Monitoring plasma FL concentration can be used as an indicator of radiation-induced marrow aplasia, and this may be of use in accidental irradiation situations.
To assess the therapeutic efficacy of ex vivo-expanded hematopoietic cells in the treatment of radiation-induced pancytopenia, we have set up a non-human primate model. Two ex vivo expansion protocols for bone marrow mononuclear cells (BMMNC) were studied. The first consisted of a 7-day culture in the presence of stem cell factor (SCF), Flt3-ligand, thrombopoietin (TPO), interleukin-3 (IL-3), and IL-6, which induced preferentially the expansion of immature hematopoietic cells [3.1 +/- 1.4, 10.0 +/- 5.1, 2.2 +/- 1.9, and 1.0 +/- 0.3-fold expansion for mononuclear cells (MNC), colony-forming units-granulocyte-macrophage (CFU-GM), burst-forming units erythroid (BFU-E), and long-term culture initiating cells (LTC-IC) respectively]. The second was with the same cytokine combination supplemented with granulocyte colony-stimulating factor (G-CSF) with an increased duration of culture up to 14 days and induced mainly the production of mature hematopoietic cells (17.2 +/- 11.7-fold expansion for MNC and no detectable BFU-E and LTC-IC), although expansion of CFU-GM (13.7 +/- 18.8-fold) and CD34+ cells (5.2 +/- 1.4-fold) was also observed. Results showed the presence of mesenchymal stem cells and cells from the lymphoid and the megakaryocytic lineages in 7-day expanded BMMNC. To test the ability of ex vivo-expanded cells to sustain hematopoietic recovery after radiation-induced aplasia, non-human primates were irradiated at a supralethal dose of 8 Gy and received the product of either 7-day (24 h after irradiation) or 14-day (8 days after irradiation) expanded BMMNC. Results showed that the 7-day ex vivo-expanded BMMNC shortened the period and the severity of pancytopenia and improved hematopoietic recovery, while the 14 day ex vivo-expanded BMMNC mainly produced a transfusion-like effect during 8 days, followed by hematopoietic recovery. These results suggest that ex vivo expanded BMMNC during 7 days may be highly efficient in the treatment of radiation-induced aplasia.
Perfluorooctane sulfonate (PFOS) is the degradation product of many fluoroderivatives and a widespread environmental contaminant. Its persistence, its long half-life in humans and its toxicity explain high concerns on human health side effects in future. PFOS is suspected to be a non-genotoxic carcinogen. In the present work, we assessed carcinogenic potential of PFOS by studying morphological transformation in Syrian hamster embryo (SHE) cells; cell transformation of SHE cells is an in vitro assay recommended by the Organization for Economic Cooperation and Development to detect carcinogens, genotoxic or not. Genotoxicity of PFOS and expression of PPARs genes in SHE cells were also measured. PFOS was shown to induce cell transformation (P < 0.05) at non-cytotoxic concentrations (0.2 and 2 μg/mL) (P ≤ 0.01). No genotoxic effect was recorded in the range of PFOS concentrations tested (2 × 10(-4) to 50 μg/mL) using the single-cell gel electrophoresis (comet) assay after 5 and 24 h of exposure. The expression of PPARs genes was measured by qPCR within the first 24 h and after 7 days of PFOS treatment. Results indicated an increased expression of ppar-β/δ isoform as early as 24 h. After 7 days, the increase of ppar-β/δ mRNA was significant at the concentrations inducing cell transformation (0.2 and 2 μg/mL), while overexpression of ppar-γ and ppar-α did not closely relate to effective concentrations. The results indicate that PFOS behave as a non-genotoxic carcinogen and impacted PPARs genes. Its cell transforming potential paralleled an increased expression of ppar-β/δ.
Perfluorooctane sulfonate (PFOS) (C(8)F(17)SO(3)) and perfluorooctanoic acid (PFOA) (C(8)HF(15)O(2)) are synthetic chemicals widely used in industrial applications for their hydrophobic and oleophobic properties. They are persistent, bioaccumulative, and toxic to mammalian species. Their widespread distribution on earth and contamination of human serum raised concerns about long-term side effects. They are suspected to be carcinogenic through a nongenotoxic mode of action, a mechanism supported by recent findings that PFOS induced cell transformation but no genotoxicity in Syrian hamster embryo (SHE) cells. In the present study, we evaluated carcinogenic potential of PFOA using the cell transformation assay on SHE cells. The chemical was applied alone or in combination with a nontransformant concentration of benzo[a]pyrene (BaP, 0.4 μM) in order to detect PFOA ability to act as tumor initiator or tumor promoter. The results showed that PFOA tested alone in the range 3.7 × 10(-5) to 300 μM did not induce SHE cell transformation frequency in a 7-day treatment. On the other side, the combination BaP/PFOA induced cell transformation at all PFOA concentrations tested, which revealed synergistic effects. No genotoxicity of PFOA on SHE cells was detected using the comet assay after 5 and 24 h of exposure. No significant increase in DNA breakage was found in BaP-initiated cells exposed to PFOA in a 7-day treatment. The whole results showed that PFOA acts as a tumor promoter and a nongenotoxic carcinogen. Cell transformation in initiated cells was observed at concentrations equivalent to the ones found in human serum of nonoccupationally and occupationally exposed populations. An involvement of PFOA in increased incidence of cancer recorded in occupationally exposed population cannot be ruled out.
We confirmed the long-term stability of translocations and found that it seems to depend on the type of the translocation recorded. Overall translocations were stable for up to 31 months regardless of dose, but two-way translocations were more stable than those that were non-reciprocal, especially in stable cells.
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