Impacts of Inorganic Arsenic Exposure on Genetic Stability of Human Mesenchymal Stromal Cells (hMSCs)
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PROVIDER: PRJNA1243302 | ENA |
REPOSITORIES: ENA
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Project description:Human mesenchymal stem/stromal cells (hMSCs) can differentiate into mesoderm-type cells, making them suitable candidates for tissue repair therapies. However, their relatively low frequency in adult tissue necessitates ex vivo expansion prior to regenerative medicine applications. Expansion can lead to selection of chromosomally abnormal clones and therefore, long-term hMSC stability should be studied. hMSCs applications in regenerative medicine ensures commercial availability of normal karyotype human primary cells for toxicity assessment and hMSCs could serve as alternatives to immortalized human cell models. In this work, we evaluated the potential of hMSCs in toxicity testing using inorganic arsenic (iAs) as a case study. hMSCs were exposed to iAs at different durations to track cellular aging and study long-term genetic stability. iAs exposures (48 hours) resulted in micronuclei induction. hMSCs were also exposed to iAs for 6 days to determine if hMSCs would become more susceptible to chromosomal damage following exposure to the model genotoxicant, mitomycin C (MMC). The culture duration and iAs exposure did not alter MMC potency, indicating that the hMSCs susceptibility to chromosomal damage remained unchanged. We also used gene expression analysis to investigate the molecular impacts of iAs on hMSCs over the course of short (3 days total) and long (30 days total) experiments. Both iAs exposures activated biomarkers associated with oxidative stress, but not biomarkers for direct DNA damage, providing support for an indirect mode of action for iAs genotoxicity. Overall, this study establishes the utility of hMSCs as a new model for toxicity screening and provides mechanistic information underlying iAs toxicity.
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Project description:Adult male mice (F0) were exposed to 250 ppb inorganic arsenic (iAs) in drinking water before mating with unexposed female mice to generate male F1 offspring (iAsF1-M). Unexposed male mice were bred simultaneously to generate male controls (conF1-M). Both iAsF1-M and conF1-M mice drank normal water without iAs. Adult iAsF1-M and conF1-M mice were harvested to collect liver samples to do RNA-seq.
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Project description:Arsenic and mercury are known chemical hazards. The differences in effects from organic and inorganic forms of these toxic elements is less well understood, however. The nematode Caenorhabditis elegans (C. elegans) is a suitable model to investigate the toxicity of environmental hazards. In this study, the transcriptomic profiles of C. elegans exposed to inorganic mercury chloride (HgCl2) and sodium (meta)arsenite (NaAsO2) were assessed alongside organic methylmercury chloride (meHgCl) and dimethylarsinic acid (DMA). For this purpose, adult C. elegans were exposed for 24 h to NaAsO2 (10 µg/ml), DMA (200 µg/ml), HgCl2 (2 µg/ml), and meHgCl (0.5 µg/ml), concentrations that were equitoxic in juveniles for developmental delay. Whole genome gene expression profiles were determined by using Cellegans_UnrestrictedGE_G2519F_020186 Microarray (Agilent Technologies, Santa Clara, CA). The results showed significant changes in the transcriptome of adult C. elegans exposed to NaAsO2, DMA, HgCl2, or meHgCl relative to the control group (C. elegans treated with water). A total of 927 and 1221 differentially expressed genes (DEGs) were found in C. elegans treated with 10 µg/ml NaAsO2 or 200 µg/ml DMA, respectively. Interestingly, only 161 DEGs were in common for these two chemicals. Exposure to 2 µg/ml HgCl2 or 0.5 µg/ml meHgCl altered the expression of 670 and 485 genes, respectively, and out of these genes, 154 were commonly altered by the two treatments. Analysis of DEGs revealed that organic and inorganic forms of arsenic and mercury have different effects on the transcriptome of adult C. elegans.
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Project description:DNA microarray analysis revealed that the genes related to cell cycle regulation were significantly induced at non- and sub-lethal concentrations (i.e., 0.05-6 µM), while the common feature of heavy metal toxicity such as oxidative damage and following increase in glutathione, heat shock proteins, and metallothionein were confirmed at high concentrations (i.e., 6-40 µM). The concentration dependent modulation of gene expression (induction of cell cycle genes, induction of cell cycle arrest genes and apoptotic genes) following exposure to arsenic was further supported by acceleration of cell proliferation, ROS generation, and cytotoxicity. Furthermore, three cell cycle genes (i.e., CDC25B, UBE2C, and PTTG1) were proposed as marker genes of inorganic arsenic exposure. Those results indicated the potential pro-carcinogenic actions of inorganic arsenic occur in environmentally relevant exposures (as low as 0.07 µM).
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Project description:The goal of this study is to compare gene expression levels in the livers of larval Tg(fabp10:nls-mcherry) exposed to 1 mM inorganic arsenic from 4-120 hpf to the unexposed siblings. Samples were collected from Tg(fabp10:nls-mcherry) zebrafish larvae that were derived from incrossed parents of the same strain. The background of transgenic lines were typically from mixed outcrosses of the transgenics to AB, TAB5, and TAB14 strains when regenerating the lines as the working stocks aged. All samples were collected at approximately 120 hpf - natural spawning at 8:30-9:00AM EST on day zero, samples were collected at 8-10AM EST on day 5.
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Project description:We investigate cellular responses to traditional bioactive mineral-based nanomaterials, such as hydroxyapatite (nHA), whitlockite (nWH), silicon-dioxide (nSiO2), and the emerging synthetic 2D nanosilicates (nSi), on human mesenchymal stem cells (hMSCs). Specifically, using next-generation transcriptome sequencing (RNA-seq), we uncover key signaling pathways and transcriptome dynamics due to exposure to these inorganic nanomaterials. Whole-transcriptome sequencing identified a stabilized skeletal progenitor state in stem cells treated with nanosilicates that suggests endochondral differentiation of hMSCs, resulting in increased deposition of matrix mineralization compared with control or other treatment groups.
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Project description:Chronic exposure to inorganic arsenic (iAs) or a high-fat diet (HFD) can produce liver injury. However, the interactive molecular biological effects and mechanism of iAs and HFD are as of yet unclear. We used microarrays to detail the interactive effects of arsenic and a high-fat diet on hepatic gene expression.
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Project description:Zinc finger protein with KRAB and SCAN domain 3 (ZKSCAN3), a transcriptional repressor, involves in multiple cellular functions. However, the functions of ZKSCAN3 in the homeostatic maintenance of human stem cells remains elusive. Here, we demonstrated that ZKSCAN3 was crucial for preventing human mesenchymal stem cells (hMSCs) from senescence in an autophagy-independent manner. Downregulation of ZKSCAN3 was observed in senescent hMSCs, and depletion of ZKSCAN3 led to premature aging in hMSCs. Further study uncovered that ZKSCAN3 maintained heterochromatin (HC) stability by interacting with heterochromatin associated proteins KAP1 and HP1 as well as nuclear envelope proteins Lamin B1, LBR and Emerin. Deficiency of ZKSCAN3 resulted in detachment of Lamina-associated domains (LADs) from the lamina, loss of heterochromatin and more accessible chromatin status within the heterochromatin and aberrant expression of repetitive sequences. Overexpression of ZKSCAN3, KAP1 or HP1 respectively rescued the senescent phenotypes in ZKSCAN3-/- hMSCs. Notably, reintroduction of ZKSCAN3 protein also retarded the cellular senescence in the replicative senescent hMSCs, as well as the pathological or physiological aging hMSCs. Together, our study reveals a novel, autophagy-independent role of ZKSCAN3 in the maintenance of heterochromatin stability and attenuation of hMSC senescence. Thus, ZKSCAN3 may be a candidate for alleviating human aging-related disorders.
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