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Zinc (Zn) is one of the most essential trace elements in the body and an integral part of many enzyme systems. Zn deficiency is characterized by growth retardation, loss of appetite, and impaired immune function. In contrast, Zn overdoses can be associated with liver, kidney, and stomach damage. We focused on the "chronotoxicity," or the relationship between injection time and severity of chemical toxicity. The aim of this study was to investigate the chronotoxicity of Zn and the in vivo factors involved. Seven-week-old male ICR mice were administered Zn at six different time points per day (zeitgeber time [ZT]: ZT2, ZT6, ZT10, ZT14, ZT18, and ZT22). Mortality was monitored for 7-days after administration. The mice were tolerant to Zn administered at ZT2 and ZT6, and were highly sensitive at ZT14 and ZT18. Furthermore, when mice were administered a non-lethal dose of Zn, the levels of hepatic injury indicators (AST and ALT) were much higher at ZT14 than at ZT2. To explore the mechanism of Zn-induced diurnal hepatotoxicity, we performed an in vitro experiment, focusing on the clock genes. We found that Zn downregulated the expression levels of several clock genes, neuronal PAS domain protein 2 (Npas2) and Peroid2 (Per2), in Hepa1-6 cells. Interestingly, overexpression of both Npas2 and Per2 restored Zn-induced toxicity in Hepa1-6 cells. Since NPAS2 and PER2 are known to modulate the hepatic injury induced by carbon tetrachrolide or acetaminophen, our results suggest that Zn-induced diurnal toxicity may be associated with modulation of Npas2 and Per2 gene expression. [ABSTRACT FROM AUTHOR]

Many approaches have been taken to identify new biomarkers of pancreatic ductal carcinoma (PDC). Since animal models can be sampled under controlled conditions, better standardization is possible compared with heterogeneous human studies. Transgenic rats with conditional activation of oncogenic RAS in pancreatic tissue develop PDC that closely resembles the biological and histopathological features of human PDC. Using this model, we evaluated the usefulness of leucine-rich α2-glycoprotein-1 (LRG-1) as a serum marker. In this study, we found that LRG-1 was overexpressed in rat PDC compared with normal pancreas tissue of the control rats. Serum levels of LRG-1 were also significantly higher in rats bearing PDC than in controls. Importantly, chronic pancreatitis in male Wistar Bonn/Kobori rats, which is a widely accepted as a model of chronic pancreatitis, did not cause serum levels of LRG-1 to become elevated. These results strongly support serum LRG-1 as a candidate biomarker for noninvasive diagnosis of PDC. Our models of pancreas cancer provide a useful strategy for evaluation of candidate markers applicable to human cancer. [ABSTRACT FROM AUTHOR]

The aim of the present study is to investigate the "chronotoxicity"of seven metal compounds (Hg, Pb, Ni, Cr, Cu, Zn, or Fe) by assessing how their toxicity varies with circadian periodicity. Male ICR mice were injected with each metal compound intraperitoneally at 6 different time points over the course of a day (zeitgeber time [ZT]: ZT2, ZT6, ZT10, ZT14, ZT18 and ZT22). Mortality was then monitored until 14 days after the injection. Our investigation demonstrated that mice were tolerant against Ni toxicity during dark phase, on the other hand, they were tolerant against Cr toxicity during light phase. The chronotoxicity of Hg and Pb seemed to be biphasic. Further, mice were susceptible to toxicities against Cu and Zn in the time zone during which light and dark were reversed. Interestingly, no significant differences were observed for Fe exposure at any time of the day. Our results propose that the chronotoxicology may provide valuable information regarding the importance of injection timing for not only toxicity evaluation tests but also the reproducibility of animal experiments. Furthermore, our data suggests that chronotoxicology may be an important consideration when evaluating the quality of risk assessments for night shift workers who may be exposed to toxic substances at various times of the day. [ABSTRACT FROM AUTHOR]

Genetically manipulated organisms with dysfunction of specific tissues are crucial for the study of various biological applications and mechanisms. However, the bioengineering of model organisms with tissue-specific dysfunction has not progressed because the challenges of expression of proteins, such as cytotoxins, in living cells of individual organisms need to be overcome first. Here, we report the establishment of a transgenic silkworm (Bombyx mori) with posterior silk glands (PSGs) that was designed to express the cabbage butterfly (Pieris rapae) cytotoxin pierisin-1A (P1A). P1A, a homolog of the apoptosis inducer pierisin-1, had relatively lower DNA ADP ribosyltransferase activity than pierisin-1; it also induced the repression of certain protein synthesis when expressed in B. mori-derived cultured cells. The transgene-derived P1A domain harboring enzymatic activity was successfully expressed in the transgenic silkworm PSGs. The glands showed no apoptosis-related morphological changes; however, an abnormal appearance was evident. The introduced truncated P1A resulted in the dysfunction of PSGs in that they failed to produce the silk protein fibroin. Cocoons generated by the silkworms solely consisted of the glue-like glycoprotein sericin, from which soluble sericin could be prepared to form hydrogels. Embryonic stem cells could be maintained on the hydrogels in an undifferentiated state and proliferated through stimulation by the cytokines introduced into the hydrogels. Thus, bioengineering with targeted P1A expression successfully produced silkworms with a biologically useful trait that has significant application potential. [ABSTRACT FROM AUTHOR]

A novel KRAS-mediated transgenic rat model has previously been demonstrated, in which animals develop multiple pancreatic ductal adenocarcinoma (PDAC) that is histologically similar to human PDAC within two weeks. Positron emission tomography (PET)/computed tomography (CT) is commonly used for the diagnosis and staging of PDAC in humans, and can be adopted for optimal use in animal experiments. The aim of the present study was to evaluate the carcinogenic process in a rat pancreatic carcinoma model using small-animal multimodality imaging systems. The utility of fluorodeoxyglucose (FDG)-PET/CT in detecting the location and size of PDAC during tumor development in the present transgenic rat model was assessed. A small animal multimodality PET/CT system and contrast-enhanced CT (CECT) system were used for the imaging analysis of KRASG12V male transgenic rats (n=6), which developed pancreatic tumors following the administration of an injection of Cre recombinase (Cre)-carrying adenovirus. Laparotomies performed at six weeks post-treatment revealed that all three (100%) Cre-expressing rats developed pancreatic tumors that were <2 mm in diameter, none of which were detected by 18F-FDG PET/CT or CECT. At eight weeks post-treatment, the pancreatic tumors were heterogeneously visualized by 18F-FDG-PET/CT and CECT in two of the three rats. Furthermore, the autopsies confirmed that all three rats had developed pancreatic tumors. These novel findings provide evidence that the FDG-PET/CT imaging system is a valuable tool for the evaluation of the carcinogenic process, and one which may aid in treatment and preventive methods for pancreatic tumors in mammalian models. A limitation associated with the early detection of PDACs warrants further investigation. [ABSTRACT FROM AUTHOR]

Nano-sized titanium dioxide particles (TiO2) are widely used in cosmetics, sunscreens and food additives. We previously reported that topical application of non-coated rutile type TiO2 did not exhibit a promoting effect on ultraviolet B-initiated skin carcinogenesis in rats, and that this was likely due to lack of penetration of TiO2 into the epidermis. In the present study, we examined the promoting effect of silicone coated TiO2 (sTiO2) suspended in silicone oil and non-coated TiO2 (ncTiO2) suspended in Pentalan 408 on a two-stage skin chemical carcinogenesis model: sTiO2 suspended in silicon oil forms smaller particles than ncTiO2 suspended in Pentalan because of the smaller sizes of aggregates formed. The model used skin carcinogenesis-sensitive human c-Ha-ras proto-oncogene transgenic mice (rasH2) and rats (Hras128) and their wild-type counterparts and CD-1 mice to test the effects of topical application of TiO2. Animals were initially treated with a single dose of 7,12-dimethylbenz[a]anthracene (DMBA) and then with 0, 10, or 20 mg sTiO2 (mice) or 0, 50, or 100 mg ncTiO2 (rats). The incidence and multiplicity of skin tumors (squamous cell papilloma and carcinoma) did not increase over DMBA alone controls in skin carcinogenesis-sensitive mice or rats or wild-type animals. Analysis of rat skin indicated that sTiO2 and ncTiO2 did not penetrate though either healthy or damaged skin. Furthermore sTiO2 did not penetrate an in vitro human epidermis model. Our results indicate that treatment with sTiO2 or ncTiO2 did not promote skin carcinogenesis in mice or rats, probably due to lack of penetration through the epidermis. [ABSTRACT FROM AUTHOR]