Showing papers by "Franz Oesch published in 2009"
TL;DR: It is concluded that experiences with other, non-nano, substances taught us that mechanisms of genotoxic effects can be diverse and their elucidation can be demanding, while there often is an immediate need to assess the genotoxicity hazard.
Abstract: Nanomaterials display novel properties to which most toxicologists have not consciously been exposed before the advent of their practical use. The same properties, small size and particular shape, large surface area and surface activity, which make nanomaterials attractive in many applications, may contribute to their toxicological profile. This review describes what is known about genotoxicity investigations on nanomaterials published in the openly available scientific literature to-date. The most frequently used test was the Comet assay: 19 studies, 14 with positive outcome. The second most frequently used test was the micronucleus test: 14 studies, 12 of them with positive outcome. The Ames test, popular with other materials, was less frequently used (6 studies) and was almost always negative, the bacterial cell wall possibly being a barrier for many nanomaterials. Recommendations for improvements emerging from analyzing the reports summarized in this review are: Know what nanomaterial has been tested (and in what form); Consider uptake and distribution of the nanomaterial; Use standardized methods; Recognize that nanomaterials are not all the same; Use in vivo studies to correlate in vitro results; Take nanomaterials specific properties into account; Learn about the mechanism of nanomaterials genotoxic effects. It is concluded that experiences with other, non-nano, substances (molecules and larger particles) taught us that mechanisms of genotoxic effects can be diverse and their elucidation can be demanding, while there often is an immediate need to assess the genotoxic hazard. Thus a practical, pragmatic approach is the use of a battery of standard genotoxicity testing methods covering a wide range of mechanisms. Application of these standard methods to nanomaterials demands adaptations and the interpretation of results from the genotoxicity tests may need additional considerations. This review should help to improve standard genotoxicity testing as well as investigations on the underlying mechanism and the interpretation of genotoxicity data on nanomaterials.
356 citations
TL;DR: It is found that AHR is sensitive to cAMP signaling mediated by cAMP-dependent protein kinase (PKA) which fundamentally differs from AHR signalingmediated by the exogenous ligand dioxin.
46 citations
TL;DR: It is shown that TCDD treatment of rat liver oval cells leads to induction of the transcription factor JunD, resulting in transcriptional upregulation of the proto-oncogene cyclin A which finally triggers a release from contact inhibition.
Abstract: The aryl hydrocarbon receptor (AhR) is a transcription factor involved in physiological processes, but also mediates most, if not all, toxic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Activation of the AhR by TCDD leads to its dimerization with ARNT and transcriptional activation of several phase I and II metabolising enzymes However, this classical signalling pathway so far failed to explain the pleiotrophic hazardous effects of TCDD such as developmental toxicity and tumour promotion Thus, there is an urgent need to define genetic programmes orchestrated by AhR to unravel its role in physiology and toxicology Treatment of rat liver oval cells with TCDD leads to a release from contact-inhibition Loss of contact-inhibition is one characteristic hallmark in tumourigenesis We have recently shown that TCDD-exposure leads to an elevation of JunD protein levels and to transcriptional activation of Cyclin A in an AhR-dependent, and probably ARNT-independent way Ectopic expression of Cyclin A in confluent cultures overcomes G1-arrest indicating that increased Cyclin A levels are indeed sufficient to bypass contact-inhibition Elevation of JunD precedes that of Cyclin A suggesting a role of JunD in Cyclin A induction Indeed, down-regulating JunD by siRNA blocks TCDD-induced expression of Cyclin A DNA affinity purification assays and reporter gene analysis indicate that JunD binds to an ATF/CRE consensus sequence in the rat Cyclin A promoter Using in vitro DNA affinity purification assays, we also revealed binding of ATF2, but not Fra- or Fos-proteins, to the ATF/CRE consensus sequence Down-regulating ATF2 by siRNA blocks TCDD-dependent Cyclin A induction indicating that ATF2 is the interaction partner of JunD mediating Cyclin A expression In summary, we have discovered in rat liver oval cells a novel AhR-dependent and probably ARNT-independent signalling pathway involving JunD/ATF2 and Cyclin A, which mediates deregulation of contact-inhibition by TCDD
45 citations
TL;DR: In Hepa-c7 cells AhR has no major effects on the expression of these crucial NER proteins and does not prevent genotoxin-provoked cell death, and these findings suggest cell type, species or lesion specific actions of p53 on DNA repair gene expression.
23 citations
TL;DR: Th e author thanks ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: Food Quality and Safety for financial support.
Abstract: Th e author thanks ECNIS (Environmental Cancer,
Nutrition and Individual Susceptibility), a network of
excellence operating within the European Union 6th
Framework Program, Priority 5: Food Quality and Safety
(Contract no. 513943) for financial support.
7 citations
TL;DR: By virtue of their contribution to the control of carcinogenic metabolites such modulators can act as modifiers of tumorigenesis and can be used experimentally to study the role of the various individual enzymes.
Abstract: One of the structural elements which are widely occurring in very many chemical mutagens and carcinogens are aromatic and olefinic moieties. These can be transformed into epoxides by microsomal monooxygenases. Such epoxides may spontaneously react with nucleophilic centers in the cell and thereby covalently bind to DNA, RNA and protein. Such a reaction may lead to cytotoxicity, allergy, mutagenicity and/or carcinogenicity, depending on the properties of the epoxide in question. An important contributing factor is the presence of enzymes controlling the concentration of such epoxides. There are several microsomal monooxygenases which differ in activity and substrate specificity. With large substrates, some monooxygenases preferentially attack at one specific site different from that attacked by others. Some of these pathways lead to reactive products, others are detoxification pathways. Also important are the enzymes which metabolize epoxides, such as epoxide hydrolases and glutathione transferases. Such enzymes can act as inactivating and in some specific cases also as co-activating enzymes. Moreover, precursor-sequestering enzymes such as dihydrodiol dehydrogenase, glucuronosyl transferases and sulphotransferases are important for the control of reactive epoxides. These enzymes themselves are subject to control by many endogenous and exogenous factors. By virtue of their contribution to the control of carcinogenic metabolites such modulators can act as modifiers of tumorigenesis and can be used experimentally to study the role of the various individual enzymes.
6 citations
TL;DR: No reduction of the hOGG1 repair activity after acute exposure to 50 ppm toluene was observed, and upon exposure to air a statistically insignificant median increase of hogG1 activity was determined.
Abstract: The structure and previous studies on the biotransformation of toluene lead to the suspicion that metabolites may be formed which preferentially react with strongly nucleophilic partners such as sulfhydryl groups of cysteines in proteins. Human 8-oxoguanine DNA glycosylase 1 removes the major oxidative DNA damage and possesses eight cysteines. Its potential inactivation may lead to accumulation of DNA damage by reactive oxygen species formed by exogenous agents or by ubiquitous endogenous processes. The goal of the present investigation was to study the in vivo effect in humans of an acute toluene exposure on hOGG1 activity. Twenty healthy, non-smoking males were exposed to 50 ppm toluene and to filtered air in an exposure chamber for 270 min, using a cross-over design. Before and 30 min after the end of exposure, blood samples were taken and toluene concentrations and the hOGG1 activity were measured. hOGG1 activity was determined in peripheral mononuclear blood cells. Thirty minutes after exposure to toluene, we found a median blood concentration of 0.25 mg toluene/l. Compared with the activity before exposure, upon exposure to toluene a statistically insignificant median increase of hOGG1 activity by +0.4% and upon exposure to air by +2.3% was determined. Thus, no reduction of the hOGG1 repair activity after acute exposure to 50 ppm toluene was observed.
3 citations
TL;DR: Circadian rhythm is an integral and not replaceable part of the organism's homeostasis, overlooking global networks such as chromatin remodelling, cell cycle, DNA damage and repair as well as nuclear receptors function.
Abstract: Circadian rhythm is an integral and not replaceable part of the organism's homeostasis. Its signalling is multidimensional, overlooking global networks such as chromatin remodelling, cell cycle, DNA damage and repair as well as nuclear receptors function. Understanding its global networking will allow us to follow up not only organism dysfunction and pathology (including chemical carcinogenesis) but well-being in general having in mind that time is not always on our side.
3 citations