Operational reversibility is a key aspect of carcinogenesis.
(25/320)
The article highlighted in this issue is "Reversibility and Persistence of Di-2-Ethylhexyl Phthalate (DEHP)- and Phenobarbital-Induced Hepatocellular Changes In Rodents," by Jason S. Isenberg, Lisa M. Kamendulis, David C. Ackley, Jacqueline H. Smith, George Pugh, Jr., Arthur W. Lington, Richard H. McKee, and James E. Klaunig (pp. 192-199). (+info)
Reversibility and persistence of di-2-ethylhexyl phthalate (DEHP)- and phenobarbital-induced hepatocellular changes in rodents.
(26/320)
The tumor promotion stage of chemical carcinogenesis has been shown to exhibit a persistence of cellular effects during treatment and the reversibility of these changes upon cessation of treatment. Inhibition of gap-junctional intercellular communication and increased replicative DNA synthesis appear to be important in this process. The present study assessed the persistence and reversibility of gap-junctional intercellular communication inhibition, peroxisomal proliferation, and replicative DNA synthesis in livers from male F344 rats and B6C3F1 mice. Dietary administration of 20,000 mg/kg DEHP to male rats for 2 weeks decreased intercellular communication (67% of control) and enhanced replicative DNA synthesis (4.8-fold over control). Elevation of the relative liver weight and the induction of peroxisomal beta oxidation were also observed following treatment with 20,000 mg/Kg DEHP for 2 weeks. Following DEHP administration at a dose of 6000 mg/kg for 18 months, inhibition of gap-junctional intercellular communication persisted, and the relative liver weight and induction of peroxisomal beta oxidation remained elevated in both rats and male B6C3F1 mice. Treatment of rats and mice with phenobarbital for 18 months (500-mg/kg diet) also produced an increase in relative liver weight and a decrease in cell-to-cell communication. In recovery studies in which DEHP was administered to male F344 rats for 2 weeks and then withdrawn, the relative liver weight, rate of peroxisomal beta oxidation, increase in replicative DNA synthesis, and inhibition of gap-junctional intercellular communication returned to control values within 2 to 4 weeks after DEHP treatment ceased. Recovery studies with phenobarbital produced similar results. The primary active metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP), was detected in the livers of animals treated with DEHP for greater than 2 weeks. However, it could not be detected after removal of DEHP from the diet for 2 weeks. This study demonstrated that inhibition of gap-junctional intercellular communication, along with indicators of peroxisomal proliferation, including increased relative liver weight and enhanced peroxisomal beta oxidation, persist while DEHP treatment continues but reverses when treatment is stopped. Studies with phenobarbital produced a similar pattern of response. (+info)
Aromatic dental monomers affect the activity of cholesterol esterase.
(27/320)
The dental restorative monomer, BISGMA (2,2-bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl]propane), and bisphenol A diglycidyl ether (BADGE) increase the velocity of the reaction catalyzed by pancreatic cholesterol esterase (CEase, bovine). The metabolite of these monomers, bisphenol A bis(2,3-dihydroxypropyl) ether, and a common plasticizer, di-2-ethylhexyl phthalate (DEHP), also increase the velocity of CEase-catalyzed ester hydrolysis. BISGMA at concentrations of 1.5-8.0 microM increases the velocity to 126-169% of its value in the absence of BISGMA. Increasing BISGMA above 8 microM caused no further increase in velocity. BADGE at 7-25 microM increases the velocity to 112-205% of its value without BADGE. The metabolite of BISGMA and BADGE at concentrations of 2.0-7.1 microM increases the velocity to 103-113% of its value without metabolite. DEHP at concentrations of 0.52-4.3 microM increases the velocity to 108-187% of its value without DEHP. On the other hand, bisphenol A dimethacrylate is a competitive inhibitor of CEase, with a K(i) of 3.1 microM. (+info)
Peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist, WY-14,643, increased transcription of myosin light chain-2 in cardiomyocytes.
(28/320)
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that can be activated by xenobiotics and natural fatty acids. To assess the potential physiological activity of PPAR ligands on cardiac muscular cells, the effects of PPAR alpha agonist, WY-14,643, on both rat hearts and a rat cardiomyocyte cell line (H9c2 cells) were investigated. Male F344 rats were fed a diet containing WY-14,643 at a concentration of 100 ppm for 26 weeks. Cardiac muscular hypertrophy was revealed by morphometric analysis in which the diameter of the muscular fibers in WY-14,643-treated rats was larger than those of control rats. Using H9c2 cells in vitro, the protein content per cell was increased in a dose-dependent manner with the treatment of WY-14,643. The transcription of myosin light chain-2 (MLC-2), a parameter of myocardial hypertrophy, was increased in H9c2 cells transfected with the rat MLC-2/luciferase fusion gene by WY-14,643 as well as other peroxisome proliferators, clofibrate and di(2-ethylhexyl) phthalate. In addition, accumulation of myosin light chain protein was confirmed in H9c2 cells treated with WY-14,643 at 10 micrograms/ml for 7 days or more by immunohistochemistry. These results suggest that PPAR alpha ligands have a potential to regulate MLC-2, which is a contractile protein in cardiomyocytes and may play a part of role in the pathogenesis of cardiac hypertrophy. (+info)
Assessment of carcinogenicity of di(2-ethylhexyl)phthalate in a short-term assay using Xpa-/- and Xpa-/-/p53+/- mice.
(29/320)
The potential of Xpa-/- and Xpa-/-/p53+/- mice for short-term carcinogenicity assays was evaluated with di(2-ethylhexyl)phthalate (DEHP). Groups of 15 male and female Xpa-/- mice, received diets containing 0, 1, 500, 3,000, or 6,000 ppm DEHP, and wild-type (WT) and Xpa-/-p53+/-mice 0 or 6,000 ppm DEHP for 39 weeks. Xpa-/-, Xpa-/-/p53+/-, and WT males, fed 2,500 ppm p-cresidine, served as a positive control. In all models, the survival was not altered by DEHP. Increased incidences of nonneoplastic lesions were recorded in testes and kidneys with no apparent difference between the models. The only liver tumors in all models were adenomas in males with no statistically significantly increased incidence. For p-cresidine. the survival was decreased (p < 0.05) only in transgenic models. Statistically significantly increased incidences of nonneoplastic lesions were recorded in the liver, urinary bladder, and nasal cavity in all models, and in kidneys in transgenic models. The only tumors with statistically significantly increased incidence were liver adenomas in transgenic models (XPA: I vs 7: 'XPA/p53': 0 vs 12; WT: 0 vs 5, p = 0.053) and urinary bladder carcinomas in XPA/p53 model (0 vs 7). The negative carcinogenic response to DEHP and the positive response to p-cresidine support the expected sensitivity to genotoxic carcinogens in these transgenic models. (+info)
Prediction of compound signature using high density gene expression profiling.
(30/320)
DNA microarrays, used to measure the gene expression of thousands of genes simultaneously, hold promise for future application in efficient screening of therapeutic drugs. This will be aided by the development and population of a database with gene expression profiles corresponding to biological responses to exposures to known compounds whose toxicological and pathological endpoints are well characterized. Such databases could then be interrogated, using profiles corresponding to biological responses to drugs after developmental or environmental exposures. A positive correlation with an archived profile could lead to some knowledge regarding the potential effects of the tested compound or exposure. We have previously shown that cDNA microarrays can be used to generate chemical-specific gene expression profiles that can be distinguished across and within compound classes, using clustering, simple correlation, or principal component analyses. In this report, we test the hypothesis that knowledge can be gained regarding the nature of blinded samples, using an initial training set comprised of gene expression profiles derived from rat liver exposed to clofibrate, Wyeth 14,643, gemfibrozil, or phenobarbital for 24 h or 2 weeks of exposure. Highly discriminant genes were derived from our database training set using approaches including linear discriminant analysis (LDA) and genetic algorithm/K-nearest neighbors (GA/KNN). Using these genes in the analysis of coded liver RNA samples derived from 24-h, 3-day, or 2-week exposures to phenytoin, diethylhexylpthalate, or hexobarbital led to successful prediction of whether these samples were derived from livers of rats exposed to enzyme inducers or to peroxisome proliferators. This validates our initial hypothesis and lends credibility to the concept that the further development of a gene expression database for chemical effects will greatly enhance the hazard identification processes. (+info)
Elucidation of the toxic mechanism of the plasticizers, phthalic acid esters, putative endocrine disrupters: effects of dietary di(2-ethylhexyl)phthalate on the metabolism of tryptophan to niacin in rats.
(31/320)
We have previously reported that the administration of a large amount of di(n-butyl)phthalate (DBP) increased the conversion ratio of tryptophan to niacin in rats. In the present experiment, the effect of di(2-ethylhexyl)phthalate (DEHP) on the conversion ratio and how altering the conversion ratio of tryptophan to niacin depended on the concentration of DEHP were investigated to elucidate the toxic mechanism of phthalic acid esters (PhE). Rats were fed with a diet containing 0%, 0.01%, 0.05%, 0.1%, 0.5%, 1.0%, or 3.0% DEHP for 21 days. To assess the conversion ratio of tryptophan to niacin, urine samples were collected at the last day of the experiment and measured for metabolites on the tryptophan-niacin pathway. The conversion ratio increased with increasing dietary concentration of DEHP above 0.05%; the conversion ratio was about 2% in the control group, whereas it was 28% in the 3.0% DEHP group. It is suggested that the inhibition of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) by DEHP or its metabolites caused this increase in the conversion ratio. We conclude that PhE such as DEHP and DBP disturbed the tryptophan-niacin metabolism. (+info)
Bax expression protects yeast plasma membrane against ethanol-induced permeabilization.
(32/320)
The mechanism by which the expression of pro-apoptotic protein Bax is able to kill yeast was investigated. Ethanol stress induces a permeabilization of the plasma membrane revealed by propidium iodide accumulation. Bax expression, although killing yeast cells, prevents this permeabilization. These effects are modulated by aeration, by manipulation of the unsaturation index of fatty acids and by addition of resveratrol, a known inhibitor of lipid oxidation. These data suggest that lipid oxidation is involved in Bax effects. Taken together, these data show for the first time a direct effect of Bax on plasma membrane permeability properties and suggest that yeast is a powerful tool for investigating the molecular mechanisms underlying this process. (+info)