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Biomedical subjects

U Mohr

Publications and source records attributed to U Mohr.

At least 55 records · Page 3Linked to original sources
PubMed1995

Increased risk of cancer in the descendants of Syrian hamsters exposed prenatally to diethylnitrosamine (DEN).

Transmission of site-specific tumorigenicity (papillomas in larynx and trachea) of diethylnitrosamine (DEN) to the 2 subsequent generations (F1 and F2) was studied using an outbred strain (Han:AURA) of pregnant Syrian golden hamsters (P generation), which were treated i.p. with 10 mg/kg b.w. of DEN on day 12, 13 or 14 of gestation. Laryngotracheal papillomas were induced by DEN in the P and F1 generations only, while these tumours did not occur in the F2 generation. Spontaneously occurring tumours, including uterine adenocarcinomas, lymphomas, and laryngotracheal neuro-endocrine cell tumours, were observed at higher incidences among the F2 animals derived from the P generation hamsters treated with DEN only on day 13 or 14 of gestation. In the same animals, the ratio of malignant to benign tumours was considerably higher than in controls. In addition, the F2 hamsters derived from the DEN-treated P generation showed more frequent multiple organ involvement in tumorigenesis than the F2 controls. Several uncommon malignant tumours were detected in the F2 offspring, possibly the result of damage caused to germ cells by the prenatal exposure of F1 Syrian hamsters to DEN.

Animals↗
PubMed1995

Phenyl isocyanate-induced asthma in rats following a 2-week exposure period.

This study was conducted to assess the toxic effects of repeated inhalation exposures to phenyl isocyanate vapor in male Wistar rats. Rats were exposed to design concentrations of 0, 1, 4, 7, or 10 mg/m3 phenyl isocyanate air for 2 weeks (6 hr/day, 5 days/week). The rats were assessed for normal toxicologic parameters, and pulmonary function tests, blood gas measurements, and analysis of bronchoalveolar lavage fluid (BALF) parameters were utilized shortly after exposures as well as 2 months postexposure. The results indicated that rats exposed to 7 and 10 mg/m3 experienced decreased body weights, hypoactivity, hypothermia, signs of respiratory tract irritation, delayed onset of mortality, and changes in organ weights. In addition, pulmonary function tests demonstrated decreased forced expiratory flow rates and quasistatic lung compliance. Arterial blood gases showed an arterial hypoxemia and changes consistent with a pronounced venous-admixture-like perfusion, suggesting severe mismatch of the ventilation/perfusion relationship. Delayed onset of mortality appeared to be associated with respiratory acidosis and hypoxemia. Biochemical and cellular components in BALF complemented the results of the functional alterations. Remarkable changes were indicated by increased activities of the BALF parameters, gamma-GPT, protein, and sialic acid. Histopathological findings provided evidence of increased secretory cell activity and a concentration-dependent increase in goblet cell hyperplasia at concentrations of 4 mg/m3 and above. In rats exposed to 7 mg/m3 further findings consisted of intraluminal inflammation of airways, hypertrophia of bronchial smooth muscle, epithelial desquamation, and eosinophilia of the airways. A complete regression of morphological lesions was not found in the animals exposed to 4 mg/m3 and above at the 2-month postexposure time period. In conclusion, the damage to the airways comprise most of the features characteristic of chronic airway inflammation or asthma.

Administration, Inhalation↗
PubMed1995

Chemically induced pulmonary mucoepidermoid carcinoma in a female Wistar rat.

A case of a mucoepidermoid carcinoma, conventionally classified as an adenosquamous carcinoma, is described. The tumour bearing rat was exposed to a mixture of a pyrolized pitch condensate rich in polycyclic aromatic hydrocarbons and carbon black particles by inhalation for 10 months. The neoplasm was examined by conventional histopathologic procedures and by immunohistochemical detection of intermediate filaments. Morphologically, the tumour consisted of two components. The centre of the neoplasm was predominantly of adenocarcinomatous tissue and this was surrounded by keratinized squamous epithelium. The predominantly adenocarcinomatous component had a characteristic structural pattern consisting of one or a few layers of squamous epithelium covered by a continuous layer of mature goblet cells. The flattened cells were recognizable as squamous cells on the light microscopic level only after immunohistochemical staining with cytokeratin antibodies. Goblet cells and extracellular mucin were intensely positive for the PAS-reagent. This mucoepidermoid carcinoma in the rat was morphologically similar to those described in man. It is still unclear whether pulmonary mucoepidermoid carcinomas of humans originate from the bronchial epithelium or bronchial glands. It is most probable that the mucoepidermoid carcinoma of a rat described in this communication occurred by metaplasia in a carcinoma of bronchiolo-alveolar origin.

Animals↗
PubMed1995

Formation of O6-ethylguanine in spermatogonial DNA of adult Syrian golden hamster by intraperitoneal injection of diethylnitrosamine.

17-Week-old Syrian golden hamsters received a single intraperitoneal injection of diethylnitrosamine (DEN) at a dose of 100 mg/kg body weight. The DNA alkylation product O6-ethylguanine was formed in the spermatogonia. The data demonstrate that DEN can pass the blood-testis barrier and be metabolized in the spermatogonia to yield an alkylating derivative or that externally activated metabolites themselves can pass the barrier.

Animals↗
PubMed1995

A histopathological study on alterations in DMBA-induced mammary carcinogenesis in rats with 50 Hz, 100 muT magnetic field exposure.

Several epidemiological studies have indicated that residential or occupational exposure to 50 or 60 Hz magnetic fields (MF) may increase the risk of breast cancer, possibly by suppression of pineal production of the oncostatic hormone melatonin. In view of the methodological problems of epidemiological studies on MF exposure and cancer risk, laboratory studies are needed to determine whether 50/60 Hz exposure can initiate, promote or copromote mammary cancer. In the present study, 216 female Sprague-Dawley rats were divided into four groups. Two of the groups (with 99 animals each) received oral applications of 7,12-dimethylbenz[a]anthracene (DMBA) and were either sham-exposed or exposed in a 50 Hz, 100 muT MF for 24 h/day 7 days/week for a period of 91 days. The other two groups (nine animals each) were either sham-exposed or MF-exposed without DMBA treatment. The exposure chambers and all other environmental factors were identical for MF-exposed and sham-exposed animals. At the end of the 3 month period of MF exposure, all rats were used for histopathological diagnosis of lesions. At the time of necropsy, significantly more MF-exposed DMBA-treated rats exhibited macroscopically visible mammary tumours than DMBA-treated controls. Furthermore, the size of mammary tumours was significantly larger in MF-exposed rats. Histopathological examination of the mammary gland showed that the number of neoplastic and non-neoplastic lesions did not significantly differ between groups, indicating that MF exposure had not altered the incidence of mammary lesions but had only accelerated tumour growth, consistent with a co-promoting effect. In the MF-exposed group, significantly more rats exhibited malignant mammary tumours than in controls, indicating that MF exposure had affected the progression of DMBA-induced lesions. The number of metastases of mammary tumours or of primary lesions in other organs in response to DMBA was not affected by MF exposure. In rats without DMBA application, no non-neoplastic or neoplastic lesions were determined. The data demonstrate that long-term exposure of DMBA-treated female rats promotes the growth and progression of mammary tumours, while tumour incidence is not affected, at least under the experimental conditions of the present study. The data thus add to the accumulating evidence that MF exposure exerts tumour co-promoting effects.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Neoplastic lung lesions in rat after chronic exposure to crystalline silica.

Groups of 100 SPF Fischer-344 rats were exposed 6 h a day, 5 d a week for 24 months to crystalline silica (1 mg center dot m-3, DQ 12 quartz) or titanium dioxide (5 mg center dot m-3) or air only. The animals were kept without further exposure for an additional 1.5 months. In the group exposed to crystalline silica a significantly increased incidence of 20 primary lung tumors was observed among 19 animals. The distribution of tumor types consisted of 3 adenomas, 11 adenocarcinomas, 4 benign cystic keratinizing squamous-cell tumors, 1 adenosquamous carcinoma, and 1 squamous-cell carcinoma. There were also 13 nodular hyperplasia lesions, which were interpreted to be borderline cases of adenomas. Approximately half of the adenoid tumors and all of the nodular hyperplasia lesions were characterized by moderate central fibrosis. The principal nonneoplastic findings in the silica-exposed group were lipoproteinosis, inflammation, epithelial hyperplasia, and fibrosis. The results can be considered significant due to the increased lung tumor incidence at a relatively low exposure level.

Administration, Inhalation↗
PubMed1994

Assessment of respiratory hypersensitivity in guinea-pigs sensitized to diphenylmethane-4,4'-diisocyanate (MDI) and challenged with MDI, acetylcholine or MDI-albumin conjugate.

Guinea-pigs were sensitized to monomeric diphenylmethane-4,4'-diisocyanate (MDI) by two intradermal injections (1-10% MDI, injection volumes of 50-100 microliters/day, on days 0, 2 and 4) or by a single brief high-concentration inhalation exposure (135 or 360 mg/m3, 15 min). Starting with day 21 following sensitization the animals were subjected to inhalation-challenge exposures (30 min) with non-irritating and irritating concentrations of the hapten (MDI). MDI-challenge concentrations ranged from 3.4 +/- 0.9 to 60 +/- 14.3 mg/m3 air. In some groups guinea-pigs were also challenged with acetylcholine (ACh) aerosol or the MDI-guinea pig serum albumin (GPSA) conjugate. Experimental findings indicated that from intradermally sensitized animals an immediate onset respiratory hypersensitivity response could only be elicited with concentrations exceeding the irritant threshold concentration for MDI, i.e. with concentrations greater than approximately 20 mg/m3 air. Guinea-pigs challenged with the MDI-GPSA conjugate (35.3 +/- 2.8 mg/m3 air) also experienced a weak immediate-type respiratory hypersensitivity response. An increased non-specific airway hyper-responsiveness following ACh-challenge was only observed from animals challenged with approximately 60 mg MDI/m3 air. The histopathological evaluation of lungs and lung-associated lymph nodes revealed an association of the increase in eosinophilic granulocytes and concentration of MDI used for challenge exposures. It appeared, in most instances, that this influx was more pronounced in animals sensitized with MDI as compared with concurrent controls challenged with the same MDI concentration. Guinea-pigs sensitized by a single 15-min inhalation exposure to either 135 or 360 mg MDI/m3 air were challenged sequentially with 12 +/- 2.1 mg MDI/m3 air, ACh and MDI-GPSA conjugate. Following the inhalation-induction, an airway hyper-responsiveness was elicited both after challenge with MDI and with the MDI-GPSA conjugate. The influx of eosinophilic granulocytes was more pronounced from animals sensitized by inhalation when compared with guinea-pigs sensitized intradermally and challenged with the same concentration of MDI. Thus, experimental findings suggest that elicitation of respiratory hypersensitivity is concentration-dependent and that challenge concentrations should slightly exceed the threshold concentration for irritation (approximately 20 mg/m3). Sensitization by inhalation increased the susceptibility to irritant stimuli and thus confounds the selection of the most appropriate concentration for challenge. However, the combined assessment of specific pathologic features such as airway eosinophilia and the evaluation of several breathing parameters during hapten- and ACh-challenge make it easier to distinguish effects caused by irritation and respiratory hypersensitivity.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1994

A single point mutation results in A allele-specific exon skipping in the bovine alpha s1-casein mRNA.

Bovine alpha s1-casein (alpha s1-CN) allele A is found in low allelic frequencies among different cattle breeds and is known to be characterized by the deletion of amino-acid residues 14 to 26 of the mature protein (as defined via the most common allele B), and a corresponding deletion of 39 bp from its cDNA. Based upon the genomic sequence of bovine alpha s1-CN [Koczan et al., Nucleic Acids Res. 19 (1991) 5591-5596], this allelic deviation can be interpreted as an absence of exon 4 from the A allele mRNA and protein product. We demonstrate that this allelic aberration is not caused by a genomic deletion across the exon-4 DNA, but is correlated with a single point mutation at position +6 in the splice donor sequence distal of exon 4, which results in upstream exon skipping during the serial splice reactions of the A allele alpha s1-CN pre-mRNA. The A-allele-specific mutation at position +6 is able to interrupt the perfect complementarity of the intron-4 splice donor signal (positions one to eight) with U1-snRNA, which may then no longer be able to compensate for a rather weak exon-4 upstream splice acceptor sequence in facilitating the initial binding of U2 auxiliary factor/65-kDa (U2AF65) to that polypyrimidine tract. This interpretation of the exon skipping mechanism in alpha s1-CN allele A is in agreement with similar results obtained [Hoffmann and Grabowski, Genes Dev. 6 (1992) 2554-2568] in an analysis of the rat preprotachykinin-encoding gene and in vitro experiments.

Alleles↗
PubMed1994

Spectrum of glandular differentiation in experimental carcinoma of the esophagus induced by 2,6-dimethylnitrosomorpholine under the influence of esophagojejunostomy.

To investigate the influence of reflux esophagitis (RE) on the glandular differentiation of carcinomas of the esophagus induced by 2,6-dimethylnitrosomorpholine (2,6-DMNM), a study was carried out using 4 experimental groups and 2 control groups of 8-week-old Sprague-Dawley rats, each consisting of 20 males and 20 females. An esophagojejunostomy (EJ) with gastric preservation was performed in two groups of animals. Fifteen days thereafter the potent esophagotropic carcinogen 2,6-DMNM was subcutaneously injected, once a week for life, at doses of 1/100 and 1/10 of the 50% lethal dose in each group respectively. The result was a spectrum of carcinomatous tumors mainly developing in the lower half of the esophagus, which were thoroughly investigated by serial sectioning, staining for mucins, and in selected cases by electron microscopy. They were classified as follows: 16 pure squamous cell carcinomas (SCC), 5 SCC with focal mucous or glandular differentiation (FGD), 11 pure adenocarcinomas (ADC), and 12 ADC with areas of squamous cell differentiation (SCD). By contrast, in 2 similar experimental groups in which the previous EJ was not performed, 15 animals showed SCC of the pure type, without evidence of mucous or glandular differentiation. No tumors were observed in the two control groups without carcinogen treatment. Of these, the group that underwent EJ showed reflux esophagitis. In conclusion, the tumors of the esophagus induced by 2,6 DMNM under the influence of EJ are not only pure ADC and pure SCC, as we have previously reported, but also intermediate tumors showing either SCC with focal mucous or glandular differentiation (SCC + FGD) or ADC with areas of squamous cell differentiation (ADC + SCD).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1994

Regulation of c-jun by lung carcinogens in Clara cells of hamsters.

In vitro differentiated hamster Clara cells were used to study the effects of lung carcinogens on the regulation of the c-jun oncogene. Northern blot analysis revealed a decrease in the expression of jun transcripts 24 h following the exposure of Clara cells to the direct acting forms of benzo[a]pyrene (BPDE*) or 5-methylchrysene (5MeCDE). To determine whether this decrease was mediated at the transcriptional level, we have used CAT reporter constructs driven by nested deletions of the 5' non-coding regulatory region of the c-jun oncogene. While BPDE was capable of activating certain regulatory domains of the c-jun promoter, this activation was not observed with either 5MeCDE or the less active lung carcinogens BADE or 6MeCDE. Analysis of enhancer elements identified the SP1 target site as a strong silencer after BPDE treatment. While positive regulatory element(s) mediating activation of c-jun by BPDE were localized within the promoter region up to -1639, further upstream sequences reduced this transcriptional activation. Thus, when the complete promoter region, up to -4500, was tested, no transcriptional activation was noted following BPDE treatment. These observations suggest that the regulation of c-jun in Clara cells exposed to potent lung carcinogens is mediated at the post-transcriptional level, possibly by reducing the stability and, in turn, the half life of c-jun mRNA. Overall, in contrast to the response of c-jun to numerous carcinogens and stress inducing agents noted in various other cell systems, our findings suggest the existence of a tissue-specific regulatory response for c-jun.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1993

Overseas electives.

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Clinical Clerkship↗
PubMed1993

Subchronic toxicity of 2,3,7,8-tetrabromodibenzo-p-dioxin in rats.

2,3,7,8-Tetrabromodibenzo-p-dioxin (2,3,7,8-TBDD) was administered daily to male and female rats for 91 days by gavage. Ten male and 10 female rats per group received 0.01, 0.1, 1, 3, or 10 micrograms 2,3,7,8-TBDD/kg body weight per dose per day, solubilised in arachis oil. At 1 microgram/kg per day and above, body weight gain was dose-dependently reduced by treatment. Animals in the 3 and 10 micrograms/kg dose groups showed symptoms of wasting syndrome. Fifty percent of the animals in the 3 micrograms/kg dose-group died and all animals of the highest dose (10 micrograms/kg) died or had to be killed in extremis. Hematological investigations indicated changes--mainly in the 1 and 3 micrograms/kg dose-groups--in hemoglobin content, packed cell volume and number of thrombocytes. The prothrombin-time was markedly prolonged after 3 micrograms/kg in week 13. Clinical chemistry performed at the end of treatment revealed an increase in plasma alkaline phosphatase (APh), aspartate aminotransferase, ASAT and alanine aminotransferase, ALAT (females only) in the highest surviving dose-group (3 micrograms/kg). Marginal changes of APh and ASAT were seen in rats in the 1 microgram/kg dose-group. In the same animals, total bilirubin was elevated. Triglycerides were reduced mainly at 1 and 3 micrograms/kg. Serum thyroxin was reduced, beginning with a marginal change at 0.1 micrograms/kg, triiodothyronine was elevated, starting with a dose of 1 microgram/kg. Thymus weights were reduced in rats of the 1, 3 and 10 micrograms/kg dose-groups. Histopathological analysis showed atrophy of the lymphatic tissue in thymus and spleen. Investigations of the liver indicated peliosis hepatis after treatment with 3 or 10 micrograms/kg. Activities of microsomal enzymes (ethoxyresorufin O-deethylase, ethoxycoumarin O-deethylase, aryl hydrocarbon hydroxylase, UDP-glucuronyltransferase) investigated in liver, lung and kidney were dose-dependently elevated after 13 weeks of treatment. At a dose of 3.0 micrograms/kg, activities were below those of the dose 1.0 microgram/kg, probably due to liver toxicity. The induction ratio of kidney was generally higher than in liver and lung. No signs of treatment-related toxicity were observed in the 0.01 and 0.1 micrograms/kg groups after the subchronic administration of 2,3,7,8-TBDD by gavage.

Adipose Tissue↗
PubMed1993

Experimental models of kidney tumors.

We here present in outline some outstanding results on the animal models of renal tumors submitted to the highest attention, which include two kinds of epithelial neoplasms: those developed from the epithelium lining each the renal tubules (renal cell tumors) and pelvis; the mesenchymal tumor of rat; and tumors with embryonal appearance: the nephroblastoma as well as the variant of it known as the estrogen-induced tumor in the hamster. The review deals with methods for tumor induction and the pathobiology of tumors, the latter mainly focused on the identification of the precise types of renal cells committed in tumor origin. The existence of closely related counterparts of these animal tumors in man is also emphasized, by representing a situation of great potentiality, already exploited, to improve understanding of both the nature and development of renal tumors in man.

Animals↗
PubMed1993

Influence of pancreatic and biliary reflux on the development of esophageal carcinoma.

We previously presented an experimental model of Barrett's adenocarcinoma of the esophagus by demonstrating that esophagojejunostomy combined with subcutaneous injection of 2,6-dimethylnitrosomorpholine in Sprague-Dawley rats resulted in development of adenocarcinoma in the distal esophagus. The present study was devised to investigate the influence of pancreatic and biliary duodenal-content reflux on the induction of esophageal carcinoma. Three groups of 8-week-old Sprague-Dawley rats were controls: the first was exposed to pancreatic reflux, the second to biliary reflux, and the third to both. The other three experimental groups were similar except that a 1/100 LD50 dose of 2,6-dimethylnitrosomorpholine was injected subcutaneously weekly, starting on day 15. Carcinoma of the esophagus was induced only in animals receiving the carcinogen after exposure to either pancreatic reflux (3/22, 13%) or pancreatic and biliary reflux (9/27, 33%). Half of the carcinomas were adenocarcinoma and half were squamous cell carcinoma. These findings suggest that under these experimental conditions, in which the carcinogen is used in a low dose, esophageal carcinoma is induced only when pancreatic secretions are present in the duodenal-content reflux. Biliary reflux, however, appears to exert a cocarcinogenic effect when combined with pancreatic secretions. The clinical relevance of these findings needs further evaluation. Conceivably, the elimination of pancreatic and biliary duodenal-content reflux in patients with documented Barrett's mucosa may inhibit the progression from metaplasia to adenocarcinoma.

Adenocarcinoma↗
PubMed1993

Influence of culture passages on growth kinetics, xenobiotic metabolism, chromosomal stability and transformation in a clonal fetal hamster lung epithelial cell line.

M3E3/C3 is a clonal fetal hamster lung epithelial cell line which is used for studies of epithelial differentiation as well as for in vitro toxicologic tests. In this study growth kinetics, xenobiotic metabolism, chromosomal stability and transformation were investigated at increasing culture passage numbers up to 150. Cells of higher passages grew faster and reached higher cell densities than the cells of lower ones. As an indicator of xenobiotic metabolism we measured the activity of 7-ethoxycoumarin-deethylase (ECD), an enzyme belonging to the mixed function oxidase system. Up to passage number 100 the ECD activity strongly increased, followed by a slight decrease in additional passages. The chromosomal stability was assessed by the induction of micronuclei by benzo[a]pyrene (BaP) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). More micronuclei were always detected in cells of higher passages than of lower passages. The capability of cells to be transformed to anchorage independent growth by chemical carcinogens was examined using a soft agar test. After carcinogen exposure with BaP and MNNG, cells of higher passages showed higher transformation frequencies than cells of lower passages. Many cells at passage 150 exhibited an especially high soft agar growth even without carcinogen treatment and were therefore characterized as spontaneously transformed. These results show that metabolic and genetic characteristics of permanently growing cells differ remarkably depending on the culture passage. This has always to be considered when permanently growing cells are used for toxicological studies.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1993

Neuromuscular hamartoma (benign "Triton" tumour) in a mouse.

Histological examination of a 22-month-old CD-1 mouse revealed a threefold enlargement of the right trigeminal ganglion. This change was due to the presence of well-differentiated striated muscle fibers intermingling with nerves and ganglion cells. The number of ganglionic Schwann cells was also increased as demonstrated by their positive S-100 protein staining. In addition, slight interstitial mononuclear cell infiltration and fibrosis were observed. The myocytes, which stained positive for myoglobin and desmin, and the proliferated Schwann cells did not show any signs of cellular or nuclear atypia. The lesion was diagnosed as "neuromuscular hamartoma (benign "Triton" tumor)" reflecting the capability of either Schwann cells or neural crest derived precursor cells to differentiate into various other cell types.

Animals↗