Biomedical subjects

Jürgen Hellmann

Publications and source records attributed to Jürgen Hellmann.

3 recordsLinked to original sources

PubMed2005

Use of two-dimensional gel electrophoresis in predictive toxicology: identification of potential early protein biomarkers in chemically induced hepatocarcinogenesis.

Our current approach focused on the identification of potential early protein biomarker signatures which are indicative of the carcinogenic processes in rats exposed to 20 mg/kg of the liver carcinogen N-nitrosomorpholine (NNM). Treated liver was investigated at different timepoints. Therefore, proteins were separated by two-dimensional gel electrophoresis as a first step prior to identification of differentially expressed proteins by mass spectrometry. Proteomic analysis of liver samples after one day of exposure revealed significant upregulation of proteins involved in response to cellular stress induced by NNM (superoxide dismutase, heat shock protein 60, peroxiredoxin). Eighteen weeks after withdrawal of NNM, we were able to identify cancer-related proteins in rat liver bearing malignant, transformed cells (caspase-8 precursor, vimentin, Rho GDP dissociation inhibitor). Some of these proteins were already deregulated after three weeks of exposure indicating their potential usefulness as early predictive biomarkers for liver carcinogenicity (annexin A5, fructose-1,6-bisphosphatase). As regulatory toxicology approaches usually include the investigation of carcinogenicity in two-years studies in rodents, especially the detection of early protein biomarker signatures which precede the appearance of neoplasia, demonstrates the high potential of proteomics approaches to substantially reduce the time and costs of carcinogenicity testing.

Animals↗

PubMed2004

Revised guides for organ sampling and trimming in rats and mice--Part 3. A joint publication of the RITA and NACAD groups.

This is the third part of a series of three articles on trimming instructions of rat and mouse protocol organs and tissues in regulatory type toxicity studies, covering the urinary, nervous, musculoskeletal, cardiovascular, and lymphoreticular systems. The article is based on the experience of the European RITA and American NACAD working groups and is an extended revision of trimming guides published in 1995 (BAHNEMANN et al.). The optimum localization for tissue preparation, the sample size, the direction of sectioning and the number of sections to be prepared is described organ by organ. These descriptions are illustrated for each organ by a schematic drawing and/or a macro-photograph showing the plane of section as well as a low magnification of the H&E stained slide demonstrating the optimum "end-product". The objectives of this work, as addressed in detail in the first part (Ruehl-Fehlert et al. 2003), are to standardize tissue sampling and trimming for comparison of historical data obtained from different studies and different laboratories, ensure the presence of all relevant target sites for histopathological evaluation and provide technical advice for preparatory techniques during necropsy, fixation and trimming (Crissman et al. 2004).

Animals↗

PubMed2004

[Toxicoproteomics: first experiences in a BMBF-study].

The rapid development of molecular toxicology is providing innovative approaches to an improved investigation and recognition of toxic substances. Proteome analysis offers, with 2DE/MS (two-dimensional gel electrophoresis and mass spectrometry) and SELDI (surface enhanced laser desorption/ionisation), a promising discipline to classify molecular changes caused by toxic exposure. The Rat Liver Foci Bioassay (RLFB) is a detailed, well-described model for the investigation of liver carcinogenesis induced by chemical substances. Based on this model, we examined whether proteomic methods of molecular toxicology can be used for the early recognition of toxic and/or carcinogenic characteristics of toxic substances. In addition, identification and subsequent prevalidation of new hepatocellular biomarkers was performed, enabling better prediction of toxic and/or carcinogenic effects. This could lead to a more meaningful RLFB and thus to an improved risk assessment of chemicals. 2DE analysis in this study showed that deregulated proteins are assigned to mainly anabolic and catabolic metabolism pathways in the cell. Beyond this, individual proteins were identified which play a key role in the carcinogenic process. A comparison of the differentially expressed proteins in tissue from tumour-bearing animals and tissue derived from the start of the study revealed that protein expression changes (biomarkers) were already detectable shortly after exposure. In addition, analysis by SELDI clearly showed several differentially expressed proteins and/or derived masses. The spectra represented specific differences in tissues, which could be assigned to the same histopathological endpoints. With bioinformatics analysis it was possible to identify individual discriminating mass peaks, which were indicative of tumour formation. Group specific changes can be illustrated and/or represented in more detail with further cluster analysis methods. These results give hope for an improved prediction of hepatotoxicity and carcinogenicity by means of protein markers, which could in the future lead to a shortening of carcinogenicity studies and to a reduction in the use of experimental animals.

Animals↗