Effects of Ethanol on Mouse Embryonic Stem Cells

Arzumanyan, Alla; Anni, Helen; Rubin, Raphael; Rubin, Emanuel

doi:10.1111/j.1530-0277.2009.01057.x

Cited by 32 publications

(54 citation statements)

References 71 publications

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“…We demonstrated earlier that the expression of Sox2, Oct4, and Nanog in the EB cell lysates was elevated with ethanol (100 mM) exposure [5]. However, the complexity of the multilineage EB cell aggregates and their interactions [55] does not facilitate a systematic analysis of the role of ethanol in the regulation of transcription factors along a single lineage.…”

Section: Ethanol Regulates the Expression Of Oct4 In Early Es Cell DImentioning

confidence: 99%

“…However, the earlier developmental stages and interference of ethanol with regulation of core transcription factors have not been elucidated. In our earlier study [5], we investigated the changes of Sox2, Oct4, and Nanog with ethanol during mouse ES cell spontaneous differentiation in suspension to the EBs. We demonstrated that downregulation of these transcription factors was not completed within 6 days in the presence of 100 mM ethanol.…”

Section: Introductionmentioning

confidence: 99%

“…Complex features can be reproduced by mouse and human differentiating ES cells to provide clues for the molecular determinants of processes such as neurogenesis [3,4]. We have previously employed a mouse ES cell platform to investigate the mechanisms of ethanol interference with the early stages of differentiation [5], and model prenatal exposure that is responsible for fetal alcohol spectrum disorders (FASD) [6][7][8][9]. With a rate of 9-50 cases per 1,000 live births, FASD is a leading cause among birth defects and developmental disorders [10].…”

Section: Introductionmentioning

confidence: 99%

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Ethanol Alters the Balance of Sox2, Oct4, and Nanog Expression in Distinct Subpopulations During Differentiation of Embryonic Stem Cells

Ogony

Malahias

Vadigepalli

et al. 2013

Stem Cells and Development

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The transcription factors Sox2, Oct4, and Nanog regulate within a narrow dose-range embryonic stem (ES) cell pluripotency and cell lineage commitment. Excess of Oct4 relative to Sox2 guides cells to mesoendoderm (ME), while abundance of Sox2 promotes neuroectoderm (NE) formation. Literature does not address whether ethanol interferes with these regulatory interactions during neural development. We hypothesized that ethanol exposure of ES cells in early differentiation causes an imbalance of Oct4 and Sox2 that diverts cells away from NE to ME lineage, consistent with the teratogenesis effects caused by prenatal alcohol exposure. Mouse ES cells were exposed to ethanol (0, 25, 50, and 100 mM) during retinoic acid (10 nM)-directed differentiation to NE for 0-6 days, and the expression of Sox2, Oct4, and Nanog was measured in single live cells by multiparametric flow cytometry, and the cellular phenotype was characterized by immunocytochemistry. Our data showed an ethanol dose-and time-dependent asymmetric modulation of Oct4 and Sox2 expression, as early as after 2 days of exposure. Single-cell analysis of the correlated expression of Sox2, Oct4, and Nanog revealed that ethanol promoted distinct subpopulations with a high Oct4/Sox2 ratio. Ethanol-exposed cells differentiated to fewer b-III tubulin-immunoreactive cells with an immature neuronal phenotype by 4 days. We interpret these data as suggesting that ethanol diverted cells in early differentiation from the NE fate toward the ME lineage. Our results provide a novel insight into the mode of ethanol action and opportunities for discovery of prenatal biomarkers at early stages.

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Section: Ethanol Regulates the Expression Of Oct4 In Early Es Cell DImentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ethanol Alters the Balance of Sox2, Oct4, and Nanog Expression in Distinct Subpopulations During Differentiation of Embryonic Stem Cells

Ogony

Malahias

Vadigepalli

et al. 2013

Stem Cells and Development

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“…Indeed, a critical role for ethanol in promoting apoptotic events in various cell lines and animal models has been well documented. [20][21][22][23][24][25][26][27][28][29] Also, ethanol stimulates the TRAIL-induced apoptosis in leukemic T-lymphocytes and colon cancer cells in vitro. 38,39 Despite these data, an interactive effect of ethanol and TRAIL in promoting PCa cell death has not been studied.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12][13][14][15][16][17][18][19] Ethanol-induced apoptotic cell death has been well recognized in many cell types and animal models. [20][21][22][23][24] High concentrations of ethanol can effectively destroy hepatoma tumor as well as normal cells, whereas lower concentrations of ethanol selectively induces apoptosis in hepatoma tumor cells but not in normal hepatocytes. 25 Ethanol induces significant apoptosis of purkinje cells in the developing cerebellum.…”

Section: Introductionmentioning

confidence: 99%

Ethanol promotes cytotoxic effects of tumor necrosis factor-related apoptosis-inducing ligand through induction of reactive oxygen species in prostate cancer cells

Plante

Arscott

Folsom

et al. 2012

Prostate Cancer Prostatic Dis

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BACKGROUND: Effective treatment of prostate cancer (PCa) remains a major challenge due to chemoresistance to drugs including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Ethanol and ethanol extracts are known apoptosis inducers. However, cytotoxic effects of ethanol on PCa cells are unclear. METHODS: In this study we utilized PC3 and LNCaP cell culture models. We used immunohistochemical analysis, western blot analysis, reactive oxygen species (ROS) measurement, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) Cell Proliferation Assay, Annexin-V staining and flow cytometry for quantification of apoptosis. In vitro soft agar colony formation and Boyden chamber invasion assays were used. Tumorigenicity was measured in a xenotransplantation mouse model. RESULTS: Here, we demonstrate that ethanol enhances the apoptosis-inducing potential of TRAIL in androgen-resistant PC3 cells and sensitizes TRAIL-resistant, androgen sensitive LNCaP cells to apoptosis through caspase activation, and a complete cleavage of poly (ADP)-ribose polymerase, which was in association with increased production of ROS. The cytotoxicity of ethanol was suppressed by an antioxidant N-acetyl cystein pretreatment. Furthermore, ethanol in combination with TRAIL increased the expression of cyclin-dependent kinase inhibitor p21 and decreased the levels of Bcl-2 and phosphorylated-AKT. These molecular changes were accompanied by decreased proliferation, anchorage-independent growth and invasive potential of PC3 and LNCaP cells. In vivo studies using a xenotransplantation mouse model with PC3 cells demonstrated significantly increased apoptosis in tumors treated with ethanol and TRAIL in combination. CONCLUSIONS: Taken together, use of ethanol in combination with TRAIL may be an effective strategy to augment sensitivity to TRAIL-induced apoptosis in PCa cells.

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Fetal Alcohol Spectrum Disorders: A Stem‐Cellopathy?

Mahnke

Salem

Tseng

et al. 2018

Stem Cells in Birth Defects Research and Developmental Toxicology

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Effects of Ethanol on Mouse Embryonic Stem Cells

Abstract: Our findings suggest that ethanol may contribute to the pathogenesis of FAS by triggering apoptotic pathways during differentiation of embryonic stem cells and deregulating early stages of embryogenesis.

Cited by 32 publications

References 71 publications

Ethanol Alters the Balance of Sox2, Oct4, and Nanog Expression in Distinct Subpopulations During Differentiation of Embryonic Stem Cells

Ethanol Alters the Balance of Sox2, Oct4, and Nanog Expression in Distinct Subpopulations During Differentiation of Embryonic Stem Cells

Ethanol promotes cytotoxic effects of tumor necrosis factor-related apoptosis-inducing ligand through induction of reactive oxygen species in prostate cancer cells

Fetal Alcohol Spectrum Disorders: A Stem‐Cellopathy?

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