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How benzene and its metabolites affect human marrow derived mesenchymal stem cells. 2012

Fatemeh Zolghadr, and Majid Sadeghizadeh, and Naser Amirizadeh, and Saman Hosseinkhani, and Shima Nazem
Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran.

Benzene is a known environmental pollutant with demonstrated leukemogenic activity. Marrow mesenchymal stem cells (MSCs), contribute to skeletal remodeling and repair. They also support haematopoiesis constructing important elements of haematopoietic niche. In the present study, the effects of a range of benzene concentrations along with those of its reactive metabolites, p-benzoquinone (BQ) and hydroquinone (HQ) on the viability of MSCs, apoptosis induction and caspase3/7 activity in these cells were analyzed. Our findings revealed that low concentrations of these chemicals (10μM of benzene, 5μM of either of BQ or HQ) significantly increase the number of chemically treated cells. Moreover, applied BQ/HQ concentrations were shown to be able to considerably inhibit caspase3/7 activity. While in benzene exposure experiments, the lowest concentration triggered the greatest increase in caspase3/7 activity during the initial hours of exposure. On the other hand, MSCs exposure to higher concentrations of benzene (100μM) and its metabolites, BQ/HQ (10μM and 50μM), can induce cell death after 24h of exposure mainly through apoptotic pathways. In addition, changes in the expression of six mRNAs due to being subjected to 10μM of BQ or HQ and 50μM of benzene were assessed. The genes under investigation were RUNX2, WNT5A, DKK1, JAG1, KITLG and CXCL12 which are expressed by MSCs playing roles in adipo-osteogenic differentiation of MSCs and the regulation of haematopoiesis. The analysis exhibited a great augmentation in RUNX2 expression associated with DKK1 and KITLG up-regulation. The results also indicated that treatment of cells with all three chemicals gives rise to down-regulation of JAG1 and treatment with both HQ and BQ triggers WNT5A over-expression. With regard to CXCL12, treatment with BQ caused slight up-regulation and treatment with HQ led to down-regulation. The alterations observed in the expression profile of genes could affect/modify the process of differentiation of MSCs into osteoblast. Other expected outcomes involve augmented canonical Wnt signaling activity in exposed cells with RUNX2 overexpression as the indicator which is probably forced to decrease to the normal level via DKK1 and WNT5A up-regulation. RUNX2 overexpression in MSCs can also be indicative of the RUNX2 up-regulation in myeloid progenitors thereby its involvement in AML development due to benzene exposure. Observed changes in the expression of WNT5A, DKK1, KITLG, CXCL12 and JAG1 can lead to the disturbance of HSC niche resulting in haematopoietic failure and leukemia development. It is obvious that increased viability together with caspase3/7 inhibition could aggravate the adverse effects of exposure to these chemicals.

UI MeSH Term Description Entries
D008565 Membrane Proteins Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. Cell Membrane Protein,Cell Membrane Proteins,Cell Surface Protein,Cell Surface Proteins,Integral Membrane Proteins,Membrane-Associated Protein,Surface Protein,Surface Proteins,Integral Membrane Protein,Membrane Protein,Membrane-Associated Proteins,Membrane Associated Protein,Membrane Associated Proteins,Membrane Protein, Cell,Membrane Protein, Integral,Membrane Proteins, Integral,Protein, Cell Membrane,Protein, Cell Surface,Protein, Integral Membrane,Protein, Membrane,Protein, Membrane-Associated,Protein, Surface,Proteins, Cell Membrane,Proteins, Cell Surface,Proteins, Integral Membrane,Proteins, Membrane,Proteins, Membrane-Associated,Proteins, Surface,Surface Protein, Cell
D002135 Calcium-Binding Proteins Proteins to which calcium ions are bound. They can act as transport proteins, regulator proteins, or activator proteins. They typically contain EF HAND MOTIFS. Calcium Binding Protein,Calcium-Binding Protein,Calcium Binding Proteins,Binding Protein, Calcium,Binding Proteins, Calcium,Protein, Calcium Binding,Protein, Calcium-Binding
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006873 Hydroquinones Derivatives of hydroquinone (1,4-dihydrobenzene) made by reduction of BENZOQUINONES. Quinol,p-Dihydroxybenzenes,para-Dihydroxybenzenes,Quinols,p Dihydroxybenzenes,para Dihydroxybenzenes
D000072099 Serrate-Jagged Proteins Cell surface proteins that consist of multiple extracellular EPIDERMAL GROWTH FACTOR - like repeat sequences (EGF repeats), including calcium-binding EGF repeats. They function as transmembrane ligands for NOTCH RECEPTORS to control CELL DIFFERENTIATION during development. Jagged Proteins,Serrate Protein,Serrate Proteins,Serrate Jagged Proteins
D000072100 Jagged-1 Protein A serrate-jagged protein that functions as a ligand for NOTCH RECEPTORS. It may regulate CELL DIFFERENTIATION in HEMATOPOIESIS and PHYSIOLOGIC ANGIOGENESIS. Mutations in the Jagged-1 gene are associated with ALAGILLE SYNDROME 1. Alagille Syndrome Protein,CD339 Antigen,Jagged-1,Jagged1 Protein,Serrate-1 Protein,Serrate1 Protein,Antigen, CD339,Jagged 1,Jagged 1 Protein,Serrate 1 Protein
D001554 Benzene Toxic, volatile, flammable liquid hydrocarbon byproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. Benzol,Benzole,Cyclohexatriene
D012313 RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed) RNA, Non-Polyadenylated,Ribonucleic Acid,Gene Products, RNA,Non-Polyadenylated RNA,Acid, Ribonucleic,Non Polyadenylated RNA,RNA Gene Products,RNA, Non Polyadenylated

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