UMLS:C0034063 - FACTA Search

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Query: UMLS:C0034063 (pulmonary edema)
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Environmental lung injury may take the form of acute tracheobronchitis, asthma, pulmonary edema, chronic bronchitis, emphysema, allergic pneumonitis, fibrosing alveolitis, pleurisy, and neoplastic disease. Environmental factors eliciting these responses include irritant gases and fumes, oxidants, organic allergens, inorganic dust, bacterial enzymes, and high partial pressures of oxygen. The basic pulmonary reactions to these toxic agents--bronchoconstriction, vasoconstriction, increased vascular permeability, inflammation, carcinogenesis--may be mediated, aggravated, or modulated by biologically active substances. These humoral agents include biogenic amines (e.g. histamine): peptides (e.g., bradykinin, vasoactive intestinal peptide, and spasmogenic lung peptide); enzymes (e.g., proteases, superoxide dismutase, and mixed function oxidases); and acidic lipids (e.g., prostaglandins, prostaglandin endoperoxides, and thromboxanes).
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PMID:Environmental injury of the lung: role of humoral mediators. 35 83

In this review, some common food plants and their toxic or otherwise bioactive components and mycotoxin contaminants have been considered. Crucifers contain naturally occurring components that are goitrogenic, resulting from the combined action of allyl isothiocyanate, goitrin, and thiocyanate. Although crucifers may provide some protection from cancer when taken prior to a carcinogen, when taken after a carcinogen they act as promoters of carcinogenesis. The acid-condensed mixture of indole-3-carbinol (a component of crucifers) binds to the TCDD receptor and causes responses similar to those of TCDD. Herbs contain many biologically active components, with more than 20% of the commercially prepared human drugs coming from these plants. Onion and garlic juices can help to prevent the rise of serum cholesterol. Most herbs used in treatments may have many natural constituents that act oppositely from their intended use. Some herbs like Bishop's week seed contain carcinogens, and many contain pyrrolizidine alkaloids that can cause cirrhosis of the liver. The general phytoalexin response in plants (including potatoes, tomatoes, peppers, eggplant, celery, and sweet potatoes) induced by external stimuli can increase the concentrations of toxic chemical constituents in those plants. In potatoes, two major indigenous compounds are alpha-solanine and alpha-chaconine, which are human plasma cholinesterase inhibitors and teratogens in animals. Because of its toxicity, the potato variety Lenape was withdrawn from the market. Celery, parsley, and parsnips contain the linear furanocoumarin phytoalexins psoralen, bergapten, and xanthotoxin that can cause photosensitization and also are photomutagenic and photocarcinogenic. Celery field workers and handlers continually have photosensitization problems as a result of these indigenous celery furanocoumarins. A new celery cultivar (a result of plant breeding to produce a more pest-resistant variety) was responsible for significant incidences of phytophotodermatitis of grocery employees. Since there is no regulatory agency or body designated to oversee potential toxicological issues associated with naturally occurring toxicants, photodermatitis continues to occur from celery exposure. Sweet potatoes contain phytoalexins that can cause lung edema and are hepatotoxic to mice. At least one of these, 4-ipomeanol, can cause extensive lung clara cell necrosis and can increase the severity of pneumonia in mice. Some phytoalexins in sweet potatoes are hepatotoxic and nephrotoxic to mice. The common mushroom Agaricus bisporus contains benzyl alcohol as its most abundant volatile, and A. bisporus and Gyromitra esculenta both contain hydrazine analogues. Mycotoxins are found in corn, cottonseed, fruits, grains, grain sorghums, and nuts (especially peanuts); therefore, they also occur in apple juice, bread, peanut butter, and other products made from contaminated starting materials.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Natural pesticides and bioactive components in foods. 240 25

Fusarium moniliforme (FM) is a major fungal pathogen of corn and is involved with stalk rot disease. FM is widely spread throughout the world, including the United States. Most strains of FM produce several mycotoxins, the most prominent of which is called fumonisin. Recent epidemiological studies indicated that ingestion of fumonisin correlates with a higher incidence of esophageal cancer in Southern and Northern Africa and China. Furthermore, fumonisin causes a neurodegenerative disease in horses, induces hepatic cancer in rats, and induces pulmonary edema in swine. Considering that high levels of fumonisin have been detected in healthy and diseased corn grown in the United States, fumonisin may pose a health threat to humans and livestock animals. Structurally, fumonisin resembles sphingolipids which are present in the membranes of animal and plant cells. At the present time, very little is known concerning the mechanism by which fumonisin elicits its carcinogenic effect. Our studies indicate that fumonisin represses expression of protein kinase C and AP-1-dependent transcription. In contrast, fumonisin stimulated a simple promoter containing a single cyclic AMP response element. Since fumonisin did not alter protein kinase A activity, it appears that cyclic AMP response element activation was independent of protein kinase A. It is hypothesized that the ability of fumonisin to alter signal transduction pathways plays a role in carcinogenesis.
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PMID:Repression of protein kinase C and stimulation of cyclic AMP response elements by fumonisin, a fungal encoded toxin which is a carcinogen. 771 70

Fumonisin B1 is associated with various animal and human carcinomas and toxicoses, including leukoencephalomalacia, hepatocarcinoma, pulmonary edema and esophageal carcinoma. We have examined the cellular effects of fumonisin B1 in vitro using cellular model systems relevant to potential human target tissues. Although fumonisin B1 has been described as a mitogen in Swiss 3T3 cells based on stimulation of [3H]thymidine incorporation, in the current work it was found that fumonisin B1 inhibited incorporation of [3H]thymidine by cultured neonatal human keratinocytes and HepG2 human hepatocarcinoma cells at 10(-7) and 10(-4) M respectively. Fumonisin B1 also inhibited clonal expansion of normal human keratinocytes and HET-1A human esophageal epithelial cells at 10(-5) M and growth in mass culture of normal human fibroblasts at 10(-7) M. The clonogenicity of normal human keratinocytes decreased to 45.5% of controls after exposure to 10(-4) M fumonisin B1 for 2 days. However, no differences in the cell cycle distribution of cultured keratinocytes was noted after exposure to 10(-5) M fumonisin B1 for 40 h. The viability of normal human keratinocytes and HET-1A cells decreased as a result of fumonisin B1 treatment, as determined by a fluorescein diacetate/propidium iodide flow cytometric cell viability assay. Fumonisin B1-treated keratinocytes released nucleosomal DNA fragments into the medium 2-3 days after exposure to 10(-4) M fumonisin B1 and increased DNA strand breaks were detected in attached keratinocytes exposed to 0-10(-4) M fumonisin B1 using a terminal deoxynucleotidyl transferase-based immunochemical assay system. Furthermore, fumonisin B1-treated keratinocytes and HET-1A cells developed morphological features consistent with apoptosis, as determined by phase contrast microscopy, fluorescent microscopy of acridine orange stained cells and electron microscopy. These results are consistent with the occurrence of fumonisin B1-mediated apoptosis in vitro.
Carcinogenesis 1996 Feb
PMID:Apoptotic and anti-proliferative effects of fumonisin B1 in human keratinocytes, fibroblasts, esophageal epithelial cells and hepatoma cells. 862 45

Mononitrosocaffeidine (MNC) and dinitrosocaffeidine (DNC) are new N-nitroso compounds obtained from in vitro nitrosation of caffeidine, a hydrolysis product of caffeine present in a typically made and widely consumed tea from Kashmir (India), a high incidence area of esophageal and stomach cancer. The chemical synthesis, in vitro metabolic studies and mutagenicity of the compounds has been previously reported. DNC, a nitrosamide is highly mutagenic both with and without metabolic activation whereas MNC, like several other aromatic asymmetric nitrosamines, does not exhibit genotoxic or mutagenic properties. We now report the results of the first carcinogenicity experiments on chronic oral administration of these compounds in BD-IX rats. The acute LD50 of MNC and DNC were about 1300 and 230 mg/kg b.w., respectively. Lung oedema and gastrointestinal haemorrhages were the first symptoms of intoxication observed after 2 days for both the compounds. All three dose groups of MNC treated rats showed localization of tumours in nasal cavity (93.9-100% of all malignant tumours). The tumours were histologically diagnosed as neuroepitheliomas of the olfactory epithelium (neuroblastoma of the bulbus olfactorii) and squamous cell carcinoma of the nasal cavity in the ratio of 3:1. No tumours of the nasal cavity were observed in the untreated controls. DNC, in contrast, induced squamous cell carcinoma of forestomach in 100% animals at low and high doses, of which nearly half the tumours metastasized predominantly into the peritoneum. No forestomach tumours were seen in the untreated controls. The data presented here clearly show the potential for induction of malignant tumours and distinct organ-specificity by MNC and DNC in rats, and support the postulate that a chronic exposure to these compounds may provide a carcinogenic risk for high incidence of gastrointestinal cancers in Kashmir.
Carcinogenesis 1998 May
PMID:Caffeine-derived N-nitroso compounds. V. Carcinogenicity of mononitrosocaffeidine and dinitrosocaffeidine in bd-ix rats. 963 85

Fusarium moniliforme is a widespread fungal pathogen which primarily infects corn, but can also infect rice or wheat. Fusarium moniliforme produce several mycotoxins, the most prominent of which is called fumonisin B1 (FB1). Epidemiological studies have indicated that ingestion of fumonisins correlates with a higher incidence of oesophageal cancer in Africa and China. Fumonisins also cause a neurodegenerative disease in horses, induce hepatic cancer in rats, are nephrotoxic in rats, or cause pulmonary oedema in swine. Structurally, fumonisins resemble sphingolipids and can alter sphingolipid biosynthesis. suggesting that sphingolipid alterations play a role in disease and carcinogenesis. Previous studies determined that FB1 blocked cell-cycle progression in CV-1 cells but not COS-7 cells. Herein, we have examined the effects that FB1 treatment has on cell-cycle regulatory proteins. Our studies established that FB1 treatment of CV-1 cells, but not COS-7 cells, leads to dephosphorylation of the retinoblastoma (Rb) protein. Cyclin dependent kinase 2 (CDK2) activity was repressed five- to 10-fold and cyclin E protein levels were lower in CV-1 cells after fumonisin treatment. Two CDK inhibitors, Kip1 and Kip2, were induced within 3 hours after fumonisin treatment of CV-1 cells, suggesting these two proteins mediate cell-cycle arrest induced by FB1. This mycotoxin caused large increases in sphinganine within 3 hours after addition of FB1. As sphingoid bases are known to induce Rb phosphorylation, this increase in sphinganinie might be the stimulus for the suppression of cyclin dependent kinase activities via Kip1 and Kip2. The ability of FB1 to accumulate sphingosine or sphinganine and arrest the cell cycle in some cells but not others may play an important role in carcinogenesis or disease.
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PMID:Characterization of cell-cycle arrest by fumonisin B1 in CV-1 cells. 973 26

This article describes the events leading to the discovery of the fumonisins in South Africa in 1988 and highlights the first 10 years (1988-1998) of fumonisin research. The predominant fungus isolated from moldy corn implicated in a field outbreak of equine leukoencephalomalacia (ELEM) in South Africa in 1970 was Fusarium verticillioides (F. moniliforme). This fungus was also prevalent in moldy home-grown corn consumed by people in high-incidence areas of esophageal cancer (EC) in the Transkei region of South Africa. Culture material on corn of F. verticillioides strain MRC 826, which was isolated from moldy corn in Transkei, was shown to cause ELEM in horses, porcine pulmonary edema (PPE) syndrome in pigs, and liver cancer in rats. A short-term cancer initiation/promotion assay in rat liver was used to purify the carcinogen(s) in the culture material. These efforts finally met with success when fumonisins B1 and B2 novel mycotoxins with cancer-promoting activity in rat liver, were isolated from culture material of F. verticillioides MRC 826 at the Programme on Mycotoxins and Experimental Carcinogenesis of the Medical Research Council in Tygerberg, South Africa. Following the elucidation of the chemical structure of the fumonisins, these carcinogenic mycotoxins were shown to occur naturally in moldy corn in Transkei. Shortly thereafter, high levels of fumonisins in the 1989 U.S. corn crop resulted in large-scale field outbreaks of ELEM and PPE in horses and pigs, respectively, in the United States. Subsequently the fumonisins were found to occur naturally in corn worldwide, including corn consumed as the staple diet by people at high risk for EC in Transkei and China. These findings, together with the fact that the fumonisins cause field outbreaks of mycotoxicoses in animals, are carcinogenic in rats, and disrupt sphingolipid metabolism, have resulted in much worldwide interest in these compounds during the first 10 years after the discovery of the fumonisins in 1988.
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PMID:Discovery and occurrence of the fumonisins: a historical perspective. 1135 91

Sphingoid bases are growth inhibitory and pro-apoptotic for many types of cells when added to cells exogenously, and can be elevated to toxic amounts endogenously when cells are exposed to inhibitors of ceramide synthase. An important category of naturally occurring inhibitors are the fumonisins, which inhibit ceramide synthase through structural similarities with both the sphingoid base and fatty acyl-CoA co-substrates. Fumonisins cause a wide spectrum of disease (liver and renal toxicity and carcinogenesis, neurotoxicity, induction of pulmonary edema, and others), and most-possibly all-of the pathophysiologic effects of fumonisins are attributable to disruption of the sphingolipid metabolism. The products of alkaline hydrolysis of fumonisins (which occurs during the preparation of masa flour for tortillas) are aminopentols that also inhibit ceramide synthase, but more weakly. Nonetheless, the aminopentols (and other 1-deoxy analogs of sphinganine) are acylated to derivatives that inhibit ceramide synthase, perhaps as product analogs, elevate sphinganine, and kill the cells. Somewhat paradoxically, fumonisins sometimes stimulate growth and inhibit apoptosis, possibly due to elevation of sphinganine 1-phosphate, which is known to have these cellular effects. These findings underscore the complexity of sphingolipid metabolism and the difficulty of identifying the pertinent mediators unless a full profile of the potentially bioactive species is evaluated.
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PMID:Fumonisins and fumonisin analogs as inhibitors of ceramide synthase and inducers of apoptosis. 1253 53

Tetranitromethane is a volatile contaminant formed during the manufacture of TNT and has been used as a rocket fuel and biochemical reagent. Toxicology and carcinogenesis studies were conducted in F344/N rats and B6C3F1 mice of each sex by whole body exposure to tetranitromethane vapor (greater than 99% pure), 6 hours per day, 5 days per week for 14 days, 13 weeks, or 2 years. Additional groups of male mice were exposed to tetranitromethane for evaluation at 1 year. Genetic toxicology studies were performed in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: Exposure concentrations ranged from 2 to 25 ppm for rats and from 2 to 50 ppm for mice. All rats exposed to 25 ppm and all mice exposed at the top concentration of 50 ppm died by day 2; reduced survival was seen in mice exposed to 25 ppm and in rats exposed to 10 ppm. Pulmonary edema in rats and inflammation of the lung in mice were seen in those animals in the 25- and 50-ppm exposure groups examined microscopically. Thirteen-Week Studies: Exposure concentrations ranged from 0.2 to 10 ppm for rats and mice. No exposure-related deaths occurred in rats. The final mean body weight of rats exposed to 10 ppm was 16% lower than that of controls for males and 6% lower for females. Exposure-related histologic effects included squamous metaplasia of the respiratory epithelium of the nasal mucosa and chronic inflammation of the lung. No deaths of mice could be clearly related to exposure to tetranitromethane. The final mean body weights of mice exposed to 5 or 10 ppm were 5% or 12% lower than that of controls for males and 9% or 12% lower for females. Exposure-related histologic effects in mice included inflammation and squamous metaplasia of the respiratory epithelium of the nasal mucosa and hyperplasia of the bronchiolar epithelium. Based on the incidences and severity of lesions in the respiratory at the higher concentrations used in the 13-week studies, exposure concentrations chosen for the 2-year studies were 0, 2, and 5 ppm for groups of 50 rats of each sex and 0, 0.5, and 2 ppm for groups of 50 mice of each sex. Additional groups of 6 or 10 male mice were exposed at concentrations of 0, 0.5, or 2 ppm for 1 year. Body Weights and Survival in the Two-Year Studies: Mean body weights of male and female rats exposed to 5 ppm were approximately 5%-15% lower than those of controls after week 70. Survival of rats at 104 weeks was as follows: male: control, 18/50; 2 ppm, 17/50; 5 ppm, 4/50; female: 25/50; 34/50; 15/50; survival of rats at the top concentration was reduced due to neoplasia. Mean body weights of exposed mice were variable and ranged as much as 10% below those of controls during the second year of the studies. Survival of exposed male mice at 104 weeks was significantly lower than that of controls due to neoplasia (control, 37/50; 0.5 ppm, 26/50; 2 ppm, 15/50). Survival of female mice was not significantly affected by exposure to tetranitromethane (31/50; 28/50; 24/50). Neoplastic and Nonneoplastic Effects in the Two-Year Studies: Effects of exposure to tetranitromethane were limited to the respiratory tract. Hyperplasia of the alveolar and bronchiolar epithelium was observed at increased incidences in exposed rats. The incidence of alveolar/bronchiolar adenomas and carcinomas were markedly increased in exposed male and female rats, with carcinomas (many of which metastasized to other sites) occurring in nearly all rats exposed to the top concentration of 5 ppm (adenomas or carcinomas-- male: control, 1/50; 2 ppm, 33/50; 5 ppm, 46/50; female: 0/50; 22/50; 50/50). Many of the rats exposed to 5 ppm also had squamous cell carcinomas of the lung (male: 0/50; 1/50; 19/50; female: 0/50; 1/50; 12/50). Hyperplasia of the respiratory epithelium and chronic inflammation of the nasal mucosa were observed at increased incidences in exposed male and female rats. Squamous metaplasia of the respiratory epithelium was increased in exposed male rats. No neoplasms of the nasal passage were seen. In exposed mice, hyperplasia of the alveolar and br were seen. In exposed mice, hyperplasia of the alveolar and bronchiolar epithelium was observed at increased incidences. Alveolar/bronchiolar neoplasms, primarily carcinomas (many of which metastasized to other sites), were increased in exposed male and female mice (male: control, 12/50; 0.5 ppm, 27/50; 2 ppm, 47/50; female: 4/49; 24/50; 49/50). Chronic inflammation of the nasal mucosa and hyperplasia and squamous metaplasia of the respiratory epithelium of the nasal cavity occurred at increased incidences in female mice exposed to 2 ppm. No primary neoplasms of the nasal passage were observed in mice. Oncogene Analysis: DNA from 14/19 rat and 4/4 mouse lung neoplasms caused morphologic transformation after transfection into cultured NIH/3T3 fibroblasts. The transforming gene from both rat and mouse lung neoplasms was determined by Southern blot analysis to be an activated K-ras oncogene. Further studies showed a GC-->AT transition in the second base of the 12th codon of the K-ras oncogene. Genetic Toxicology: Tetranitromethane was mutagenic in S. typhimurium strains TA98, TA100, and TA1535 with and without exogenous metabolic activation (S9); no mutagenic activity was observed in TA1537 with or without S9. Chromosomal aberrations were observed in CHO cells treated in vitro with tetranitromethane in the presence of S9. Sister chromatid exchanges were induced in CHO cells in the absence of S9. Conclusions: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of tetranitromethane for male and female F344/N rats and male and female B6C3F1 mice, based on increased incidences of alveolar/bronchiolar neoplasms in both species and squamous cell carcinomas of the lung in rats. Chronic inflammation of the nasal mucosa was related to exposure in rats and female mice, and hyperplasia and squamous metaplasia of the respiratory epithelium were increased in exposed male rats. Synonym: TNM
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PMID:NTP Toxicology and Carcinogenesis Studies of Tetranitromethane (CAS No. 509-14-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1263 73