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Heise T.,Federal Institute for Risk Assessment BfR | Schmidt F.,Federal Institute for Risk Assessment BfR | Knebel C.,Federal Institute for Risk Assessment BfR | Rieke S.,Federal Institute for Risk Assessment BfR | And 5 more authors.
Archives of Toxicology | Year: 2014

The toxicological relevance of effects observed at molecular stage, which occur at dose levels well below classical no-observed adverse effect levels is currently subject to controversial scientific debate. While the importance of molecular effects for the identification of a mode of action or an adverse outcome pathway is undisputed, their impact for other regulatory purposes remains uncertain. Here, we report the results of a 28-day rat-feeding study including three widely used hepatotoxic (tri)azole fungicides (cyproconazole, epoxiconazole and prochloraz) administered individually at five dose levels, ranging from slightly above the reference values to a clear toxic effect dose. Parameters analysed included pathology, histopathology, clinical chemistry and particularly effects on the molecular level. Since azole fungicides are considered to cause liver toxicity by a mechanism involving the constitutive androstane receptor (CAR), a known CAR activator (phenobarbital, PB) was administered to investigate potential similarities between triazoles and PB-mediated liver toxicity by pathway-focused gene expression analysis. Our results show an increase in liver weights and additionally histopathological changes (hepatocellular hypertrophy) for all substances at the top dose levels. The effects on liver weight were most pronounced for cyproconazole by which also the animals receiving the next lower dose were affected. In addition, vacuolisation of hepatocytes was observed at the top dose level. No such findings were obtained with any substance at lower doses to which consumers and operators might be exposed to. In contrast, the expression of sensitive marker genes (like some cytochrome-P-450 isoforms) was significantly affected also at the lower dose levels. While some of these changes, like the induction of genes related to fatty acid and phospholipid metabolism (e.g. Fasn, Fat/Cd36, Ppargc1a) or xenobiotic metabolism (Cyp1a1, Cyp2b1, Cyp3a2), could be associated with high dose effects like hepatocellular vacuolisation or hypertrophy, a histopathological correlate was lacking for others. © 2014 Springer-Verlag Berlin Heidelberg. Source

Lenhard D.C.,Charite - Medical University of Berlin | May E.,Indication Expansion | Morgenroth C.,Bayer AG | Jost G.,Bayer AG | And 2 more authors.
Investigative Radiology | Year: 2014

Purpose: The aim of this preclinical study on healthy Sprague-Dawley rats was to determine whether differences exist in the induction of adverse skin reactions after the intravenous administration of a monomeric and 2 dimeric iodinated nonionic contrast agents. Materials and Methods: After intravenous injection of iopromide (monomeric), iodixanol (dimeric), and iotrolan (dimeric) at a dose of 4 g iodine/kg of body weight, mechanical ear volume measurements (10 minute after injection) and intravital microscopy (baseline, 5 minutes after injection) of the ear with the near-infrared dye indocyanine green were performed to determine the volume change and plasma extravasation. Histopathological analysis (20 minutes, 1 hour, and 3 hours after injection) was performed to diagnose alterations in the skin. Blood plasma was analyzed to identify elevated levels of histamine (5 minutes after injection) and inflammatory markers (a multianalyte profile of 58 markers; 1 hour and 3 hours after injection). Results: Only iodixanol induced immediate angioedema formation, with a 100% incidence rate and with slight mast cell infiltration in the ear, muzzle, and paws. The ear showed a 53% volume increase and strong extravasation of plasma proteins into the interstitium, which correlated with highly (11-fold) increased plasma histamine levels 5 minutes after injection. Elevated levels of tumor necrosis factor-α (7.1-fold), macrophage inflammatory protein (MIP)-1> (3.2-fold), and MIP-2 (7.7-fold) were identified 1 hour after the iodixanol injection. Increased levels (fold-change) of MIP-1β (14; 6.3), monocyte chemotactic protein-1 (3.3; 3.7), monocyte chemotactic protein-3 (2.4; 3.0), stem cell factor (1.7; 2), vascular endothelial growth factor (2; 2.1), and interferon gamma-induced protein-10 (4.1; 39.1) were identified 1 hour and 3 hours after the iodixanol administration, respectively. The level of these molecules remained unchanged after the iopromide and iotrolan injections (except for stem cell factor). Conclusions: A reversible anaphylactoid-like reaction in healthy Sprague-Dawley rats was observed after the iodixanol administration but not after the monomeric iopromide or dimeric iotrolan injections. Therefore, we conclude that the induction of adverse skin reactions is not per se because of a class effect of dimeric contrast agent. Copyright © 2014 by Lippincott Williams & Wilkins. Source

Wenzel J.,Max Delbruck Center for Molecular Medicine | Wenzel J.,Charite - Medical University of Berlin | Zeisig R.,Experimental Pharmacology and Oncology Berlin Buch GmbH EPO GmbH | Haider W.,Institute for Animal Pathology | Fichtner I.,Max Delbruck Center for Molecular Medicine
Breast Cancer Research and Treatment | Year: 2010

The process of metastasis formation in cancer is not completely understood and is the main reason cancer therapies fail. Previously, we showed that dual liposomes simultaneously containing the hemostatic inhibitor, dipyridamole and the anticancer drug, perifosine potently inhibited metastasis, causing a 90% reduction in the number of lung metastases in a murine experimental metastasis model. To gain deeper insight into the mechanisms leading to the inhibition of metastasis by these dual liposomes, in the present study, the development of metastases by MT3 breast cancer cells in a mouse xenograft model was analyzed in more detail with regard to tumor cell settlement and metastatic growth. We found that the development of lung metastases by MT3 tumor cells is essentially dependent on the formation of fibrin clots as a precondition for the pulmonary arrest of tumor cells and the subsequent intravascular expansion of micrometastases before their invasion into the surrounding tissue. © 2009 Springer Science+Business Media, LLC. Source

Lemos C.,Experimental and Clinical Research Center | Hardt M.S.,Experimental and Clinical Research Center | Juneja M.,Experimental and Clinical Research Center | Voss C.,Experimental and Clinical Research Center | And 5 more authors.
Clinical Cancer Research | Year: 2016

Purpose: We have previously identified the gene MACC1 as a strong prognostic biomarker for colorectal cancer metastasis and patient survival. Here, we report for the first time the generation of transgenic mouse models for MACC1. Experimental Design: We generated mice with transgenic overexpression of MACC1 in the intestine driven by the villin promoter (vil-MACC1) and crossed them with ApcMin mice (vil- MACC1/ApcMin). Results: vil-MACC1/ApcMin mice significantly increased the total number of tumors (P = 0.0056). This was particularly apparent in large tumors (3-mm diameter; P = 0.0024). A detailed histopathologic analysis of these lesions demonstrated that the tumors from the vil-MACC1/ApcMin mice had a more invasive phenotype and, consequently, showed a significantly reduced survival time than ApcMin mice (P = 0.03). Molecular analysis revealed an increased Wnt and pluripotency signaling in the tumors of vil-MACC1/ApcMin mice. Specifically, we observed a prominent upregulation of the pluripotency markers Oct4 and Nanog in these tumors compared with ApcMin controls. Finally, we could also validate that Oct4 and Nanog are regulated by MACC1 in vitro and strongly correlate with MACC1 levels in a cohort of 60 tumors of colorectal cancer patients (r = 0.7005 and r = 0.6808, respectively; P > 0.0001 and P > 0.0002, respectively). Conclusions: We provide proof of principle that MACC1- induced tumor progression in colorectal cancer acts, at least in part, via the newly discovered MACC1/Nanog/Oct4 axis. These findings might have important implications for the design of novel therapeutic intervention strategies to restrict tumor progression. Clin Cancer Res; 22(11); 2812-24. © 2016 American Association for Cancer Research. Source

Niemann L.,German Federal Institute for Risk Assessment | Haider W.,Institute for Animal Pathology | Grote K.,German Federal Institute for Risk Assessment | Grote K.,Institute for Clinical Pharmacology and Toxicology | Chahoud I.,Institute for Clinical Pharmacology and Toxicology
Avian Biology Research | Year: 2010

Histopathology proved a sensitive tool to detect adverse effects of environmental chemicals on testis morphology and function in Japanese quail even if there was no evidence of reduced fertility. This became apparent in one-generation studies with the fungicides vinclozolin and epoxiconazole in which microscopic findings, such as atrophy or epithelial degeneration, paralleled a reduction in spermatid count whereas testis weight was not altered and reproductive success not compromised at the same dose levels. In a study with methyl testosterone in which fertility was in fact reduced, lower spermatid count was accompanied by a strong decrease in testis weight. Histological examination of the testis and counting of spermatids might be suitable and sensitive methods to elucidate the mechanism if a male-mediated decline in reproductive success is suspected. Source

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