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Biomedical subjects

J Fink-Gremmels

Publications and source records attributed to J Fink-Gremmels.

53 records · Page 3Linked to original sources
PubMed1999

Mycotoxins: their implications for human and animal health.

Mycotoxins contaminate various feed and food commodities, due to the global occurrence of toxinogenic molds. They exert adverse health effects in human and animals. The nature of these toxic effects varies depending on the chemical structure of the toxin. The degree of these adverse effects is not only determined by the toxin concentration present in foods and feeds, but also by the time of exposure. Whilst in animals, next to acute intoxication, losses in productivity, reduced weight gain and immunosuppression are considered as most important feature of mycotoxicoses, genotoxic effects and the involvement of certain mycotoxins such as aflatoxin, ochratoxins and fumonisins in the etiology of human cancers have obtained particular attention. This implies that recent research activities concentrate on mechanistic aspects of mycotoxin-induced pathologies, rather than compiling analytical measures of mycotoxin concentrations in food and feeds.

Animal Feed↗
PubMed1996

Development of human cytochrome P450-expressing cell lines: application in mutagenicity testing of ochratoxin A.

With the aim to assess the involvement of distinct forms of cytochrome P450 enzymes in the activation of procarcinogens, we have developed by means of retroviral infection a series of NIH/3T3 cell lines stably expressing human CYP1A1, CYP1A2, CYP2C10, CYP2D6, and CYP2E1 cDNA. The levels of cytochrome P450 enzyme activities were determined using specific substrates. An increase in specific catalytic activity could be observed in all cell lines compared to background activity in vector-infected cells. Furthermore, we developed a test system in which we are able to combine P450-expressing cells with a shuttle vector containing the lacZ' gene, which serves as a reporter gene for mutations. Using this system, we investigated the cytotoxicity and mutagenicity of the mycotoxin ochratoxin A. Natural occurrence of ochratoxin A in food commodities has been linked to an increased incidence of urinary tract tumors in certain geographic regions. Although biotransformation seems to play a crucial role in ochratoxin A toxicity, the possible contribution of metabolites to genotoxicity and carcinogenicity remained unelucidated. We have demonstrated that the mutation frequency of ochratoxin A was increased dependent upon concentration in NIH/3T3 cell lines, stably expressing human CYP1A1, CYP1A2, CYP2C10, and CYP3A4. In contrast, neither in vector-infected NIH/3T3 cells nor in CYP2D6- and CYP2E1-expressing cells was an increase of mutation frequency observed.

3T3 Cells↗
PubMed1995

Toxicity and metabolism of ochratoxin A.

The frequent occurrence of ochratoxin A (OA) in food and feed commodities and the high incidence of human exposure, as confirmed by different surveillance studies initiated several investigations devoted to elucidating the molecular mechanisms underlying OA toxicity. Previous studies indicated that the primary effects of OA are the inhibition of tRNA synthetase, the inhibition of mitochondrial respiration, and a disturbance of intracellular calcium homeostasis inherent to lipid peroxidation processes. We here report the effect of OA on a number of toxicological endpoints including cytotoxicity in different cell lines and effects on macromolecular synthesis and cell proliferation in primary cultures of hepatocytes at concentrations corresponding to overall exposure levels. These studies provide evidence that prominent toxicological effects might be linked to biotransformation processes. Analysis of hepatic biotransformation resulted in the detection of a number of distinct stable OA-metabolites. As metabolic activation has also been identified as an essential step in OA mutagenicity, the biological relevance on this mechanistic data is discussed.

Animals↗
PubMed1995

Effects of the subchronic administration of zinc ethylene-bis-dithiocarbamate (zineb) to rabbits.

The effects of subchronic administration (90 d) of zineb were studied in male New Zealand White rabbits. Rabbits were allotted to 3 groups of 8 animals each and offered diets containing 0, 0.3 or 0.6% zineb. A marked decline in weight gain, hemoglobin concentration, hematocrit, and erythrocyte and leucocyte counts occurred at the highest zineb dosage. There was a dose-related depression in circulating thyroid hormones, whereas serum lipid concentration, particularly that of cholesterol and triglycerides, increased. Hepatic lipid concentration was considerably reduced in rabbits exposed to 0.6% zineb. Neither serum testosterone nor the activities of selected testicular enzymes showed changes suggestive of testicular involvement. Pathological changes were in agreement with biochemical findings; there was a marked dose-related enlargement of the thyroid showing histological colloid struma. An increase in relative weight and moderate glycogenosis were detected in liver, whereas no lesions occurred in testes. It was concluded that thyroid and liver are the main targets for zineb toxicity in the rabbit. Unlike the results from previous studies conducted on other food-producing species, repeated exposure of rabbits to zineb failed to cause testicular damage. This might be related to the inability of zineb to significantly accumulate in the testes.

Analysis of Variance↗
PubMed1994

Veterinary drugs: disposition, biotransformation and risk evaluation.

Veterinary drugs may only be produced, distributed and administered after being licensed. This implies that, prior to marketing, a critical evaluation of the pharmaceutical quality, the clinical efficacy and the over-all pharmacological and toxicological properties of the active substances will be performed by national and/or supranational authorities. However, despite a sophisticated legal (harmonized) framework, a number of factors involved in residue formation and safety assessment remain unpredictable or dependant on the current 'state of the art' in the understanding of molecular pharmacology and toxicology. For example, drug disposition and residue formation in the target animal species may be influenced by a broad variety of physiological parameters including age, sex and diet, as well as by pathological conditions especially the acute phase response to infection. These factors affect both drug disposition and metabolite formation. Furthermore, current thinking in toxicological risk assessment is influenced by recent developments in molecular toxicology and thus by an increased but still incomplete understanding of the interaction of a toxic compound with the living organism. General recognized principles in the evaluation of potential toxicants are applied in the recommendation of withdrawal times and the establishment of maximum residue limits (MRL values). Apart from toxicological-based assessment, increasing awareness is directed to other than toxicological responses, especially the potential risk of effects of antimicrobial residues on human gastrointestinal microflora. Thus, the methodology of risk assessment is discussed in the context of the recently established legal framework within the European Union.

Animals↗
PubMed1991

Pathogenesis of sodium selenite and dimethylselenide acute toxicosis in pigs: cardiovascular changes.

In pigs and other food producing animals, relatively little is known about the mode of action of excess selenium. This study reports the cardiovascular effects brought about in anaesthetised Landrace pigs by 2 mg selenium kg-1 bodyweight intravenously as either sodium selenite or dimethylselenide. Sodium selenite dosing was characterised by a dramatic fall in systemic blood pressure with an increase in cardiac output and heart frequency. The only significant change elicited by dimethylselenide was a linear rise of cardiac output. Neither of the tested compounds significantly affected pulmonary arterial pressure. These results suggest that under the experimental conditions in this study, sodium selenite induces a vasculogenic shock without primarily affecting cardiac performance. The lack of detrimental effects on cardiovascular parameters with dimethylselenide indicates the importance of methylation in detoxifying excess selenium.

Animals↗
PubMed1991

Mutagenicity and effects of ochratoxin A on the frequency of sister chromatid exchange after metabolic activation.

Primary cultures of hepatocytes derived from untreated rats were incubated in the presence of ochratoxin A for 24 h. Five different strains of histidine auxotroph Salmonella typhimurium were exposed to conditioned cell culture medium before being tested for mutagenicity. A clear hepatocyte-mediated mutagenic response was observed in TA1535, TA1538 and TA100. In addition, sister chromatid exchange frequency was increased in human peripheral lymphocytes that had been incubated in the presence of conditioned medium derived from ochratoxin A-exposed hepatocytes.

Animals↗
PubMed1990

Effects of fungal metabolites on testosterone secretion in vitro.

To study the direct effect of mycotoxins belonging to different chemical classes on testicular function, dispersed interstitial cells from testes of adult gerbils were short-term cultured either in the absence or presence of mycotoxins, and testosterone secretion was measured. When interstitial cells were incubated with T-2 toxin (0.0076-38.3 nM) there was a dose-dependent decrease of testosterone production (r = -0.72, ID50 = 0.042 nM). Since neither progesteronenor DHEA-stimulated testosterone production was affected by T-2 toxin, the observed inhibition of basal secretion was apparently due to a decrease of pregnenolone production and/or conversion of pregnenolone to progesterone. Much higher concentrations of zearalenone or of ochratoxin A were necessary to induce a similar inhibition of steroidogenesis (369 microM and 1838 microM, respectively) when compared to T-2 toxin. In contrast, citrinin or cyclopiazonic acid affected testosterone secretion only slightly, values reaching significant levels at doses of 1.74 nM (citrinin) and 149 nM (cyclopiazonic acid). In the presence of kojic acid (2.63-2633 nM) a significant, though not dose-dependent inhibition of testosterone secretion was observed. From these experiments it is concluded that mycotoxins of distinct chemical structure act directly on testicular tissue, presumably by inhibiting early steps of the steroidogenic pathway.

Animals↗
PubMed1990

Action of dexamethasone in an equine model of acute non-immune inflammation.

In a crossover study in seven New Forest ponies the actions of dexamethasone, at a dose rate of 0.06 mg kg-1 administered intravenously, were compared with those of a placebo treatment. Dexamethasone exerted expected effects on plasma and inflammatory exudate concentrations of cortisol and on blood glucose concentration and circulating leucocyte numbers, but it failed to affect exudate concentrations of the eicosanoids, prostaglandin E2, thromboxane B2, 6-keto-PGF1 alpha and leukotriene B4. These findings do not support the hypothesis that the anti-inflammatory actions of dexamethasone in the horse are mediated by inhibition of phospholipase A2.

Animals↗
PubMedDate not supplied

[The significance of mycotoxin assimilation for meat animals].

Mycotoxins may influence animal health and may be responsible for alterations in carcass composition and quality. Of major interest is the formation of residues in edible tissues, which had been demonstrated for the mycotoxins aflatoxin B1 and its metabolites, for ochratoxin A, zearalenone, as well as some trichothecenes. The amount of detectable residue depends on the initial feed contamination, duration of toxin exposure and persistence of the toxin within the animal the latter varying according to the species. Thus, residues of aflatoxins and ochratoxin A could be detected with a higher frequency than residues of trichothecenes which are rapidly metabolized and therefore only rarely contribute to a contamination of edible tissues. However, sufficient data for the evaluation of approximative carry over rates are not available for all mycotoxins. The majority of mycotoxins are heat tolerant and therefore a decomposition during cooking or processing is almost unlikely.

Animals↗