Genetic and Environmental Toxicology

The metabolism of xenobiotic substances occurs primarily in the liver via oxidations (cytochromes P-450) and conjugation reactions (i.e. with glutathione), and is called biotransformation. The metabolites generated should be more water soluble than the parent compounds and thus more readily excretable. In many cases, however, reactive metabolites are formed especially via the oxidative metabolism. These, for example epoxides, are capable of binding to DNA and as a consequence can lead to mutations. Examples of mutagens/carcinogens acting this way are aflatoxins, nitrosamines, polycyclic aromatic hydrocarbons such as benzo(a)pyrene, etc.


Mutagenicity testing

Since the site of formation of reactive metabolites should also be the site of primary damage, we developed a mutagenicity test with primary rat hepatocytes based on the endpoints sister chromatid exchanges= SCE, chromosomal aberrations and micronuclei. Compared to tests with mammalian and human cell lines even in the presence of liver microsomal fractions this test proved to be more sensitive - based on the endpoint SCE by a factor of at least 100. Due to this high sensitivity and the finding that DNA damage persists in the liver the following applications were developed: a) Testing of complex environmental mixtures such as surface and groundwater as well as aerosol samples, i.e. water samples from the Aral Sea b) Biomonitoring with feral rodents a) Dietary intake of mutagens b) Testing of antimutagenic effects of pure compounds or complex mixtures, i. e. herbal extracts


Oxidative Stress

The background rates of the analysed mutagenic effects in primary hepatocytes are significantly higher than those in established cell lines; based on the endpoint SCE this means a factor of 2 to 3. This difference could be demonstrated by us to be in part dependent on the diet. Mainly, however, oxidative stress in primary culture is responsible for this effect and is due to a change of the oxygen partial pressure from approximately 8% in vivo to approximately 17% in vitro. Supplementation of antioxidants such as the vitamines E and C therefore can reduce the background levels by almost 50%.

This high sensitivity towards oxidative stress appears not to depend on the excess of molecular oxygen itself but rather on lipid peroxidation products generated, especially 4-hydroxynonenal = HNE, since hepatocytes react more sensitive to it than other cells. The dose response relationships obtained with HNE are not linear. Instead, they represent saturation-type curves indicating that either there is a saturation of the damage induced or that adaptation to the stressor occurs.

Oxidative stress appears to play an important role in a variety of pathological events ranging from cancer to Alzheimer´s desease to tissue damages after stroke and ischemia. In the latter cases endothelial cells are thought to be important mediators. In cooperation with Hans Bauer from the Institute of Molecular Biology of the Austrian Academy of Sciences we were able to confirm the sensitivity of brain endothelial cells and astrocytes to HNE and hypoxia/reoxygenation. These investigations are currently extended to primary human astrocytes and astrocytoma cells in a cooperation with the Christian Doppler Clinics, Salzburg (Peter Strasser).


Antioxidants and the β-Carotene paradox

All aerobic forms of life maintain elaborate anti-free-radical defense systems, also known as antioxidant systems. Antioxidants are molecules which can interact with oxidising agents before other molecules are damaged. Every cell in the body has antioxidant enzymes, the specialty of which is reducing oxygen radicals and ROS.

As a second line of defense, the body makes use of vitamins and other nutrients to antagonize the oxygen radical effects. Among these ‘’nonenzymatic antioxidants’’, the major antioxidants are the lipid-soluble vitamins (vitamin E and carotenoids) and the water-soluble vitamin C.

Results obtained from experiments on animals indicate a cancer preventive effect of antioxidants. Antioxidants (β-carotene, vitamin C, E, and other substances), interact with free radicals and prevent the damages they may cause.

β-Carotene, a natural fat-soluble pigment, is a precursor of vitamin A (retinol) and is present in liver, egg yolk, milk, butter, spinach, carrots, squash, broccoli, yams, tomato, cantaloupe, peaches, grains, etc.. It is essential for normal growth and development.

Beside the beneficial effects of β-carotene, the epidemiological evidence for such a beneficial role of β-carotene could not be supported by several large scale, randomized supplementation trials. Strikingly, in two major trials cancer incidence was increased with β-carotene supplementation in both smokers and asbestos workers.

It was therefore hypothesized that heavy oxidative stress leads to degradation of β-carotene giving rise to the formation of high amounts of cleavage products with prooxidant properties. These cleavage products were tested in the primary rat hepatocyte assay and proved to have a genotoxic potential even at concentrations which can be achieved in vivo. Furthermore, β-carotene supplementation during oxidative stress, i.e. hypoxia/reoxygenation leads to a dose-dependent increase of genotoxic effects compared to standard culture conditions. Currently, a project funded by the FWF addresses the genotoxic potential of β-carotene in primary rat and human pneumocytes, and the nature of the cleavage products formed apart from those already identified.


Isolation and characterisation of apoptosis inclucing factors

In the normal liver, apoptosis is a rare event. However, it has been shown that apoptosis can be induced by a variety of environmental conditions (e.g. acute ischemia, reoxygenation after hypoxia, intoxications) but also by the activity of growth inhibitory factors such as TGF 1 , TNF or activation of the Fas pathway.

We have made the observation, that a conditioned medium which had been collected after the first three hours of primary hepatocyte culture (CM0-3) is able to induce prominent changes in cell morphology and reveals a time dependent apoptosis inducing activity in primary cultures of rat hepatocytes. These effects can be modulated by different growth promoting regimens. Notably, apoptosis induction can be inhibited by proliferative stimulation or treatment with dexamethasone, a synthetic corticosteroid which is known to stabilize differentiated hepatocyte functions. In addition, CM0-3 also induces apoptosis in transformed human hepatocytes (human hepatocarcinoma cells) even under culture conditions, which reduce apoptosis induction in cultures of primary (= non-transformed) rat hepatocyte cultures.

Since well known apoptosis inducers in hepatocytes (TGFβ , TNFα and FasL) could be excluded as candidates responsible for CM0-3 mediated apoptosis purified the apoptosis inducing activity. In collaboration with Prof. Lottspeich, MPI- Martinsried – Munich ferritin was identified as apoptosis inducer.



Ferritin, a regulator of the intracellular iron homeostasis, is a multimeric protein composed of 24 heavy (H) and light (L) chain subunits comprising tissue specific isoforms with varying ratios of heavy to light chains. Based on its composition, these ferritin isoforms can also be distinguished as basic (L-rich) and acidic (H-rich) isoferritins. Under normal conditions, cells release only small amounts of ferritin into the bloodstream, however, the serum levels of H-chain rich acidic isoferritins are increased during pregnancy and several pathological conditions such as acute lymphocytic leukemia, Hodgkin‘s disease, breast cancer and certain liver diseases.

Hepatocyte derived acidic isoferritins, which share homology with PLF (placental ferritin) and melanoma derived isoferritin, are able to stimulate apoptosis in hepatocytes by addressing the Fas pathway and intrinsic mitochondrial signalling mediated by the bcl-family member Bid.

Since ferritin is well known as an iron storage protein, it can be speculated that an increased release of Fe2+ from the protein leads to the formation of hydroxyl radicals via the Fenton reaction inducing lipid peroxidation. Lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE), are potent mutagens causing DNA damage and protein modification. Interestingly, HNE-modified proteins and micronuclei resulting from DNA damage were found in cultures of primary rat hepatocytes treated with acidic isoferritins. Furthermore HNE modified proteins colocalised with ferritin after immunohistochemical staining. These results clearly point to Fenton reaction driven oxidative stress in ferritin mediated apoptosis.

Growing evidence indicates oxidative stress as a mechanism of several pathological conditions originating from chronic inflammation such as hepatitis and hepatocellular carcinomas (HCC). Interestingly, levels of serum ferritin are markedly increased in hepatocarcinomas and certain liver diseases (hepatitis).

  • News
    Der Bücherbasar des Vereins für Humanitäre Aktionen der Universität Salzburg H.A.U.S. findet am FR 22. und SA 23.6. statt.
    „PISA, TIMSS &Co und die Folgen“: Wie können wir mit Ergebnissen der internationalen Bildungsforschung in der LehrerInnenbildung arbeiten?
    Menschliches Leben vollzieht sich in der Zeit, aber auch im Raum. Räume gelten als die dritten Erzieher und werden pädagogisch oft unterschätzt. In den Vorträgen und Arbeitskreisen der 67. Internationale Pädagogische Werktagung, die vom 09.–13. Juli 2018 in Salzburg stattfindet, wird u.a. erörtert: In welchen Räumen wachsen Kinder heute auf? Wie gehen wir mit digitalen Räumen um? Welche Räume sind pädagogisch besonders relevant? Wie steht es um innere Räume, Imaginationen und Fantasien?
    Rita Grandori hält am 25. Juni 2018 um 16 Uhr im Hörsaal 403 der NW-Fakultät einen Gastvortrag zum Thema "Protein conformational transitions and intermolecular interactions by native mass spectrometry and complementary biophysical methods". Der Fachbereich Biowissenschaften lädt herzlich dazu ein!
    Digital Humanities modellieren ein neues Setting für die Forschenden: Sie verändern die Wissensumwelt und schaffen zeitgemäße Zugänge für die Forschenden. Digital Humanities unterstützen Forschende, bieten neue Wege für etablierte Methoden, ermöglichen gesellschaftliche Teilhabe am Forschungsdiskurs. Lassen Sie uns gemeinsam daran arbeiten, das Netzwerk zwischen Disziplinen, Forschungsgegenständen und Forschenden zu stärken.
    Die 6. Salzburg Summer School findet vom 3. bis 4. September 2018 statt. Zwei Tage lang wird ein umfassendes pädagogisches Sommerfortbildungsprogramm für Lehrkräfte und Lehramtsstudierende aller Schulformen und Unterrichtsfächer angeboten. Anmeldungen sind möglich.
    Herr PD Dr. Reinhard Jung (Österreichische Akademie der Wissenschaften, OREA) hält am 26. Juni einen Vortrag zum Thema "Mykenisches Griechenland und Italien: verschiedene Arten des Gebens und Nehmens". Wann: 18.30 - Wo: Abguss-Sammlung SR E.33, Residenzplatz 1.
    Romana Limberger hält am 29. Juni 2018 um 14 Uhr im Hörsaal 421 der NW-Fakultät einen Gastvortrag zum Thema "Food Webs in Changing Environments". Der Fachbereich Biowissenschaften lädt herzlich dazu ein!
    Dank einer großzügigen Hinterlassenschaft seitens Herrn Kurt Zopf schreibt die Universität Salzburg den mit 10.000,-- Euro dotierten Kurt-Zopf-Förderpreis für habilitierte Angehörige der Universität aus. Die Ausschreibung dieses Jahres zielt auf die Fachgebiete "Naturwissenschaften", "Humanmedizin" und "Technische Wissenschaften" ab.
    Christoph Czerwenka hält am 27. Juni 2018 um 14:00 Uhr im Hörsaal 403 der NW-Fakultät einen Gastvortrag zum Thema "Lebensmittelkontaminanten – ständig neue Herausforderungen für den analytischen Chemiker". Der Fachbereich Biowissenschaften lädt herzlich dazu ein!
    Die Digitalisierung der Wirtschaft und Industrie 4.0 sind in aller Munde. Die kapitalistische Gesellschaft ist im Wandel und zugleich bleibt sie kapitalistisch. Was ist neu? Inwiefern lebt das Alte im Neuen fort? Wie können wir alle die technologischen Entwicklungen so gestalten, dass sie dem Wohl der gesamten Gesellschaft dienen? Die Referenten und Referentinnen sprechen diese Fragen aus unterschiedlichen Perspektiven an.
    Am Mittwoch, 27. Juni 2018 um 17 Uhr s.t. findet im HS 389 die Präsentation der 5. Ausgabe des Onlinemagazins historioPlus statt.
    Satyrchor contra „einsamstes Lied“. Zu Nietzsches Ästhetik des Chorischen
    Vom Hortus Medicus zur Pharmaforschung. Eine Ausstellung des Verbandes Botanischer Gärten 2018
    12. Juni – 10. Juli 2018 - enter: Raum für Kunst im KunstQuartier, Bergstraße 12a, 5020 Salzburg, Erdgeschoß
    Die KinderUNI sucht im Jubiläumsjahr TeilnehmerInnen der ersten Stunde! Wer war bei den ersten KinderUNIs hier in Salzburg im Jahr 2004 oder 2006 mit dabei?
    Freitag, 8. Juni: 09.45h KEYNOTE: Eliot Borenstein (New York): Plots against Russia: Conspiracy, Sincerity, and Propaganda // 17.30h ROUND TABLE: Why Do Conspiracy Theories Thrive in Post-Soviet Russia? mit Alexander Panchenko, Konstantin Bogdanov, Sergey Shtyrkov, Svetlana Tambovtseva (St. Petersburg) // Erzabt-Klotz-Str. 1, FB Slawistik, 3. Stock, Raum 3.409 //
    Ab sofort bis 3. Juli ist die Anmeldung zur ditact_women’s IT summer school der Universität Salzburg, die von 20. August bis 1. September am Unipark Nonntal und an der Fachhochschule Salzburg stattfindet, möglich.
    Bildung des Subjekts, Summerschool 4.-5. Juli 2018
    DANIEL FULDA (Martin-Luther-Universität Halle-Wittenberg) beschließt am 27. Juni um 18h im Unipark Nonntal die öffentliche Ringvorlesung AUFKLÄRUNG UND GEGENAUFKLÄRUNG: RELIGIÖSE POLEMIK GEGEN KUNST - KÜNSTLERISCHE POLEMIK GEGEN RELIGION mit seinem Gastvortrag über Sinnfülle und Sinnsuche in der Literatur der deutschen Aufklärung.
  • Veranstaltungen
  • 22.06.18 Kapitalismus 4.0: Digitalisierung - Finanzkapital - Alternativen
    26.06.18 Kanonische Texte
    26.06.18 Mykenisches Griechenland und Italien: verschiedene Arten des Gebens und Nehmens
    26.06.18 Satyrchor contra „einsamstes Lied“. Zu Nietzsches Ästhetik des Chorischen
    27.06.18 "Ich weiß nicht, ob dieser Glaube die Leute glücklich macht." Sinnfülle und Sinnsuche in der Literatur der deutschen Aufklärung
    28.06.18 Higher differentiability results in calculus of variations
    28.06.18 Salzburger Juristische Gesellschaft
  • Alumni Club
  • Uni-Shop
  • Facebook-Auftritt der Universität Salzburg Twitter-Auftritt der Universität Salzburg Instagram-Auftritt der Universität Salzburg Flickr-Auftritt der Universität Salzburg Vimeo-Auftritt der Universität Salzburg