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Genotoxic Carcinogens (genotoxic + carcinogen)
Selected AbstractsPrinciples of risk assessment for determining the safety of chemicals: Recent assessment of residual solvents in drugs and di(2-ethylhexyl) phthalateCONGENITAL ANOMALIES, Issue 2 2004Ryuichi Hasegawa ABSTRACT Risk assessment of chemicals is essential for the estimation of chemical safety, and animal toxicity data are typically used in the evaluation process, which consists of hazard identification, dose,response assessment, exposure assessment, and risk characterization. Hazard identification entails the collection of all available toxicity data and assessment of toxicity endpoints based on findings for repeated dose toxicity, carcinogenicity or genotoxicity and species-specificity. Once a review is compiled, the allowable lifetime exposure level of a chemical is estimated from a dose,response assessment based on several measures. For non-carcinogens and non-genotoxic carcinogens, the no-observed-adverse-effect-level (NOAEL) is divided by uncertainty factors (e.g. with environmental pollutants) or safety factors (e.g. with food additives) to derive a tolerable daily intake (TDI) or acceptable daily intake (ADI), respectively. These factors include interspecies and individual differences, duration of exposure, quality of data, and nature of toxicity such as carcinogenicity or neurotoxicity. For genotoxic carcinogens, low dose extrapolation is accomplished with mathematical modeling (e.g. linearized multistage model) from the point of departure to obtain exposure levels that will be associated with an excess lifetime cancer risk of a certain level. Data for levels of chemicals in food, water and air, are routinely used for exposure assessment. Finally, risk characterization is performed to ensure that the established ,safe' level of exposure exceeds the estimated level of actual exposure. These principles have led to the evaluation of several existing chemicals. To establish a guideline for residual solvents in medicine, the permitted daily exposure (PDE), equivalent to TDI, of N,N-dimethylformamide was derived on the basis of developmental toxicity (malformation) and of N-methylpyrrolidone on the basis of the developmental neurotoxicity. A TDI for di(2-ethylhexyl)phthalate was derived from assessment of testicular toxicity. [source] Absence of acute apoptotic response to genotoxic carcinogens in p53 -deficient mice is associated with increased susceptibility to azoxymethane-induced colon tumoursINTERNATIONAL JOURNAL OF CANCER, Issue 4 2005Ying Hu Abstract Acute apoptotic response to genotoxic carcinogens (AARGC) might be important for controlling the consequences of mutational load in the colon. It has been shown to occur in parallel with activation of DNA repair mechanisms. Inadequate AARGC might allow development of mutated clones with the potential to progress to cancer. In this study, we tested if p53 levels were important for AARGC in the colon and whether defective AARGC was associated with increased risk for colorectal oncogenesis. Apoptosis was measured in colonic epithelium of mice from each p53 genotype (p53,/,, p53+/,, wild-type) without and 8 hr following a single injection of azoxymethane (AOM). To determine risk for carcinogen-induced colorectal cancer (CRC), groups of mice from each p53 genotype received 3 weekly injections of AOM and colons were examined for tumour 20 weeks later. Rates of spontaneous apoptosis in colon were not affected by p53 level. However, AARGC was absent in p53,/, mice and reduced by 50% in p53+/, mice (both p < 0.01) compared to wild-type mice. AOM induced tumours in 30% of wild-type mice (average multiplicity 1.0 tumours/mouse) compared to 72% of p53+/, mice (2.0 tumours/mouse, p < 0.01) and 100% of p53,/, mice (2.8 tumours/mouse, p < 0.01). Without AOM, significantly fewer mice in all groups had tumours. Rates of apoptosis in tumours were independent of p53 status. p53 dysfunction puts intestinal epithelia at increased risk of genotoxin-induced oncogenesis due to impairment of apoptotic response mechanisms. p53 levels do not appear, however, to be important for spontaneous apoptosis in normal epithelium or apoptosis in tumours. Subsequent studies are now warranted to test the converse, namely, that enhanced apoptotic response to carcinogen reduces risk for colorectal oncogenesis. © 2005 Wiley-Liss, Inc. [source] ACUTE APOPTOTIC RESPONSE INDUCED BY THE COLON CARCINOGEN AOM IS DEPENDENT ON P53 GENE and NOT THE APC GENEJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2001Background/objective, Apoptosis is disordered in tumourigensis, however, the importance of apoptosis in relation to DNA damage created at the time of initiation by genotoxic carcinogens, i.e. the acute apoptotic response to genotoxic carcinogens (AARGC), has hardly been explored. p53 and APC are tumor suppressor genes known to be altered frequently in colon cancer, however, it remains unclear whether AARGC is dependent on the function of p53 or APC. p53 ,/,, p53 ± and APCMin/+ mice provide an excellent model to test the biological significance of AARGC in colon in terms of its ability to delete genetically damaged cells that might progress to cancer. Thus, we have tested the hypothesis that p53 and APC play a critical role in AARGC, by studying AARGC in p53+/, , p53 ,/, mice and APCMin/+0. Methods, p53 knockout mice were produced by breeding male p53+/, with female C57BL/J mice or interbreeding p53+/, mice. APCMin/+ mice were produced by breeding male APCMin/+ mice with female C57BL/J mice. Mice geno-typing were confirmed by PCR. At 10,12 weeks age, 44 mice were given a single subcutaneous azoxymethane (AOM 10 mg/kg) injection to induce AARGC, and killed 6 h later (the time of the maximal response). There were eight p53,/, mice, 11 p53+/, mice, nine p53+/+mice, 12 APCMin/+ mice, and six APC+/+ mice. Three p53,/, mice, four p53+/, mice, seven p53+/+ mice, two APCMin/+, and six APC+/+ mice without AOM injection were used as controls. Apoptosis in colon was measured by classic morphological H & E criteria. Results, In p53+/+ mice, AOM induced a significant increase in apoptosis (4.70 ± 0.35, SEM, apoptotic cells per crypt column) in the distal colon, located almost exclusively in the proliferative compartment. In comparison to the pattern of apoptosis observed in the p53+/+ mice, the apoptotic response of p53,/, mice was almost nonexistent (0.12 ± 0.06) while in p53+/, mice it was significantly suppressed by approximately 50% (2.26 ± 0.28); P < 0.01. In contrast to the importance of p53 gene on AARGC, absence of the APC gene had no obvious effect on AARGC: APCMin/+ mice (5.07 ± 0.30) and APC+/+ (5.50 ± 0.33); P > 0.05. Conclusion, p53 function appears to be critically important for carcinogen-induced apoptosis in colon, while APC homeostasis appears not to be involved in this type of apoptosis. The loss of just one allele of p53, interferes with its function. Further studies are required to determine whether defective AARGC in p53 knockout mice puts them at increased risk of subsequent events in tumorigensis, and whether AARGC can be regulated by known protective agents. [source] Epigenetic reprogramming of liver cells in tamoxifen-induced rat hepatocarcinogenesisMOLECULAR CARCINOGENESIS, Issue 3 2007Volodymyr P. Tryndyak Abstract Tamoxifen, a nonsteroidal anti-estrogen, is a potent genotoxic hepatocarcinogen in rats, with both tumor initiating and promoting properties. Recently it has been demonstrated that genotoxic carcinogens, in addition to exerting genotoxic effects, often cause epigenetic alterations and these induced epigenetic changes may play important mechanistic role in carcinogenesis. In the present study, we investigated the role of tamoxifen-induced epigenetic changes in hepatocarcinogenic process. The results of the study showed that exposure of female F344 rats to tamoxifen resulted in progressive loss of CpG methylation in regulatory sequences of long interspersed nucleotide elements (LINE-1) and prominent increase in expression of LINE-1 elements and c- myc proto-oncogene. The accumulation of tamoxifen-induced DNA lesions was accompanied by the decreased level of Rad51, Ku70, and DNA polymerase , (Pol,) proteins that play a crucial role in maintenance of genomic stability. Furthermore, feeding rats with tamoxifen-containing diet led to increased regenerative cell proliferation, as indicated by the increased level of Ki-67 and proliferating cell nuclear antigen (PCNA) proteins. These data indicate that exposure of animals to genotoxic hepatocarcinogen tamoxifen led to early phenotypical alterations in livers characterized by emergence of epigenetically reprogrammed cells with a specific cancer-related epigenetic phenotype prior to tumor formation. © 2006 Wiley-Liss, Inc. [source] Lack of a Dose-response Relationship for Carcinogenicity in the Rat Liver with Low Doses of 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline or N-NitrosodiethylamineCANCER SCIENCE, Issue 10 2002Shoji Fukushima For a long period, it has been generally considered that carcinogens, particularly genotoxic ones, have no threshold in exerting their potential for cancer induction. However, the non-threshold theory can be challenged with regard to assessment of cancer risk to humans. Here we show that a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5- f]quinoxaline, forms DNA adducts at low doses, but does not induce glutathione S-transferase placental form (GST-P)-positive foci (considered to be preneoplastic lesions) or 8-hydroxy-2,-deoxyguanosine in rat liver. Moreover a N -nitroso compound, N -nitrosodiethylamine, at low doses was also found not to induce GST-P-positive foci in rat liver. These results imply that there is a no-observed effect level for hepatocarcinogenesis by these genotoxic carcinogens. [source] | ||||||||||