A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens

Distinguishing between clastogens and aneugens is vital in cancer risk assessment because the default assumption is that clastogens and aneugens have linear and non-linear dose-response curves, respectively. Any observed non-linearity must be supported by mode of action (MOA) analyses where biological mechanisms are linked with dose-response evaluations. For aneugens, the MOA has been well characterised as disruptors of mitotic machinery where chromosome loss via micronuclei (MN) formation is an accepted endpoint used in risk assessment. In this study we performed the cytokinesis-block micronucleus assay and immunofluorescence mitotic machinery visualisation in human lymphoblastoid (AHH-1) and Chinese Hamster fibroblast (V79) cell lines after treatment with the aneugen 17-β-oestradiol (E₂). Results were compared to previously published data on bisphenol-A (BPA) and Rotenone data. Two concentration-response approaches (the threshold-[Td] and benchmark-dose [BMD] approaches) were applied to derive a point of departure (POD) for in vitro MN induction. BMDs were also derived from the most sensitive carcinogenic endpoint. Ranking comparisons of the PODs from the in vitro MN and the carcinogenicity studies demonstrated a link between these two endpoints for BPA, E₂ and Rotenone. This analysis was extended to include 5 additional aneugens, 5 clastogens and 3 mutagens and further concentration and dose-response correlations were observed between PODs from the in vitro MN and carcinogenicity. This approach is promising and may be further extended to other genotoxic carcinogens, where MOA and quantitative information from the in vitro MN studies could be used in a quantitative manner to further inform cancer risk assessment

Laten we Irak onze ISIS-gangers maar ophangen?

In Irak zijn deze week zes Franse ISIS-leden veroordeeld tot de dood door ophanging. De Europese landen laten Irak en vooral de Syrische Koerden zitten met westerse ISIS-strijders, én met de vrouwen en kinderen. Dat kan op den duur gevaarlijk zijn, zeggen deskundigen.Security and Global Affair

Dampened Transient Actuation of Hydrogels Autonomously Controlled by pH-Responsive Bicontinuous Nanospheres

The fabrication of a soft actuator with a dampened actuation response is presented. This was achieved via the incorporation into an actuating hydrogel of urease-loaded pH-responsive bicontinuous nanospheres (BCNs), whose membrane was able to regulate the permeability and thus conversion of fuel urea into ammonia. The dampened response of these nanoreactors to the enzymatically induced pH change was translated to a pH-responsive soft actuator. In hydrogels composed of a pH-responsive and nonresponsive layer, the transient pH gradient yielded an asymmetric swelling behavior, which induced a bending response. The transient actuation profile could be controlled by varying the external fuel concentrations. Furthermore, we showed that the spatial organization of the BCNs within the actuator had a great influence on the actuation response. Embedding the urease-loaded nanoreactors within the active, pH-responsive layer resulted in a reduced response due to local substrate conversion in comparison to embedding them within the passive layer of the bilayer hydrogel. Finally, we were able to induce transient actuation in a hydrogel comprising two identical active layers by the immobilization of the BCNs within one specific layer. Upon addition of urea, a local pH gradient was generated, which caused accelerated swelling in the BCN layer and transient bending of the device before the pH gradient was attenuated over time.</p

Symbolic Model Checking for Dynamic Epistemic Logic

Dynamic Epistemic Logic (DEL) can model complex information scenarios in a way that appeals to logicians. However, existing DEL implementations are ad-hoc, so we do not know how the framework really performs. For this purpose, we want to hook up with the best available model-checking and SAT techniques in computational logic. We do this by first providing a bridge: a new faithful representation of DEL models as so-called knowledge structures that allow for symbolic model checking. Next, we show that we can now solve well-known benchmark problems in epistemic scenarios much faster than with existing DEL methods. Finally, we show that our method is not just a matter of implementation, but that it raises significant issues about logical representation and update

Prediction of carcinogenic potential of chemicals using repeated-dose (13-week) toxicity data

AbstractSub-chronic toxicity studies of 163 non-genotoxic chemicals were evaluated in order to predict the tumour outcome of 24-month rat carcinogenicity studies obtained from the EFSA and ToxRef databases. Hundred eleven of the 148 chemicals that did not induce putative preneoplastic lesions in the sub-chronic study also did not induce tumours in the carcinogenicity study (True Negatives). Cellular hypertrophy appeared to be an unreliable predictor of carcinogenicity. The negative predictivity, the measure of the compounds evaluated that did not show any putative preneoplastic lesion in de sub-chronic studies and were negative in the carcinogenicity studies, was 75%, whereas the sensitivity, a measure of the sub-chronic study to predict a positive carcinogenicity outcome was only 5%. The specificity, the accuracy of the sub-chronic study to correctly identify non-carcinogens was 90%. When the chemicals which induced tumours generally considered not relevant for humans (33 out of 37 False Negatives) are classified as True Negatives, the negative predictivity amounts to 97%. Overall, the results of this retrospective study support the concept that chemicals showing no histopathological risk factors for neoplasia in a sub-chronic study in rats may be considered non-carcinogenic and do not require further testing in a carcinogenicity study

Comparison of clastogen-induced gene expression profiles in wild-type and DNA repair-deficient Rad54/Rad54B cells

Background: Previously we found that Rad54/Rad54B cells are more sensitive towards mitomycin C (MMC) as compared to wild-type (WT) cells. This difference in sensitivity was absent upon exposure to other clastogens like bleomycin (BLM) and g-radiation. In order to get further insight into possible underlying mechanisms, gene expression changes in WT and Rad54/Rad54B MEFs (mouse embryonic fibroblasts) after exposure to the clastogens MMC and BLM were investigated. Exposures of these cells to mutagens (N-ac-AAF and ENU) and vehicle were taken as controls. Results: Most exposures resulted in an induction of DNA damage signaling and apoptosis genes and a reduced expression of cell division genes in cells of both genotypes. As expected, responses to N-ac-AAF were very similar in both genotypes. ENU exposure did not lead to significant gene expression changes in cells of both genotypes, presumably due to its short half-life. Gene expression responses to clastogens, however, showed a genotype-dependent effect for BLM and MMC. MMC treated Rad54/Rad54B MEFs showed no induction of p53-signaling, DNA damage response and apoptosis as seen for all the other treatments. Conclusion: These data support our finding that different types of clastogens exist and that responses to these types depend on the DNA repair status of the cells.Toxicogenomics and risk assessmen

Benzo(a)pyrene induces similar gene expression changes in testis of DNA repair proficient and deficient mice

<p>Abstract</p> <p>Background</p> <p>Benzo [a]pyrene (B[a]P) exposure induces DNA adducts at all stages of spermatogenesis and in testis, and removal of these lesions is less efficient in nucleotide excision repair deficient <it>Xpc</it>^-/-mice than in wild type mice. In this study, we investigated by using microarray technology whether compromised DNA repair in <it>Xpc</it>^-/-mice may lead to a transcriptional reaction of the testis to cope with increased levels of B[a]P induced DNA damage.</p> <p>Results</p> <p>Two-Way ANOVA revealed only 4 genes differentially expressed between wild type and <it>Xpc</it>^-/-mice, and 984 genes between testes of B[a]P treated and untreated mice irrespective of the mouse genotype. However, the level in which these B[a]P regulated genes are expressed differs between Wt and <it>Xpc</it>^-/-mice (p = 0.000000141), and were predominantly involved in the regulation of cell cycle, translation, chromatin structure and spermatogenesis, indicating a general stress response. In addition, analysis of cell cycle phase dependent gene expression revealed that expression of genes involved in G1-S and G2-M phase arrest was increased after B[a]P exposure in both genotypes. A slightly higher induction of average gene expression was observed at the G2-M checkpoint in <it>Xpc</it>^-/-mice, but this did not reach statistical significance (P = 0.086). Other processes that were expected to have changed by exposure, like apoptosis and DNA repair, were not found to be modulated at the level of gene expression.</p> <p>Conclusion</p> <p>Gene expression in testis of untreated <it>Xpc</it>^-/-and wild type mice were very similar, with only 4 genes differentially expressed. Exposure to benzo(a)pyrene affected the expression of genes that are involved in cell cycle regulation in both genotypes, indicating that the presence of unrepaired DNA damage in testis blocks cell proliferation to protect DNA integrity in both DNA repair proficient and deficient animals.</p