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Biomedical subjects

R M Kovatch

Publications and source records attributed to R M Kovatch.

88 records · Page 5Linked to original sources
PubMed1971

Virulence and pathogenesis of yellow fever virus serially passaged in cell culture.

Viscerotropic virulence of the Asibi strain of yellow fever virus (YFV) for monkeys has been known to be lost after serial passage in HeLa cell monolayers. This phenomenon was investigated in several other mammalian and insect tissue cell lines. Assay in monkeys of original seed virus and of virus after 7 and 11 passages in a porcine kidney cell line (PK) indicated essentially equal infectivity and mortality. Moreover, monkeys receiving the passaged virus exhibited more rapid onset of disease and death than animals infected with original seed virus. Histological changes in animals inoculated with passaged virus were identical to those in animals receiving the seed virus. Virus from later passages in PK cells was also lethal for approximately 50% of the monkeys; however, evidence for progressive attenuation was seen in these preparations. Similar results were obtained with a mosquito (Aedes aegypti) cell line. In contrast to results obtained in PK and mosquito cells, YFV became essentially avirulent (nonlethal and less infective) for monkeys after only seven passages in HeLa cell cultures.

Aedes↗
PubMedDate not supplied

Carcinogenesis by nitrosobis-(2-oxopropyl)amine labeled with deuterium and by nitroso-2-hydroxypropyl-2-oxopropylamine in rats and hamsters.

The effects of the labeling with deuterium of the alpha-methylene groups of the carcinogen nitrosobis-(2-oxopropyl)amine (NBOP) on its carcinogenic effectiveness in rats and hamsters have been studied. The greater strength of the C-D bond compared with the C-H bond often leads to slower metabolism and lesser carcinogenic activity. When NBOP and NBOP-d4 were given to male and female rats in drinking water at equimolar doses, the mortality rate from tumors was lower in the rats given the deuterium-labeled compound, although the results were statistically significant (P = 0.012) only in males. The incidences of tumors of several groups was similar for NBOP and NBOP-d4, but there was a marked difference between males and females, females having a high incidence of liver tumors, and males very few. When NBOP and NBOP-d4 were given by gavage to rats or Syrian hamsters at identical doses there was no difference in rate of mortality from tumors, or in the pattern of tumors induced by either compound. In rats, both compounds were given at two dose rates, and in neither was a difference seen. To complement the studies with NBOP, a normal reduction product formed metabolically in vivo, nitroso-(2-hydroxypropyl) (2-oxopropyl)amine (NHPOP) was administered to rats in drinking water at the same dose rate. In male rats, the mortality rate was lower with NHPOP than with NBOP, while with female rats the opposite was the case (P less than 0.01 in both cases) and there was little difference in the pattern of tumors induced in either sex. NHPOP appears to have a quite distinct carcinogenic effect from NBOP, suggesting that the metabolic conversion of one to the other does not play a large role. The weak deuterium-isotope effect of NBOP-d4 given to rats in drinking water, but not detected in rats or hamsters treated by gavage, suggests that alpha-oxidation of NBOP is not likely to be a rate-limiting step in carcinogenesis by NBOP.

Animals↗
PubMedDate not supplied

Rat kidney pathology induced by chronic exposure to fumonisin B1 includes rare variants of renal tubule tumor.

The carcinogenicity of fumonisin B1 (FB1), a worldwide contaminant of corn produced by Fusaria species of fungi, has been tested recently in 2-year feeding studies in Fischer F344 rats and B6C3F1 mice. Inclusion of FB1 at 50 and 80 ppm in the diet induced liver tumors in female mice, and at 50 and 150 ppm induced renal tumors in male rats (22). In the present study, the kidneys from the rat bioassay were examined to characterize the various histopathological changes associated with renal tumor induction. In all high-dose (150 ppm) and mid-dose (50 ppm) male rats, and to a lesser extent in high-dose (100 ppm) female rats, there was evidence of sustained nephrotoxicity manifested as basophilia, apoptosis, cell regeneration, and simple tubule hyperplasia, affecting proximal convoluted tubules in the deep cortex, extending into the outer region of the outer stripe of outer medulla. A further alteration consisted of sporadic areas of interstitial hyalinization in deep cortex, suggestive of expanded basement membrane, coupled with tubule atrophy. The continued presence of nephrotoxicity throughout chronic exposure to FB1 suggested that renal tumor development may have been an outcome of sustained cell loss and compensatory regeneration. In some cases, preneoplastic tubules or incipient renal tumors presented an immature or fetal form in association with interstitial hyalinization. The renal tubule tumors induced by FB1 were typified by a rare, highly malignant, anaplastic variant capable of growth by infiltration. Of the 10 renal tubule tumors diagnosed in the mid-dose males, and the 16 in the high-dose males, 8 and 10, respectively, were graded as carcinomas. Anaplastic variants represented 50% of the mid-dose carcinomas and 80% of the high-dose carcinomas. One of the anaplastic carcinomas in a mid-dose male was a true sarcomatoid phenotype not previously recorded in the rodent. Metastatic invasion of the lung occurred with 25% of the mid-dose carcinomas and 50% of the high-dose carcinomas. It was speculated that FB1 may have been influencing the growth characteristics of the induced renal tumors via its inhibitory action on the synthesis of sphingolipids, which in turn, participate in regulating cell contact, growth, and differentiation, or alternatively by affecting cell adhesion molecules.

Adenoma↗
PubMedDate not supplied

Chronic toxicity/oncogenicity evaluation of 60 Hz (power frequency) magnetic fields in F344/N rats.

A 2-yr whole-body exposure study was conducted to evaluate the chronic toxicity and possible oncogenicity of 60 Hz (power frequency) magnetic fields in rats. Groups of 100 male and 100 female F344/N rats were exposed continuously to pure, linearly polarized, transient-free 60 Hz magnetic fields at flux densities of 0 Gauss (G) (sham control), 20 milligauss (mG), 2 G, and 10 G; an additional group of 100 male and 100 female F344/N rats received intermittent (1 hr on/1 hr off) exposure to 10 G fields. Mortality patterns, body weight gains throughout the study, and the total incidence and number of malignant and benign tumors in all groups exposed to magnetic fields were similar to those found in sex-matched sham controls. Statistically significant increases in the combined incidence of C-cell adenomas and carcinomas of the thyroid were seen in male rats chronically exposed to 20 mG and 2 G magnetic fields. These increases were not seen in male rats exposed continuously or intermittently to 10 G fields or in female rats at any magnetic field exposure level. No increases in the incidence of neoplasms, which have been identified in epidemiology studies as possible targets of magnetic field action (leukemia, breast cancer, and brain cancer), were found in any group exposed to magnetic fields. There was a decrease in leukemia in male rats exposed to 10 G intermittent fields. The occurrence of C-cell tumors at the 2 lower field intensities in male rats is interpreted as equivocal evidence of carcinogenicity; data from female rats provides no evidence of carcinogenicity in that sex. These data, when considered as a whole, are interpreted as indicating that chronic exposure to pure linearly polarized 60 Hz magnetic fields has little or no effect on cancer development in the F344/N rat.

Adenoma↗
PubMedDate not supplied

Promotion of mouse lung tumors by bioaccumulated polychlorinated aromatic hydrocarbons.

Lung tumors initiated in infant Swiss mice by N-nitrosodimethylamine (NDMA) were promoted by a single dose of a mixture of polychlorinated biphenyls (PCBs), Aroclor 1254 (250 or 500 mg/kg) given 4 days later. The tumors were typical alveologenic adenomas, and their number increased gradually over the course of 1 year to a maximum 4-fold enhancement in average tumor number compared with those given NDMA alone. The time course pattern suggested continuous tumor stimulation by the nonmetabolized PCB congeners retained in the tissues. Content of the nine major bioretained PCB congeners in carcass, liver, and lung was determined at intervals after treatment. Several showed tissue-specific retention patterns: 2,3,3',4,4'-PCB was selectively retained in lung and liver, and 2,2',3,4,4', 5'-HCB in lung. In tests of the tumor-promoting ability of individual congeners, the 2,2',3,4,4',5'-HCB, an Ah receptor agonist, promoted lung tumors when given singly, whereas another prominent bioretained congener, the 2,2',4,4',5,5'-HCB, an Ah receptor antagonist, did not promote, and in fact abrogated the positive effect of the 2,2',3,4,4',5'-HCB. In a parallel examination of persistent biochemical effects, a single low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (5 nmole/kg) resulted in significant elevation of immunochemically detected protein and enzymatic activity of cytochrome P450 IA1 in lung for at least 12 weeks; these parameters were elevated for at least 30 weeks after a single dose of Aroclor 1254 (500 mg/kg). Taken together these results suggest that Ah-receptor-dependent induction of cytochrome P450 IA1 in mouse lung is correlated with and possibly causally involved in promotion of tumors by retained congeners.

Animals↗
PubMedDate not supplied

A study of the carcinogenicity of glycidol in Syrian hamsters.

The industrial chemical glycidol is a directly acting mutagen and a broadly acting carcinogen in rats. It was administered to Syrian golden hamsters (20 male and 20 female) by gavage of 12 mg twice a week for 60 weeks. The total dose per animal was 1.45 g or 20 mmol. Survival was not different from control hamsters treated with corn oil/ethyl acetate. Of the treated males, 9 had tumors and 13 of the treated females had tumors, some of which were adrenal cortex tumors seen in controls. More tumors were seen in the glycidol-treated hamsters than in controls, but the spleen was the only notable target organ and the number of animals with spleen hemangiosarcomas was small. Glycidol appeared to be less carcinogenic in hamsters than in rats or mice.

1-Propanol↗
PubMedDate not supplied

Carcinogenesis in rats by substituted dialkylnitrosamines given by gavage.

A number of nitrosamines that have been studied by administration to rats as solutions in drinking water have been examined by gavage administration of similar doses, for assessment of the role of pharmacokinetics in organ-specific carcinogenesis. Methylnitrosoethylamine was more effective as a liver carcinogen by gavage than in drinking water and gave rise to tumors of the lung and nasal mucosa by the former route, but not the latter. By gavage, methylnitroso-2-oxopropylamine and methylnitroso-2-hydroxypropylamine induced mainly tumors of the esophagus, as they did when given to rats in drinking water, but the potency was greater by gavage. At a higher dose rate (85 micromoles per week) methylnitrosohydroxypropylamine induced a high incidence of mesenchymal tumors of the kidney and lung tumors, in addition to esophageal tumors, but methylnitrosooxopropylamine did not. The tobacco-specific carcinogen NNK induced tumors of the liver, and to a lesser extent, of the lung and nasal mucosa when given by gavage to rats, as it did by other routes of administration. The similarly basic nitrosamine methylnitroso-N, N-dimethylaminoethylamine was equally potent, whether administered by gavage or in drinking water to rats, and gave rise only to tumors of the esophagus. The cyclic nitrosamine nitrosomorpholine was equally effective by gavage and in drinking water, but induced in rats more esophageal tumors by gavage in addition to a high incidence of liver tumors. Its 2-hydroxy derivative, a postulated metabolic intermediate of nitrosodiethanolamine, was a very much weaker carcinogen than either the latter or nitrosomorpholine, and induced low incidences of liver and lung tumors toward the end of the lifespan of the rats.

Administration, Oral↗
PubMedDate not supplied

Carcinogenesis in rats by nitrosodialkylureas containing oxygenated alkyl groups.

A number of asymmetric nitrosodialkylureas containing ethyl, hydroxyethyl, 2-hydroxypropyl, 2-oxopropyl or chloroethyl on one or the other side of the nitroso function were given to male and female F344 rats in drinking water. The two compounds containing a 2-oxopropyl group, ethylnitrosooxopropylurea and oxopropylnitrosochloroethylurea were also given by gavage at the same weekly doses as in drinking water. The effect was greater following gavage treatment, both in tumor incidence and in mortality rate. The most potent carcinogen was ethylnitrosooxopropylurea which induced a large variety of tumors, including lung, nervous system, colon, intestine, thyroid, skin and uterus tumors, mammary adenocarcinomas and mesotheliomas. A similar pattern of tumors was induced by ethylnitrosohydroxyethylurea and hydroxyethylnitrosoethylurea. Hydroxyethylnitrosochloroethylurea, hydroxypropylnitrosochloroethylurea and oxopropylnitrosochloroethylurea gave rise to tumors in fewer organs. Chloroethylnitrosohydroxypropylurea was very toxic to the kidneys and induced a few lung tumors. Skin tumors were commonly induced by the nitrosodialkylureas in drinking water, but not when given by gavage.

Administration, Oral↗