Mutagenesis最新文献

{"title":"A novel in vitro 3D model of the human bone marrow to bridge the gap between in vitro and in vivo genotoxicity testing.","authors":"Alexander R Vernon,Roy M Pemberton,H Ruth Morse","doi":"10.1093/mutage/geac009","DOIUrl":"https://doi.org/10.1093/mutage/geac009","url":null,"abstract":"The regulatory 2D in vitro micronucleus (MN) assay is part of a battery of tests, used to test for genotoxicity of new and existing compounds before they are assessed in vivo (ICH S2). The 2D MN assay consists of a monolayer of cells, whereas the in vivo bone marrow (BM) setting comprises a multicellular environment within a three-dimensional extracellular matrix. Although the in vitro MN assay follows a robust protocol set out by the Organisation for Economic Co-operation and Development (OECD) to comply with regulatory bodies, some compounds have been identified as negative genotoxicants within the in vitro MN assay but marginally positive when assessed in vivo. The glucocorticoids, which are weakly positive in vivo, have generally been suggested to pose no long-term carcinogenic risk; however, for novel compounds of unknown activity, improved prediction of genotoxicity is imperative. To help address this observation, we describe a novel 3D in vitro assay which aims to replicate the results seen within the in vivo BM microenvironment. AlgiMatrix scaffolds were optimized for seeding with HS-5 human BM stromal cells as a BM microenvironment, to which the human lymphoblast cell line TK6 was added. An MN assay was performed aligning with the 2D regulatory assay protocol. Utilizing this novel 3D in vitro model of the BM, known genotoxicants (mitomycin C, etoposide, and paclitaxel), a negative control (caffeine), and in vivo positive glucocorticoids (dexamethasone and prednisolone) were investigated for the induction of MN. It was found, in agreement with historical in vivo data, that the model could accurately predict the in vivo outcome of the glucocorticoids, unlike the regulatory 2D in vitro MN assay. These preliminary results suggest our 3D MN assay may better predict the outcome of in vivo MN tests, compared with the standard 2D assay.","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":"62 2 1","pages":"112-129"},"PeriodicalIF":2.7,"publicationDate":"2022-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138518396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of human umbilical cord mesenchymal stem cells-derived exosomal microRNA-431-5p in survival and prognosis of colorectal cancer patients.","authors":"Muwen Qu,&nbsp;Junyi Li,&nbsp;Zifu Hong,&nbsp;Fei Jia,&nbsp;Yinghua He,&nbsp;Lingling Yuan","doi":"10.1093/mutage/geac007","DOIUrl":"https://doi.org/10.1093/mutage/geac007","url":null,"abstract":"<p><p>We aim to discuss the role of miR-431-5p in colorectal cancer (CRC) progression via regulating peroxiredoxin 1 (PRDX1). miR-431-5p and PRDX1 expression were detected in CRC tissues and cells, and the relationship between miR-431-5p expression and prognosis of CRC patients was analyzed. Exosomes were extracted from human umbilical cord mesenchymal stem cells (hUCMSCs) and co-cultured with LoVo cells. MTT assay, flow cytometry and Transwell assay were implemented to test cell viability, apoptosis and invasion and migration ability, respectively. The tumor growth was determined as well, and the binding relation between miR-431-5p and PRDX1 was confirmed. miR-431-5p was downregulated and PRDX1 was upregulated in CRC, and miR-431-5p downregulation was associated with poor prognosis. hUCMSC-Exos suppressed the malignant behaviors of LoVo cells, and overexpression of miR-431-5p further aggravated the inhibitory effect of hUCMSC-Exos on LoVo cells. hUCMSC-Exos inhibited PRDX1 expression via miR-431-5p. PRDX1 was targeted by miR-431-5p. miR-431-5p serves as a prognostic biomarker in CRC, and hUCMSC-Exos transfer of miR-431-5p decelerates CRC cell growth by inhibiting PRDX1.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":"37 2","pages":"164-171"},"PeriodicalIF":2.7,"publicationDate":"2022-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9071100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10247993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mitochondrial poison carbonyl cyanide 3-chlorophenyl hydrazone (CCCP) induces aneugenic effects in primary human fibroblasts: a possible link between mitochondrial dysfunction and chromosomal loss.","authors":"F. Marcon, Francesca De Battistis, E. Siniscalchi, R. Crebelli, R. Meschini","doi":"10.1093/mutage/geac008","DOIUrl":"https://doi.org/10.1093/mutage/geac008","url":null,"abstract":"An association between proper chromosome segregation and intact mitochondria has been extensively reported. This could be related to the effects on the progression of cell division of altered energy production, increased oxidative stress, and deregulated calcium homeostasis. However, evidence for a direct relationship is still lacking. The present study was aimed at investigating the possible effect of mitochondrial dysfunction on chromosomal instability as detected in primary human cells treated with the mitochondrial poison carbonyl cyanide 3-chlorophenyl hydrazone (CCCP). Chromosome instability was analyzed in anaphase and interphase cells to follow the fate of chromosome damage during the progression of mitosis and the subsequent cell cycle. Through the combination of cytogenetic approaches and molecular analyses, i.e. morphological cell analysis, formation and characterization of micronucleus content, Comet assay, and gene expression, it was demonstrated that the prevalent DNA damage associated with CCCP treatment was the induction of chromosome loss, while primary DNA damage was not detected. No alterations in the shape of anaphase cells were observed nor induction of multipolar spindles. The proper activation of mitotic checkpoint was maintained. A linear dose-response curve characterizing the CCCP effects suggested that multiple cellular targets could be affected by the CCCP-induced mitochondrial dysfunctions triggering aneuploidy. Conversely, a steep increase was induced by the positive control vinblastine, known to have tubulin as a unique target. In addition, the effect of CCCP on mitochondrial function was demonstrated by changes in mitochondrial DNA copy number and in the expression of genes involved in mitochondrial maintenance. Overall, these results indicate that the mitochondrial poison CCCP may induce aneugenic effects.","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":"1 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2022-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60857483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Folate deficiency enhances the in vitro genotoxicity of bile acids in human colon and liver cells.","authors":"Jianfei Li,&nbsp;Cheng Zhang,&nbsp;Lingzhi Li,&nbsp;Xueqin Hu,&nbsp;Yizhen Jia,&nbsp;Yanan Huang,&nbsp;Ting Lyu,&nbsp;Xu Wang,&nbsp;Xihan Guo","doi":"10.1093/mutage/geab041","DOIUrl":"https://doi.org/10.1093/mutage/geab041","url":null,"abstract":"<p><p>Obese subjects have a high baseline of genotoxic stress, but the underlying mechanism is poorly understood. Given that obesity is associated with high bile acids (BA) and low folate, we aimed to determine the interactive effect of folate deficient or supplementation to the genotoxicity and cytotoxicity of BA in human colon and liver cells. NCM460 and L-02 cells were cultured in folate-deficient (22.6 nM) and replete (2260 nM) Roswell Park Memorial Institute (RPMI)-1640 medium with or without 50 μM deoxycholic acid (DCA) or lithocholic acid (LCA) for 7 days. Moreover, these cells were cultured in folate supplemented (5.65, 11.3 and 22.6 μM) and standard (2.26 μM) medium with 200 μM DCA or LCA for 7 days. Genotoxicity and cytotoxicity were measured using the cytokinesis-block micronucleus cytome assay. Our results showed that under folate-replete condition, 50 μM DCA or LCA significantly increased the rate of micronuclei (MN) in NCM460 and L-02 cells. Significantly, the MN-inducing effect of 50 μM DCA or LCA was further enhanced by folate deficiency. Interestingly, folate supplementation exerted a dose-dependent manner to significantly decrease the rates of MN, nucleoplasmic bridges, nuclear buds, apoptosis, and necrosis induced by 200 μM DCA or LCA in NCM460 and L-02 cells. In conclusion, the genotoxicity of moderate BA (50 μM) was exacerbated by folate deficiency and folate supplementation could efficiently protect cells against the genotoxicity and cytotoxicity of high BA (200 μM).</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":"37 1","pages":"34-43"},"PeriodicalIF":2.7,"publicationDate":"2022-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39634341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The suitability of micronuclei as markers of relative biological effect.","authors":"Charlotte J Heaven, Hannah C Wanstall, Nicholas T Henthorn, John-William Warmenhoven, Samuel P Ingram, Amy L Chadwick, Elham Santina, Jamie Honeychurch, Christine K Schmidt, Karen J Kirkby, Norman F Kirkby, Neil G Burnet, Michael J Merchant","doi":"10.1093/mutage/geac001","DOIUrl":"10.1093/mutage/geac001","url":null,"abstract":"<p><p>Micronucleus (MN) formation is routinely used as a biodosimeter for radiation exposures and has historically been used as a measure of DNA damage in cells. Strongly correlating with dose, MN are also suggested to indicate radiation quality, differentiating between particle and photon irradiation. The \"gold standard\" for measuring MN formation is Fenech's cytokinesis-block micronucleus (CBMN) cytome assay, which uses the cytokinesis blocking agent cytochalasin-B. Here, we present a comprehensive analysis of the literature investigating MN induction trends in vitro, collating 193 publications, with 2476 data points. Data were collected from original studies that used the CBMN assay to quantify MN in response to ionizing radiation in vitro. Overall, the meta-analysis showed that individual studies mostly have a linear increase of MN with dose [85% of MN per cell (MNPC) datasets and 89% of percentage containing MN (PCMN) datasets had an R2 greater than 0.90]. However, there is high variation between studies, resulting in a low R2 when data are combined (0.47 for MNPC datasets and 0.60 for PCMN datasets). Particle type, species, cell type, and cytochalasin-B concentration were suggested to influence MN frequency. However, variation in the data meant that the effects could not be strongly correlated with the experimental parameters investigated. There is less variation between studies when comparing the PCMN rather than the number of MNPC. Deviation from CBMN protocol specified timings did not have a large effect on MN induction. However, further analysis showed less variation between studies following Fenech's protocol closely, which provided more reliable results. By limiting the cell type and species as well as only selecting studies following the Fenech protocol, R2 was increased to 0.64 for both measures. We therefore determine that due to variation between studies, MN are currently a poor predictor of radiation-induced DNA damage and make recommendations for futures studies assessing MN to improve consistency between datasets.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":"37 1","pages":"3-12"},"PeriodicalIF":2.7,"publicationDate":"2022-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8976228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39901882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Folic acid deficiency increases sensitivity to DNA damage by glucose and methylglyoxal.","authors":"Leigh Donnellan,&nbsp;Bradley S Simpson,&nbsp;Varinderpal S Dhillon,&nbsp;Maurizio Costabile,&nbsp;Michael Fenech,&nbsp;Permal Deo","doi":"10.1093/mutage/geac003","DOIUrl":"https://doi.org/10.1093/mutage/geac003","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) is associated with elevated frequencies of micronuclei (MNi) and other DNA damage biomarkers. Interestingly, individuals with T2D are more likely to be deficient in micronutrients (folic acid, pyridoxal-phosphate, cobalamin) that play key roles in one-carbon metabolism and maintaining genomic integrity. Furthermore, it has recently been shown that deficiencies in these nutrients, in particular folic acid leaves cells susceptible to glucose-induced DNA damage. Therefore, we sought to investigate if the B lymphoblastoid WIL2-NS cell line cultured under folic acid-deficient conditions was more sensitive to DNA damage induced by glucose, or the reactive glycolytic byproduct methylglyoxal (MGO) and subsequent advanced glycation endproduct formation. Here, we show that only WIL2-NS cultured under folic acid-deficient conditions (23 nmol/l) experience an increase in MNi frequency when exposed to high concentrations of glucose (45 mmol/l) or MGO (100 µmol/l). Furthermore, we showed aminoguanidine, a well-validated MGO and free radical scavenger was able to prevent further MNi formation in folic acid-deficient cells exposed to high glucose, which may be due to a reduction in MGO-induced oxidative stress. Interestingly, we also observed an increase in MGO and other dicarbonyl stress biomarkers in folic acid-deficient cells, irrespective of glucose concentrations. Overall, our evidence shows that folic acid-deficient WIL2-NS cells are more susceptible to glucose and/or MGO-induced MNi formation. These results suggest that individuals with T2D experiencing hyperglycemia and folic acid deficiency may be at higher risk of chromosomal instability.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":"37 1","pages":"24-33"},"PeriodicalIF":2.7,"publicationDate":"2022-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9186029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39860125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The BlueScreen HC assay to predict the genotoxic potential of fragrance materials.","authors":"Yax Thakkar,Kaushal Joshi,Christina Hickey,Joseph Wahler,Brian Wall,Sylvain Etter,Benjamin Smith,Peter Griem,Matthew Tate,Frank Jones,Gladys Oudraogo,Stefan Pfuhler,Christopher Choi,Gary Williams,Helmut Greim,Gerhard Eisenbrand,Wolfgang Dekant,Anne Marie Api","doi":"10.1093/mutage/geac004","DOIUrl":"https://doi.org/10.1093/mutage/geac004","url":null,"abstract":"BlueScreen HC is a mammalian cell-based assay for measuring the genotoxicity and cytotoxicity of chemical compounds and mixtures. The BlueScreen HC assay has been utilized at the Research Institute for Fragrance Materials in a safety assessment program as a screening tool to prioritize fragrance materials for higher-tier testing, as supporting evidence when using a read-across approach, and as evidence to adjust the threshold of toxicological concern. Predictive values for the BlueScreen HC assay were evaluated based on the ability of the assay to predict the outcome of in vitro and in vivo mutagenicity and chromosomal damage genotoxicity assays. A set of 371 fragrance materials was assessed in the BlueScreen HC assay along with existing or newly generated in vitro and in vivo genotoxicity data. Based on a weight-of-evidence approach, the majority of materials in the data set were deemed negative and concluded not to have the potential to be genotoxic, while only a small proportion of materials were determined to show genotoxic effects in these assays. Analysis of the data set showed a combination of high positive agreement but low negative agreement between BlueScreen HC results, in vitro regulatory genotoxicity assays, and higher-tier test results. The BlueScreen HC assay did not generate any false negatives, thereby providing robustness when utilizing it as a high-throughput screening tool to evaluate the large inventory of fragrance materials. From the perspective of protecting public health, it is desirable to have no or minimal false negatives, as a false-negative result may incorrectly indicate the lack of a genotoxicity hazard. However, the assay did have a high percentage of false-positive results, resulting in poor positive predictivity of the in vitro genotoxicity test battery outcome. Overall, the assay generated 100% negative predictivity and 3.9% positive predictivity. In addition to the data set of 371 fragrance materials, 30 natural complex substances were evaluated for BlueScreen HC, Ames, and in vitro micronucleus assay, and a good correlation in all three assays was observed. Overall, while a positive result may have to be further investigated, these findings suggest that the BlueScreen HC assay can be a valuable screening tool to detect the genotoxic potential of fragrance materials and mixtures.","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":"67 1 1","pages":"13-23"},"PeriodicalIF":2.7,"publicationDate":"2022-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138518401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cobalt oxide (Co3O4) nanoparticles induced genotoxicity in Chinese hamster lung fibroblast (V79) cells through modulation of reactive oxygen species.","authors":"Onila Lugun, Jagreeti Singh, R. Thakur, A. Pandey","doi":"10.1093/mutage/geac005","DOIUrl":"https://doi.org/10.1093/mutage/geac005","url":null,"abstract":"Incessant production, pervasive applications in different fields, and eventually unintended exposure of cobalt oxide nanoparticles (Co3O4 NPs) lead to rise in their toxicity studies toward human health. However, the information regarding the potential toxicity mechanisms of Co3O4 NPs especially genotoxicity is still sparse with missing interconnections. So far, only solitary reports on Co3O4 NPs are at hand, bearing witness to reactive oxygen species (ROS)-mediated DNA damage in lung cells. To address this, we evaluated the Co3O4 NP-induced cytotoxic and genotoxic potential in Chinese hamster lung fibroblast cell line (V79). Our preliminary results demonstrate that Co3O4 NPs at concentrations of 20-100 µg/ml induced moderate mortality after 24-h exposure. However, these low concentrations caused a significant reduction in various organelles' activity in a concentration-dependent manner. Mitochondrial activity and membrane potential were found to be compromised due to NP exposure in a concentration-dependent manner. The study affirms that Co3O4 NPs inhibited lysosomal activity in V79 cells. In addition to this, Co3O4 NPs are also found to stimulate free oxygen radical generation. Genotoxicity studies revealed a potent and dose-dependent effect of non-cytotoxic concentrations of Co3O4 NPs in the induction of DNA lesions. Interestingly, N-acetylcysteine, a free oxygen radical scavenger (5, 10 mM, pretreatment) inhibited the progression of free oxygen radicals and induction of Co3O4 NP-mediated DNA lesions. This suggests the ROS-mediated genotoxic potential of Co3O4 NPs.","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":"1 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60857442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obituary for David G. Gatehouse (1951–2021)","authors":"","doi":"10.1093/mutage/geac002","DOIUrl":"https://doi.org/10.1093/mutage/geac002","url":null,"abstract":"<span></span>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":"67 1 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2022-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138518400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primary mesenchymal stromal cells in co-culture with leukaemic HL-60 cells are sensitised to cytarabine-induced genotoxicity, while leukaemic cells are protected.","authors":"Liana E Gynn,&nbsp;Elizabeth Anderson,&nbsp;Gareth Robinson,&nbsp;Sarah A Wexler,&nbsp;Gillian Upstill-Goddard,&nbsp;Christine Cox,&nbsp;Jennifer E May","doi":"10.1093/mutage/geab033","DOIUrl":"https://doi.org/10.1093/mutage/geab033","url":null,"abstract":"<p><p>Tumour microenvironments are hallmarked in many cancer types. In haematological malignancies, bone marrow (BM) mesenchymal stromal cells (MSC) protect malignant cells from drug-induced cytotoxicity. However, less is known about malignant impact on supportive stroma. Notably, it is unknown whether these interactions alter long-term genotoxic damage in either direction. The nucleoside analogue cytarabine (ara-C), common in haematological therapies, remains the most effective agent for acute myeloid leukaemia, yet one-third of patients develop resistance. This study aimed to evaluate the bidirectional effect of MSC and malignant cell co-culture on ara-C genotoxicity modulation. Primary MSC, isolated from patient BM aspirates for haematological investigations, and malignant haematopoietic cells (leukaemic HL-60) were co-cultured using trans-well inserts, prior to treatment with physiological dose ara-C. Co-culture genotoxic effects were assessed by micronucleus and alkaline comet assays. Patient BM cells from chemotherapy-treated patients had reduced ex vivo survival (P = 0.0049) and increased genotoxicity (P = 0.3172) than untreated patients. It was shown for the first time that HL-60 were protected by MSC from ara-C-induced genotoxicity, with reduced MN incidence in co-culture as compared to mono-culture (P = 0.0068). Comet tail intensity also significantly increased in ara-C-treated MSC with HL-60 influence (P = 0.0308). MSC sensitisation to ara-C genotoxicity was also demonstrated following co-culture with HL60 (P = 0.0116), which showed significantly greater sensitisation when MSC-HL-60 co-cultures were exposed to ara-C (P = 0.0409). This study shows for the first time that malignant HSC and MSC bidirectionally modulate genotoxicity, providing grounding for future research identifying mechanisms of altered genotoxicity in leukaemic microenvironments. MSC retain long-term genotoxic and functional damage following chemotherapy exposure. Understanding the interactions perpetuating such damage may inform modifications to reduce therapy-related complications, such as secondary malignancies and BM failure.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":"36 6","pages":"419-428"},"PeriodicalIF":2.7,"publicationDate":"2021-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39403608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}