Hepatic peroxisome proliferators induce morphologic transformation of Syrian hamster embryo cells, but not peroxisomal beta oxidation.
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2,4,5-Trichlorophenoxyacetic Acid↗
Biomedical subjects
E Rivedal
Publications and source records attributed to E Rivedal.
The non-phorbol ester tumor promoter okadaic acid does not promote morphological transformation or inhibit junctional communication in hamster embryo cells.
Okadaic acid is a potent non-phorbol ester mouse skin tumor promoter. Unlike the phorbol ester tumor promoters, okadaic acid is unable to promote the induction of morphological transformation in Syrian hamster embryo cell colonies. On the contrary, okadaic acid seems to counteract the effect of phorbol esters on transformation. Also unlike phorbol ester tumor promoters, okadaic acid does not inhibit intercellular communication, neither in primary hamster embryo cells, nor in the phorbol ester sensitive cell line BPNi. Furthermore, okadaic acid has no effect on the reoccurrence of communication following removal of 12-O-tetradecanoylphorbol-13-acetate.
Animals↗
Vanadium compounds promote the induction of morphological transformation of hamster embryo cells with no effect on gap junctional cell communication.
Vanadium compounds were found to promote the induction of morphological transformation of hamster embryo cells. Exposure of the cells to Na-O-vanadate, vanadin (V) oxide or vanadin (IV) oxide sulfate following pre-exposure to a low concentration of benzo[a]pyrene, potentiated the induction of transformed colonies similar to 12-O-tetradecanoylphorbol-13-acetate. Unlike this phorbol ester, vanadium compounds did not inhibit intercellular communication, or active protein kinase C. Nor did vanadate influence the reoccurrence of communication after removal of a communication blocking phorbol ester. On the other hand, vanadate showed strong synergism with the phorbol ester on induction of transformed morphology in the phorbol ester sensitive cell line BPNi. This suggests that vanadium and tumor promoting phorbol esters mediate their effect on the induction of morphological transformation of hamster embryo cells through different mechanisms.
Animals↗
Contrasting duration of inhibition of cell-cell communication in primary mouse epidermal cells by phorbol 12,13-dibutyrate and by bryostatin 1.
The bryostatins, macrocyclic lactones isolated on the basis of their antineoplastic activity, activate protein kinase C in vitro and inhibit phorbol ester binding to the enzyme. In intact cells, the bryostatins induce some phorbol ester responses, such as neutrophil activation, but paradoxically they not only fail to induce other responses, e.g., differentiation in HL-60 promyelocytic leukemia cells, but actually block response to the phorbol esters. We compare here bryostatin I and phorbol 12,13-dibutyrate as inhibitors of cell-cell communication in cultured primary mouse epidermal cells. Like phorbol 12,13-dibutyrate, bryostatin I at nanomolar concentrations markedly inhibited cell coupling. It differed from the phorbol esters, however, in that its action was more transient. By 4 h of incubation bryostatin 1 caused little inhibition of coupling. Moreover, coincubation of bryostatin 1 and phorbol 12,13-dibutyrate gave no greater response at this time than that found for bryostatin 1 alone. Time-dependent inhibition of the protein kinase C pathway could account for many of the observed differences between the actions of the phorbol esters and bryostatin 1.
Animals↗
Morphological transformation of Syrian hamster embryo cells induced by mineral fibres and the alleged enhancement of benzo[a]pyrene.
The ability of different mineral fibres to induce morphological transformation of Syrian hamster embryo cells has been studied. Increased transformation frequencies were obtained in the presence of chrysotile, crocidolite, amosite, anthophyllite and the glass fibres (GF) 100, while no significant increase in transformation frequency was observed with GF 110 and TiO2. Chrysotile was the most potent of the fibres tested. GF 100 was more potent than crocidolite, amosite and anthophyllite. By comparing transformation frequency and toxicity, it could be concluded that induction of transformation is not caused by unspecific cytotoxic effects. In contrast to some earlier studies, no synergistic effect was observed between benzo[a]pyrene (BaP) and asbestos fibres. Adsorption of BaP to crocidolite fibres had no effect on the transformation frequency. Moreover, crocidolite was not able to promote the transformation of cells pre-exposed to BaP. Electron microscopy studies showed that the fibres were rapidly phagocytosed. Blebs were often formed on the cell surface and were most pronounced after crocidolite exposure. The blebs did not seem to be associated with the areas of physical interaction between the cells and the fibres, but were distributed throughout the cell surface.
Animals↗
Cell transformation and promoter activity of insulation oils in the Syrian hamster embryo cell and in the C3H/10T1/2 mouse embryo fibroblast test systems.
The ability of mineral-oil-based and synthetic cable insulating fluids to transform and promote transformation of mammalian cells in vitro have been studied. In experiments with the Syrian hamster embryo cell transformation assay, it was found that C15-C18 alkylbenzenes were the most potent inducers of transformation, followed by low-viscosity and residual mineral oils. No activity and low cytotoxicity were found for a low-viscosity polyisobutylene-based oil. In the two-stage transformation assay of C3H/10T1/2 cells, promoter activity was obtained with all fluids tested. A blend of residual and low-viscosity mineral oils showed the highest activity. This oil possessed a low cytotoxicity and was tested at a relatively high concentration. The alkylbenzenes were more potent than the polyisobutylene-based fluid. The alkylbenzenes were also found to possess initiating activity in the two-stage assay, when 12-O-tetradecanoylphorbol 13-acetate (TPA) was used as promoter. All the fluids showed low potency compared to benzo[a]pyrene and the tumor promoter TPA.
Animals↗
Studies on the mechanism of acetamide hepatocarcinogenicity.
The hepatocarcinogen acetamide, in single doses of 100 and 400 mg/kg b.wt., was shown to act as an initiator in a dose-dependent fashion in rat liver using the Solt-Farber method. Acetamide and its putative metabolite N-hydroxy-acetamide did not cause liver necrosis in single dose experiments. Acetamide showed no evidence for genotoxicity in tests for mutations in Salmonella typhimurium, for DNA damage in rat hepatoma cells or for DNA repair in isolated rat hepatocytes. In contrast, N-hydroxy-acetamide displayed genotoxic activity in all 3 test systems. Neither acetamide nor N-hydroxy-acetamide induced transformation of primary Syrian hamster embryo cells or gave evidence of inhibition of metabolic cooperation in V79 cells. Radiolabelled acetamide and N-hydroxy-acetamide were not bound covalently to proteins in the presence of various metabolic activation systems (microsomes plus NADPH or xanthine/xanthine oxidase, cytosol or cytosol plus acetyl CoA or proline plus ATP). N-Hydroxy-acetamide was cytotoxic to monolayers of isolated hepatocytes at concentrations above 2.5 mM. This cytotoxicity was increased after diethyl maleate treatment, but N-hydroxy-acetamide did not deplete cellular glutathione. A HPLC system was developed for the separation and quantification of acetamide, N-hydroxy-acetamide and acetic acid. No significant excretion of N-hydroxy-acetamide or acetic acid in the urine could be demonstrated after treatment of rats with 100 or 1,000 mg/kg b.wt. of acetamide. The underlying mechanism for the observed initiating effect of acetamide is obscure.
Acetamides↗
Mechanistic studies of acetamide hepatocarcinogenicity.
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Acetamides↗
Caffeine and other phosphodiesterase inhibitors are potent inhibitors of the promotional effect of TPA on morphological transformation of hamster embryo cells.
The phosphodiesterase inhibitors caffeine, theophylline, aminophylline and isobutyl-methylxanthine (IBMX) were found to inhibit induction of morphologically transformed hamster embryo cell colonies by sequential exposure to benzo[a]pyrene (BaP) and the tumor promoter TPA. Almost complete inhibition of cell transformation was observed when 50 micrograms/ml theophylline, aminophylline, IBMX, or 200 micrograms/ml caffeine was present together with the tumor promoter. The compounds had no effect on the transformation frequency when present together with the initiator, BaP, in the first exposure period. Substances that stimulate the adenylate cyclase and the addition of exogenous dibutyryl-cAMP had similar inhibitory effects.
Adenylyl Cyclases↗
The genotoxicity of 2-bromoacrolein and 2,3-dibromopropanal.
2-Bromoacrolein (2-BA) and 2,3-dibromopropanal (2,3-DBPA), an identified and a postulated reactive metabolite of tris(2,3-dibromopropyl)phosphate (Tris-BP), respectively, were found to cause mutations in Salmonella typhimurium TA 100 both in the absence and presence of a metabolic system. 2-BA, as well as 2,3-DBPA, caused extensive DNA single-stranded breaks as evidenced by alkaline elution of DNA from exposed Reuber hepatoma cells in culture. The data with Syrian hamster embryo cells suggest that both 2-BA and 2,3-DBPA were more potent than Tris-BP in transforming these cells in culture. On the other hand, neither 2-BA, nor 2,3-DBPA, was found to cause increased unscheduled DNA repair synthesis in isolated rat hepatocytes in monolayer cultures, whereas Tris-BP had a significant effect at low concentrations (10-50 microM). There was no correlation between the observed mutagenic effects of 2-BA and 2,3-DBPA and their alkylating activities using the nitrobenzyl-pyridine test. The genotoxic effects associated with 2-BA and its detection in microsomal incubations makes it a likely candidate for a role in the mutagenicity of Tris-BP.
Acrolein↗
Inhibition of intercellular communication and enhancement of morphological transformation of Syrian hamster embryo cells by TPA. Use of TPA-sensitive and TPA-resistant cell lines.
The possible role of blocked intercellular communication in the process of cell transformation has been studied with Syrian hamster embryo cell lines which are sensitive or resistant to TPA-induced enhancement of morphological transformation. Both the TPA-sensitive (BPNi) and the TPA-resistant (83-106 and 74-100) cell lines showed gap-junctional communication when measured by a dye-transfer method. However, TPA inhibited the communication only in TPA-sensitive cells, and not in TPA-resistant cells. These results are consistent with the idea that blocked intercellular communication is involved in a late stage of cell transformation and/or expression of the transformed phenotype.
Animals↗
Retinoids have different effects on morphological transformation and anchorage independent growth of Syrian hamster embryo cells.
The effect of different retinoids on morphological transformation and anchorage independent growth of Syrian hamster embryo cells has been studied. Retinoic acid and its derivatives were found to induce morphological transformation of hamster embryo cells, and to synergistically increase the transformation frequency when exposed in combination with benzo[a]pyrene. The increase was maintained when the cells were sequentially exposed to benzo[a]pyrene and retinoids in a similar way as observed for tumor promoting phorbol esters. At the same time retinoids were found to strongly decrease anchorage independent growth of a hamster embryo cell line. The present results support previous findings indicating that retinoids may have an enhancing effect on the early stages in carcinogenesis, and an inhibitory effect on the later stages.
Animals↗
Comparative genotoxicity and nephrotoxicity studies of the two halogenated flame retardants tris(1,3-dichloro-2-propyl)phosphate and tris(2,3-dibromopropyl)phosphate.
Tris(1,3-dichloro-2-propyl)phosphate (Tris-CP) was metabolized to products which were mutagenic for Salmonella typhimurium TA100 in the presence of liver microsomes from phenobarbital (PB)-pretreated rats and NADPH. Effects of various inhibitors and inducers of cytochrome P-450 on Tris-CP mutagenicity were in accordance with PB-inducible forms of this enzyme system being responsible for the formation of mutagenic product(s). A comparison was made between the toxic potential of the two halogenated flame retardants Tris-CP and tris(2,3-dibromopropyl)phosphate (Tris-BP) in 5 in vitro tests. Tris-CP was much less potent than Tris-BP with respect to bacterial (Salmonella/microsome or Salmonella/hepatocyte assay) and mammalian (V79 cells) mutagenicity, as well as DNA repair synthesis in hepatocytes. On the other hand, Tris-CP and Tris-BP were both equally effective in transforming Syrian hamster embryo cells in vitro. Tris-CP was not nephrotoxic to rats after a single dose of 500 mg/kg intraperitoneally, whereas Tris-BP caused extensive tubular necrosis accompanied by elevated levels of plasma urea and creatinine.
Animals↗
Studies of tumor promoters with the Syrian hamster embryo cell transformation assay.
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Animals↗
Short-term bioassays of fractionated emission samples from wood combustion.
Extracts of an emission sample from wood burning, consisting of particles and volatiles, have been fractionated on an HPLC silica gel column into five fractions of increasing polarity. Nonfractionated samples and the individual fractions have been tested in three different short-term bioassays: the Ames Salmonella assay, the sister chromatid exchange (SCE) induction-test in Chinese hamster ovary cells (CHO), and the cell transformation test on Syrian hamster embryo (SHE) cells. Most of the total activity was found in the volatile part of the sample with all three bioassays, whereas the particle extract had the highest activity per unit mass extracted. The second most polar fraction contained most of the mass and was also highly active in all assays. The most polar fraction was very potent in the Salmonella assay, but showed only a weak response in the eukaryotic bioassays. Storage of the samples for several months at 0 degrees C revealed that the bacterial mutagens present in the most polar fraction were labile; the mutagenicity was almost totally lost after 1 year's storage.
Animals↗
Expression of transformed morphology and anchorage independent growth of hamster embryo cells.
Formation of morphologically transformed colonies and the ability to grow in semi-solid agar has been compared for 3 different cell lines from hamster embryo and for primary hamster embryo cells. By manipulating the growth conditions, transformed colony morphology and growth in agar could be induced for all cell types studied. Conditions that induced morphologically transformed colonies, also produced growing colonies in agar. One cell line and the primary cells needed the presence of the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate for the expression of transformed morphology and agar growth, while the two other cell lines produced both morphologically transformed colonies and growth in soft agar without any additions. None of the cell lines would produce morphologically transformed colonies in the presence of newborn bovine serum. Likewise, the cells were dependent on fetal bovine serum in order to grow in soft agar, except for one of the cell lines which produced a low number of agar growing colonies in newborn bovine serum. The data indicate a close relation between morphological transformation and growth in soft agar.
Agar↗
Reversal of the promotional effect of 12-O-tetradecanoylphorbol-13-acetate on morphological transformation of hamster embryo cells by glucocorticoids.
The effects of glucocorticoids and cholesterol on morphological transformation have been studied using hamster embryo cells. The cells were exposed sequentially to benzo[a]pyrene (BP) (3 days) and the tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA) (4 days) before scoring for morphologically transformed colonies. Dexamethasone and hydrocortisone strongly inhibited the formation of morphologically transformed colonies when applied to the cells in the second period of exposure together with TPA, but had no effect when present with BP during the first period. Corticosterone had only a weak effect, while cortisone had no effect on the transformation frequency. Cholesterol gave rise to an enhanced number of transformed colonies. Dexamethasone, being the most potent compound tested, inhibited morphological transformation by more than 50% when present in a concentration of 0.25 nM. The finding that dexamethasone reduced the frequency of transformation even when added only 6 h prior to staining, indicates that the glucocorticoids may also reduce the transformation frequency by reversing morphologically transformed cell colonies to a normal appearance.
Animals↗
Promotional effect of different phorbol esters on morphological transformation of hamster embryo cells.
Hamster embryo cells were sequentially exposed to benzo[a]pyrene (BaP) (3 days) and different phorbol esters (4 days). Compounds which have been shown to act as tumor promoters in mouse skin carcinogenesis, showed a promotion-like effect on the formation of morphologically transformed colonies, while non-promoting analogs did not enhance the transformation frequency. In experiments where the exposure sequence was reversed, i.e. 12-O-tetradecanoyl phorbol-13-acetate (TPA) in the first exposure period and BaP in the second period, no significant enhancement of the transformation frequency was observed. The exposure to a low concentration of BaP in the second exposure period following a higher concentration in the first period, resulted in a strong enhancement of the transformation frequency suggesting that BaP also acts as a promoter.
Animals↗