Strong nasal carcinogenicity and genotoxicity of 1-nitroso-4-methylpiperazine after low dose inhalation in rats.
(25/865)Sprague-Dawley rats were exposed by inhalation to 1-nitroso-4-methylpiperazine (NMPz) vapor at 2.4 p.p.m. for 15 h/day for 74 days over a 7.5 month period. After a dose of 1.1 mg/day NMPz (total dose 340 mg/kg body wt) 10/10 animals developed tumors of the nasal cavity, mostly invasive muco-epidermoidal carcinomas; no such tumors were observed in sham-exposed controls. This high tumor yield was seen at an 80 times lower dose and a shorter latency period when compared with rat carcinogenicity studies reported earlier. The single cell microgel electrophoresis (Comet) assay was used to determine genotoxicity in target tissues. Short-term in vitro exposure of rat and human nasal epithelial tissues to NMPz caused genotoxic effects in cells of both species. Short-term in vivo exposure of rats to NMPz vapor for 1 h induced DNA damage in nasal epithelial cells. Our results revealed NMPz as a potent genotoxic nitrosamine in rat and human nasal cells, the carcinogenicity of inhaled NMPz vapor in rats being remarkably higher as compared with oral uptake. (+info)
The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis.
(26/865)Matrix metalloproteinases (MMPs) are invariably upregulated in the stromal compartment of epithelial cancers and appear to promote invasion and metastasis. Here we report that phenotypically normal mammary epithelial cells with tetracycline-regulated expression of MMP3/stromelysin-1 (Str1) form epithelial glandular structures in vivo without Str1 but form invasive mesenchymal-like tumors with Str1. Once initiated, the tumors become independent of continued Str1 expression. Str1 also promotes spontaneous premalignant changes and malignant conversion in mammary glands of transgenic mice. These changes are blocked by coexpression of a TIMP1 transgene. The premalignant and malignant lesions have stereotyped genomic changes unlike those seen in other murine mammary cancer models. These data indicate that Str1 influences tumor initiation and alters neoplastic risk. (+info)
Urinary bladder carcinogenicity of dimethylarsinic acid in male F344 rats.
(27/865)The present study was conducted to determine the carcinogenicity of dimethylarsinic acid (DMA) administered to male F344 rats in a 2 year bioassay. A total of 144 rats (10 weeks old at the start) were divided into four groups of 36 rats each. Groups 1-4 received DMA (purity 100%) at concentrations of 200, 50, 12.5 and 0 p.p.m. in the drinking water, respectively, for 104 weeks. From weeks 97 to 104, urinary bladder tumors were observed in 12 of 31, eight of 31 and none of 33 in groups 1-3, respectively. No bladder tumors were observed in group 4. The present study demonstrated that long-term p. o. administration of DMA induced urinary bladder carcinomas in male F344 rats. Therefore, the results indicate that DMA is carcinogenic for the rat urinary bladder, which may be related to the human carcinogenicity of arsenicals. (+info)
The Single Exposure Carcinogen Database: assessing the circumstances under which a single exposure to a carcinogen can cause cancer.
(28/865)A relational retrieval database has been developed compiling toxicological studies that assess whether a single dose of a chemical or physical agent, without exogenous promotional stimuli, could cause tumor development in animal models. This database allows for an evaluation of these studies over numerous parameters important to tumor outcome, which include type and quality of the studies as well as physical/chemical properties of the agents. An assessment of the database, which currently contains approximately 5500 studies involving about 800 chemicals from 2000 articles, reveals that a single dose of an agent can cause tumors to develop in males and females of numerous animal models in all principal age groups. In addition, the range of the 426 agents causing a positive response is chemically diverse, with representatives from over several dozen chemical classes. The dose caused a tumor endpoint was generally not acutely life threatening and was frequently a low proportion of the LD50 (i.e., less than 1/50 LD50). Positive responses also were reported via multiple routes of exposure, mainly oral, by injection, or dermal. These findings indicate that the phenomenon of single-exposure carcinogenesis is widespread and highly generalizable across chemical class, route, dose range, species, age, and gender. Single-exposure carcinogenesis, a concept long de-emphasized by regulatory agencies, requires a careful and formal consideration, especially as it may pertain to accidental spills, leaks, fires, explosions, and exposure excursions, but not necessarily limited to these. (+info)
N-nitrosodiethylamine initiation of carcinogenesis in Japanese medaka (Oryzias latipes): hepatocellular proliferation, toxicity, and neoplastic lesions resulting from short term, low level exposure.
(29/865)To investigate relationships among carcinogen exposure, cell proliferation, and carcinogenesis, 14-day post-hatch Japanese medaka (Oryzias latipes) were exposed to 0, 10, 25, 50, or 100 ppm N-nitrosodiethylamine (DEN) for 48 h under static renewal conditions. They were then held in clean water until sampling at 3 and 6 months. The frequencies of hepatic lesions and neoplasms were determined from hematoxylin/eosin-stained paraffin sections. A significant (p < 0.0001) concentration-related increase in hepatic vacuolated foci occurred in 3- and 6-month samples, with males having a significantly (p = 0.02) higher incidence than females. Concentration-related increases in degenerative lesions were documented for spongiosis hepatis at 3 months (p = 0.053) and hepatic vacuoles at 6 months (p = 0.005). There was a significant (p = 0.0001) concentration-related increase in macrophage aggregates at 6 months. Basophilic foci were significantly related (p < 0.0001) to DEN concentration at 3 months post-exposure and were unaffected by gender or age. At both 3 and 6 months, there were significant concentration-related increases in hepatocellular carcinoma (p < or = 0.02). Hepatocyte proliferation in 3-month whole specimens was quantified using an immunohistochemical assay for proliferating-cell nuclear antigen. Trend tests and a probit dose-response model showed a significantly positive correlation (p = 0.015) between proliferating hepatocytes and DEN concentrations. These results confirm that short-term exposure to low and moderate levels of DEN initiates concentration-dependent carcinogenic effects in medaka that are apparent at 3 months postexposure. DEN could be an effective initiator in an initiation/promotion assay for medaka using a 48-h exposure period, DEN concentrations < or = 10 ppm, and a 6-month sampling period. (+info)
Chronic peroxisome proliferation and hepatomegaly associated with the hepatocellular tumorigenesis of di(2-ethylhexyl)phthalate and the effects of recovery.
(30/865)This study compared the levels of cell proliferation and peroxisome proliferation in rodent liver with tumor incidence, to provide more information on the relationship between these events following chronic exposure. Fischer 344 rats were treated with 0, 100, 500, 2500, or 12,500 ppm DEHP, and B6C3F1 mice were treated with 0, 100, 500, 1500, or 6000 ppm DEHP in the diet for up to 104 weeks. Additional groups of rats and mice received the highest concentration for 78 weeks and then the control diet for an additional 26 weeks (recovery groups). Animals were terminated at weeks 79 and 105 for histopathologic examination. Elevated palmitoyl CoA oxidation activity and higher liver-to-body weight ratios were observed for the 2500- and 12,500-ppm groups of rats, and for the 500-, 1500-, and 6000-ppm groups of mice at Week 105. No increase in palmitoyl CoA oxidation activity was evident in the recovery group, and relative liver weights were near control levels following recovery. No hepatic cell proliferation was detected at Weeks 79 or 105 in either species although preliminary data indicated that cell proliferation did occur within the first 13 weeks of exposure. A significantly higher incidence of hepatocellular tumors was only observed for the 2500- and 12,500-ppm group and its recovery group of rats, and for the 500-, 1500-, and 6000-ppm groups and the recovery group of mice. The tumor incidences were reduced for the recovery groups compared with the groups fed DEHP continuously for 104 weeks. The data indicate that high levels of peroxisome proliferation and hepatomegaly are associated with DEHP hepatocarcinogenesis in rodent liver, and that the tumorigenic process may be arrested by cessation of DEHP treatment, suggesting that extended treatment with DEHP acts to promote tumor growth. (+info)
Toxicologic and carcinogenic effects of the type IV phosphodiesterase inhibitor RP 73401 on the nasal olfactory tissue in rats.
(31/865)RP 73401, a type IV phosphodiesterase inhibitor, caused toxic effects in the nasal olfactory region of Sprague-Dawley rats when administered by either oral or inhalation exposure. A single oral administration of RP 73401 (at a dose of > or = 50 mg/kg) or 5-day inhalation exposure (1 hr/day) at a dose of approximately 1.0 mg/kg per day caused degeneration and sloughing of the olfactory surface epithelium. Degeneration and loss of Bowman's glands were noted in the underlying lamina propria and submucosa. Electron microscopy of these lesions demonstrated that sustentacular cells and the epithelial cells lining Bowman's glands were the primary target cells in the olfactory mucosa. The earliest ultrastructural changes detected in these cells were dilatation and vesiculation of the endoplasmic reticulum, suggesting that metabolic activation is important for the toxic effects. In repeated-dose studies, 13 wk of oral dosing at 2.0 or 6.0 mg/kg per day resulted in subtle disorganization of the olfactory epithelium, whereas basal cell hyperplasia in the olfactory epithelium was identified in a 6-month inhalation study at a dose of 1.0 mg/kg per day. A 2-yr inhalation carcinogenicity study resulted in tumors of the nasal olfactory region in rats treated at 0.5 and 1.0 mg/kg per day. Most tumors were classified as olfactory neuroblastomas, and immunohistochemistry on selected tumors was consistent with their being of neuroectodermal origin. Of the species studied (rat, mouse, and dog), the olfactory toxicity of RP 73401 was confined to the rat, and the toxicity was likely related to metabolic activation by olfactory epithelial cells rather than the phosphodiesterase activity of the compound. (+info)
Modulation of in vivo growth of thyroid tumor-derived cell lines by sense and antisense vascular endothelial growth factor gene.
(32/865)Vascular endothelial growth factor A (VEGF) is a potent mitogen for endothelial cells in vitro and promotes neo-angiogenesis in vivo. VEGF overexpression occurs in most human malignancies including thyroid carcinomas in which elevated VEGF expression is associated with a high tumorigenic potential. To investigate the role of VEGF in angiogenesis associated with development of thyroid carcinomas, we constitutively expressed VEGF121 into a poorly tumorigenic cell line (NPA) expressing minimal levels of endogenous VEGF. Here we report that VEGF overexpressing NPA cells showed the same growth potential as untransfected NPA in vitro but formed well-vascularized tumors when injected subcutaneously into nude mice with markedly reduced latency compared to parental cells. A complementary approach was to suppress VEGF expression in a highly tumorigenic anaplastic cell line (ARO) by the transfection of an antisense construct. Antisense-transfected ARO cells expressed reduced constitutive levels of VEGF, showed the same growth potential as untransfected ARO cells in vitro and formed small tumors characterized by minimal vascularization, extensive necrosis and longer latency compared to parental or vector-transfected ARO cells in vivo. Finally, we investigated the expression of both VEGF tyrosine kinase receptors (Flt-1 and Flk-1/KDR) in tumor specimens by RT - PCR. Expression of (Flt-1 and Flk-1/KDR) was low in tissue specimens derived from NPA tumors, but was found enhanced in NPA VEGF tumors; conversely, the expression of VEGF receptors was high in tissue specimens derived from ARO tumors but was decreased in tumors derived from VEGF depleted ARO cells. These results clearly demonstrate that VEGF indirectly promotes the growth of thyroid tumors by stimulating angiogenesis. (+info)