three experimental concentrations of Apitol® (0.001, 0.01 and 0.1 mg/ml). All concentrations significantly (p
TL;DR: The comet assay technique was applied to CHO-K1 cells in order to evaluate the genotoxic potential of the waters of the Sapucaizinho River, Brazil, which receive tannery effluents and therefore are contaminated with chromium.
Abstract: The comet assay technique has been considered to be more efficient in the biomonitoring of aquatic environments that the micronucleus and sister chromatid exchange techniques. The comet assay has b...
TL;DR: Free radical attack on β‐carotene results in the formation of high amounts of cleavage products with prooxidant activities towards subcellular organelles such as mitochondria, a finding which could provide an explanation for the contradictory results obtained with β‐ carotene in clinical efficacy and cancer prevention trials.
Abstract: Free radical attack on beta-carotene results in the formation of high amounts of cleavage products with prooxidant activities towards subcellular organelles such as mitochondria, a finding which could provide an explanation for the contradictory results obtained with beta-carotene in clinical efficacy and cancer prevention trials. Since primary hepatocytes proved to be very sensitive indicators for the genotoxic action of suspect mutagens/carcinogens we therefore investigated a beta-carotene cleavage products mixture (CP), apo-8'-beta-carotenal (apo-8') and beta-carotene in the primary rat hepatocyte assay in the presence and absence of oxidative stress provided by hypoxia/reoxygenation (Hy/re). The endpoints tested were: the mitotic indices, the percentages of necrotic and apoptotic cells, micronucleated cells (MN), chromosomal aberrations (CA) and sister chromatid exchanges (SCE). The results obtained indicate a genotoxic potential of both CP and apo-8' already in the concentration range of 100 nM and 1 microM, i.e. at physiologically relevant levels of beta-carotene and beta-carotene breakdown products. In contrast, no significant cytotoxic effects of these substances were observed, nor did beta-carotene induce significant cytotoxic or genotoxic effects at concentrations ranging from 0.01 up to 10 microM. However, when beta-carotene is supplemented during oxidative stress induced by hypoxia/reoxygenation, a dose-dependent increase of CP is observed accompanied by increasing genotoxicity. Furthermore, when beta-carotene cleavage products were supplied during oxidative stress significant additional increases of genotoxic effects were observed, the additional increases indicating an additive effect of both exposures. Summarizing, these results provide strong evidence that beta-carotene breakdown products are responsible for the occurrence of carcinogenic effects found in the Alpha-Tocopherol Beta-carotene-Cancer prevention (ATBC) study and the beta-CArotene and RETinol Efficacy (CARET) Trial.
TL;DR: The results showed that the mixture induced the formation of SCE and MN in barley root cells with different effective concentrations and with different trends as treatment concentrations increased, suggesting that SO(2) is genotoxic agent and its genotoxicity may influence the mitotic activity and plant growth under SO( 2) stress.
TL;DR: This study investigated genotoxic effects of desflurane on the frequency of sister chromatid exchange in peripheral blood lymphocytes of patients during and after anaesthesia to find out the effect on frequency of SCE.
Abstract: Background: We investigated genotoxic effects of desflurane on the frequency of sister chromatid exchange (SCE) in peripheral blood lymphocytes of patients during and after anaesthesia.
Methods: Fifteen female patients, ASA classification I-II, aged 26–54 years, undergoing elective surgery were enroled in this study. Anaesthesia was induced by injection of thiopental 5–7 mg/kg and fentanyl 1 µg/kg. Vecuronium 0.1 mg/kg was given to facilitate tracheal intubation. Anaesthesia was maintained with desflurane 5–6% in an oxygen/air mixture (FiO2 0.3). N2O was not used for any patient. Using a heparinized syringe, venous blood was collected in patients before anaesthesia. Additional venous blood samples were taken from all patients at 60 and 120 min after the initiation of anaesthesia. Post-operative blood samples were taken and first, third, seventh and twelfth day samples were coded.
Results: Number of SCEs per cell at 60 and 120 min were significantly higher than the number of SCEs per cell before anaesthesia. In addition, number of SCEs per cell at 1, 3 and 7th post-operative days were significantly higher than pre-operative levels (P 0.05).
Conclusion: In the present study, because exposure to desflurane increased sister chromatid exchange in human lymphocytes in our group of patients, we conclude that this agent may be capable of producing genetic damage.
TL;DR: The results indicate that long-term exposure to low-dose ionizing radiation, even below the permitted levels, could result in increased oxidative stress, which may lead to DNA damage and mutagenicity.
Abstract: Investigations carried out to estimate the effect of long-term occupational exposure to low levels of external ionizing radiation indicated that exposed hospital staff showed an increase in chromosome aberrations. The purpose of this study was to evaluate whether genomic instability or an alteration in pteridine synthesis could be used as a marker of the potential hazard of ionizing radiation in hospital workers. Twenty gamma-radiation- and 33 X-ray-exposed technicians working in radiotherapy and radio-diagnostic units were included in this study, along with 22 healthy matched individuals. Plasma concentrations of nitrite plus nitrate (NO(x)) were measured to estimate reactive nitrogen species. Urinary neopterin, biopterin and creatinine concentrations were measured by high-performance liquid chromatography to determine metabolic activity along the pteridine pathway. Sister chromatid exchange was used as a measure of mutagenicity. Apoptosis was evaluated morphologically and also with a DNA-fragmentation test. The plasma NO(x) levels of both gamma-radiation- and X-ray-exposed technicians were significantly higher than those of the healthy controls (p<0.05). While the urinary biopterin concentrations were significantly higher in radiation-exposed groups compared with the healthy subjects (p<0.05), urinary neopterin concentrations remained unchanged. The apoptosis rates of gamma-radiation- and X-ray-exposed workers were significantly elevated in comparison with those in the control group (both p<0.05). Also, the increase in sister chromatid exchange frequency was significant in each of the radiation-exposed groups (exposed groups versus controls; p<0.05). These results indicate that long-term exposure to low-dose ionizing radiation, even below the permitted levels, could result in increased oxidative stress, which may lead to DNA damage and mutagenicity.
TL;DR: The results encourage further preclinical studies of these compounds in both in vitro and in vivo models (particularly for analogues D1 and D2), to determine their toxicological profile and establish the possibility of using them in humans.
TL;DR: Significant differences between exposed and non-exposed groups found in CAs, SCEs and MI demonstrate the mutagenic, clastogenic and also the cytotoxic effect of karathane LC.
Abstract: Karathane LC (active ingredient dinocap), a contact fungicide and a non-systemic acaricide was investigated for its ability to induce chromosome aberrations (CAs) and sister chromatid exchanges (SCEs) in cultured human lymphocytes of peripheral blood. In addition to the cytogenetic analysis, the effect of karathane LC on the cell proliferation kinetics (CPK) by the replication index (RI) was studied. The mitotic index (MI) was also determined to detect the cytotoxic effect. Lymphocytes were treated with four different concentrations (5, 10, 15 and 20 microg/ml) of karathane LC for 24 and 48 h. Significant differences between exposed and non-exposed groups found in CAs, SCEs and MI demonstrate the mutagenic, clastogenic and also the cytotoxic effect of karathane LC.
TL;DR: The genotoxic potential of FB1 has been underestimated until now and should be reconsidered according to the information obtained, compared with that of other Authors.
Abstract: The fumonisins, produced by fungi that infest foodstuffs, in particular corn, are responsible for a series of illnesses and toxicosis in various species of animals, including humans. There is still not detailed information about the genotoxic and mutagenic activity of Fumonisin B1 (FB1), but it is clear that it interferes with growth control, differentiation and cellu- lar apoptosis. The purpose of this study was to assess the genotoxic potential of Fumonisin B1 using in vitro cultures of bovine lymphocytes, through the calculation of the ‘mitotic index’ (MI), the frequency of ‘sister chromatid exchange’ (SCE) and the ‘micronucleus test’ (MN). The bovine lymphocytes were exposed to different concentrations of FB1 (25, 50 and 100 µ M) in order to find out which amount is sufficient to cause a reduction in the mitotic potential of the cells, the onset of MN and a higher frequency of SCE. The results obtained show a considerable reduction in the ‘mitotic index’ with a FB1 concentration of 50 µ M, an increase in the frequency of MN with a concentration of 50 µ M and a significant increase in the SCE with a concentration of 100 µ M. In the light of the information we have obtained, compared with that of other Authors, we feel that the genotoxic poten- tial of FB1 has been underestimated until now and should, therefore, be reconsidered.
TL;DR: MCPA is not genotoxic in vivo, consistent with its lack of carcinogenicity in rats and mice, and increases in percentage aberrant cells were found on analysis of metaphases of human peripheral lymphocytes treated in vitro in the presence of auxiliary metabolic activation.
Abstract: 4-Chloro-2-methylphenoxyacetic acid (MCPA) has been examined for genotoxicity in a range of in vitro and in vivo assays, including assays for gene mutation and clastogenicity. MCPA is non-mutagenic in bacterial and mammalian cell gene mutation assays. Increases in percentage aberrant cells were found on analysis of metaphases of human peripheral lymphocytes treated in vitro in the presence of auxiliary metabolic activation (S9), but only at doses approaching 10 mM and causing significant cytotoxicity. These increases may therefore be non-specific. No evidence for clastogenicity in vivo was found in the mouse bone marrow micronucleus assay or the Chinese hamster bone marrow metaphase assay. No evidence for either increases in sister chromatid exchange (SCE) frequency or DNA binding was found in the rat. Very small (less than 1.5 times controls) increases in SCE were observed in vivo in the hamster at toxic or maximum tolerated dose levels. MCPA is not alerting for likely genotoxic activity using established structure-activity relationship principles and it is concluded that, on the weight of evidence from the available data, MCPA is not genotoxic in vivo. This is consistent with its lack of carcinogenicity in rats and mice.
TL;DR: Cytogenetically, a girl presented with severely stunted growth, photosensitivity, and a characteristic facies was found to be a low sister chromatid exchange mosaicism of Bloom syndrome.
Abstract: A girl presented with severely stunted growth, photosensitivity, and a characteristic facies. Cytogenetic studies were suggestive of Bloom syndrome. This disorder has not been previously documented in the literature in an Indian child. Minor variations in characteristics in this patient have been highlighted. Cytogenetically, she was found to be a low sister chromatid exchange mosaicism of Bloom syndrome.
TL;DR: The data indicate that RAD53, not CHK1, is required for DSB-initiated SCE, and DNA damage-associated SCE after exposure to X-ray-mimetic and UV- mimetic chemicals.
TL;DR: The high rate of genomic rearrangements in telomerase deficient ES cells, when compared to murine splenocytes, may reflect the cultured cells’ gained ability to protect chromosome ends with eroded telomeres allowing them to escape “end crisis”.
Abstract: We have recently demonstrated that several types of genomic rearrangements (i.e., telomere sister chromatid exchange (T-SCE), genomic-SCE, or end-to-end fusions) were more often detected in long-term cultured murine telomerase deficient embryonic stem (ES) cells than in freshly prepared murine splenocytes, even through they possessed similar frequencies of critically short telomeres. The high rate of genomic rearrangements in telomerase deficient ES cells, when compared to murine splenocytes, may reflect the cultured cells' gained ability to protect chromosome ends with eroded telomeres allowing them to escape "end crisis". However, the possibility that ES cells were more permissive to genomic rearrangements than other cell types or that differences in the microenvironment or genetic background of the animals might consequentially determine the rate of T-SCEs or other genomic rearrangements at critically short telomeres could not be ruled out.