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BackgroundColorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide and thus mouse models of CRC are of significant value to study the pathogenesis. The Azoxymethane/Dextran sulfate sodium (AOM/DSS) model is a widely used, robust initiation-promotion model for chemical induction of colitis-associated CRC in rodents. However, the dosage of chemicals, treatment regimens and outcome measures vary greatly among studies employing this model. Thus, the aim of this study was to examine an AOM/DSS model involving a reduced (1%) dose of DSS for induction of carcinogenesis in A/J and C57BL/6J (B6) mice.ResultsWe show that colonic preneoplastic lesions can be reliably detected in A/J and B6 mice by use of a AOM/DSS model involving a single injection of 10 mg/kg AOM followed by three 7-day cycles of a low-dose (1%) DSS administration. Supporting existing evidence of A/J mice exhibiting higher susceptibility to AOM than B6 mice, our AOM/DSS-treated A/J mice developed the highest number of large colonic lesions. Clinical symptoms in both strains subjected to the AOM/DSS treatment did not persist in-between treatment cycles, demonstrating that the animals tolerated the treatment well.ConclusionsOur findings suggest that a reduced dose of DSS in the AOM/DSS model can be considered in future studies of early phase colorectal carcinogenesis in the A/J and B6 mouse strains using preneoplastic lesions as an outcome measure, and that such regimen may reduce the risk of early trial terminations to accommodate human endpoints. Overall, our data emphasize the importance of devoting attention towards choice of protocol, outcome measures and mouse strain in studies of CRC in mice according to the study purpose.

Telomere shortening can result in cellular senescence and in increased level of genome instability, which are key events in numerous of cancer types. Despite this, few studies have focused on the effect of nanomaterial exposure on telomere length as a possible mechanism involved in nanomaterial-induced carcinogenesis. In this study, effects of exposure to multiwalled carbon nanotubes (MWCNT) on telomere length were investigated in mice exposed by intrapleural injection, as well as in human lung epithelial and mesothelial cell lines. In addition, cell cycle, apoptosis, and regulation of genes involved in DNA damage repair were assessed. Exposure to MWCNT led to severe fibrosis, infiltration of inflammatory cells in pleura, and mesothelial cell hyperplasia. These histological alterations were accompanied by deregulation of genes involved in fibrosis and immune cell recruitment, as well as a significant shortening of telomeres in the pleura and the lung. Assessment of key carcinogenic mechanisms in vitro confirmed that long-term exposure to the long MWCNT led to a prominent telomere shortening in epithelial cells, which coincided with G1-phase arrest and enhanced apoptosis. Altogether, our data show that telomere shortening resulting in cell cycle arrest and apoptosis may be an important mechanism in long MWCNT-induced inflammation and fibrosis.

The ability of persistent organic pollutants (POPs) with endocrine disrupting properties to interfere with the developing reproductive system is of increasing concern. POPs are transferred from dams to offspring and the high sensitivity of neonates to endocrine disturbances may be caused by underdeveloped systems of metabolism and excretion. The present study aimed to characterize the effect of in utero and lactational exposure to a human relevant mixture of POPs on the female mammary gland, ovarian folliculogenesis and liver function in CD-1 offspring mice. Dams were exposed to the mixture through the diet at Control, Low or High doses (representing 0x, 5000x and 100 000x human estimated daily intake levels, respectively) from weaning and throughout mating, gestation, and lactation. Perinatally exposed female offspring exhibited altered mammary gland development and a suppressed ovarian follicle maturation. Increased hepatic cytochrome P450 enzymatic activities indirectly indicated activation of nuclear receptors and potential generation of reactive products. Hepatocellular hypertrophy was observed from weaning until 30 weeks of age and could potentially lead to hepatotoxicity. Further studies should investigate the effects of human relevant mixtures of POPs on several hormones combined with female reproductive ability and liver function.

An increased risk of developing colorectal cancer has been associated with exposure to persistent organic pollutants (POPs) and alteration in the gut bacterial community. However, there is limited understanding about the impact of maternal exposure to POPs on colorectal cancer and gut microbiota. This study characterized the influence of exposure to a human relevant mixture of POPs during gestation and lactation on colorectal cancer, intestinal metabolite composition and microbiota in the A/J Min/+ mouse model. Surprisingly, the maternal POP exposure decreased colonic tumor burden, as shown by light microscopy and histopathological evaluation, indicating a restriction of colorectal carcinogenesis. 1H nuclear magnetic resonance spectroscopy-based metabolomic analysis identified alterations in the metabolism of amino acids, lipids, glycerophospholipids and energy in intestinal tissue. In addition, 16S rRNA sequencing of gut microbiota indicated that maternal exposure modified fecal bacterial composition. In conclusion, the results showed that early-life exposure to a mixture of POPs reduced colorectal cancer initiation and promotion, possibly through modulation of the microbial and biochemical environment. Further studies should focus on the development of colorectal cancer after combined maternal and dietary exposures to environmentally relevant low-dose POP mixtures.

Sudden unexpected death in epilepsy (SUDEP) is a significant cause of premature seizure-related death. An association between SUDEP and cardiac remodeling has been suggested. However, whether SUDEP is a direct consequence of acute or recurrent seizures is unsettled. The purpose of this study was to evaluate the impact of status epilepticus (SE) and chronic seizures on myocardial structure and function. We used the intracortical kainate injection model of temporal lobe epilepsy to elicit SE and chronic epilepsy in mice. In total, 24 C57/BL6 mice (13 kainate, 11 sham) were studied 2 and 30 days post-injection. Cardiac structure and function were investigated in-vivo with a 9.4 T MRI, electrocardiography (ECG), echocardiography, and histology [Haematoxylin/Eosin (HE) and Martius Scarlet Blue (MSB)] for staining of collagen proliferation and fibrin accumulation. In conclusion, we did not detect any significant changes in cardiac structure and function neither in mice 2 days nor 30 days post-injection.

A multitude of cancer types, including breast, testicular, liver and colorectal cancer, have associations with exposure to Persistent Organic Pollutants (POPs). The present study aimed to investigate whether a mixture of POPs could affect intestinal tumorigenesis in the A/J Min/+ mouse, a model for human colorectal cancer (CRC). Pollutants were selected for their presence in Scandinavian food products and the mixture was designed based on defined human estimated daily intake levels. Mice were exposed through the diet, at control, low and high mixture concentrations, for 10 weeks. In a separate experiment, mice also received one subcutaneous injection of Azoxymethane (AOM) to explore whether this carcinogenic compound influenced the effect of the POPs. Intestinal tumorigenesis was examined by surface microscopy and histopathology. Moderate and dose-dependent increases in tumorigenesis were observed after dietary POP exposure. The AOM treatment alone stimulated the growth of colonic lesions, but did not increase the formation of new lesions. Combined AOM treatment and POP exposure demonstrated a synergistic effect on lesion formation in the colon, and to a lesser extent in the small intestine. This synergy was also evident by an increased number of malignant colonic tumors (carcinomas). In conclusion, the study shows that a mixture of POPs interacted synergistically with a known carcinogen (AOM), causing increased intestinal tumorigenesis in the A/J Min/+ mouse model.

Upon inhalation, multi-walled carbon nanotubes (MWCNTs) may reach the subpleura and pleural spaces, and induce pleural inflammation and/or mesothelioma in humans. However, the mechanisms of MWCNT-induced pathology after direct intrapleural injections are still only partly elucidated. In particular, a role of the proinflammatory interleukin-1 (IL-1) cytokines in pleural inflammation has so far not been published. We examined the MWCNT-induced pleural inflammation, gene expression abnormalities, and the modifying role of IL-1α and β cytokines following intrapleural injection of two types of MWCNTs (CNT-1 and CNT-2) compared with crocidolite asbestos in IL-1 wild-type (WT) and IL-1α/β KO (IL1-KO) mice. Histopathological examination of the pleura 28 days post-exposure revealed mesothelial cell hyperplasia, leukocyte infiltration, and fibrosis occurring in the CNT-1 (Mitsui-7)-exposed group. The pleura of these mice also showed the greatest changes in mRNA and miRNA expression levels, closely followed by CNT-2. In addition, the CNT-1-exposed group also presented the greatest infiltrations of leukocytes and proliferation of fibrous tissue. WT mice were more prone to development of sustained inflammation and fibrosis than IL1-KO mice. Prominent differences in genetic and epigenetic changes were also observed between the two genotypes. In conclusion, the fibrotic response to MWCNTs in the pleura depends on the particles' physico-chemical properties and on the presence or absence of the IL-1 genes. Furthermore, we found that CNT-1 was the most potent inducer of inflammatory responses, followed by CNT-2 and crocidolite asbestos.

International audience; The amount, distribution and phenotype of ovine NCR1+ cells were investigated during developing GALT from day 70 of gestation. Antibodies against CD3 and CD79 were used to identify the compartments of GALT, and the localization of NCR1+ cells were correlated within these structures. Markers CD34 and c-kit, in addition to Ki67, were used to investigate possible origin and the stage of development of the NCR1+ cells. NCR1+ cells were present as single cells in the subepithelial tissue as early as 70 days of gestation, and were predominantly present in the T cell rich IFAs and domes as these intestinal wall compartments developed. While NCR1+ cells proliferated more intensively at mid-gestation (70-104 days), the number of NCR1+ cells also expressing c-kit, increased at the end of gestation. In conclusion, NCR1+ cells appeared early in T cell areas of the gut and displayed a phenotype consistent with intermediate stages of cNK cells and/or a subpopulation of ILC22. (C) 2016 Elsevier B.V. All rights reserved.