Concordance between Results of Medium-term Liver Carcinogenesis Bioassays and Long-term Findings for Carcinogenic 2-Nitropropane and Non-carcinogenic1-Nitropropane in F344 Rats

This study was conducted to determine the concordance of results for a pair of structural isomers, 2-nitropropane (2-NP) and 1-nitropropane (1-NP), using the rat medium-term liver carcinogenesis bioassay (Ito test) and previously published long-term carcinogenicity tests. Male F344 rats were given a single intraperitoneal injection of DEN (200 mg/kg b.w.) to initiate hepatocarcinogenesis. After 2 weeks, they received per os 0, 0.8, 4 or 20 mg/kg/day of 2-NP or 1-NP six times a week and were subjected to two-thirds partial hepatectomy at week 3. Non-initiated groups receiving 0 or 20 mg/kg/day were also included. The animals were sacrificed for quantitative analysis of GST-P-positive foci at week 8. With the highest dose of 2-NP, significantly increased numbers and areas of GST-P-positive foci were demonstrated as compared with the respective control but were not noted with 1-NP. In the non-DEN-initiated groups, many small GST-P-positive foci of less than 0.2 mm in diameter were also induced in the rats treated with 2-NP at 20 mg/kg/day but were lacking with 1-NP. These results strongly support that 2-NP is a complete hepatocarcinogen with a potent initiation activity, whereas 1-NP is not.     

Lack of Hepatocarcinogenicity of Combinations of Low Doses of 2-amino-3, 8-dimethylimidazo[4,5- f ]quinoxaline and Diethylnitrosamine in Rats: Indication for the Existence of a Threshold for Genotoxic Carcinogens

The purposes of the present study were to evaluate the hepatocarcinogenicity of concurrent treatment of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and diethylnitrosamine (DEN) in rats and to determine whether no effect levels of combinations of these two different structural categories of genotoxic hepatocarcinogens exist. Two 16-week rat hepatocarcinogenesis assays were performed using a total of 790 male F344 rats. In experiment 1, we evaluated the effects of concurrent treatment of a subcarcinogenic dose of DEN on rat hepatocarcinogenesis induced by various doses of MeIQx. In experiment 2, we determined hepatocarcinogenicities of combinations of MeIQx and DEN at subcarcinogenic doses, low carcinogenic doses and high carcinogenic doses. Quantitative analyses of glutathione S-transferase placental form (GST-P)-positive foci, a preneoplastic lesion of the liver in rats, revealed that concurrent treatment with subcarcinogenic doses of DEN did not enhance MeIQx-induced rat hepatocarcinogenicity. We also found that concurrent treatment with combinations of subcarcinogenic doses of DEN and MeIQx was not hepatocarcinogenic, indicating that the combined effects of subcarcinogenic doses of DEN and MeIQx were neither additive nor synergistic. Moreover, concurrent treatment with low carcinogenic doses of these 2 carcinogens did not show additive or synergistic effects. Synergetic effects were observed only in rats coadministered high carcinogenic doses of the 2 carcinogens. These results demonstrate the existence of no effect levels of combinations of these 2 genotoxic hepatocarcinogens, and provide new evidence supporting our idea that there is a threshold, at least a practical threshold, that should be considered when evaluating the risk of genotoxic carcinogens.     

Dehydroeffusol Rescues Amyloid β25–35-Induced Spatial Working Memory Deficit

Plant Foods for Human Nutrition - Amyloid β (Aβ) peptides produced from the amyloid precursor protein, a transmembrane protein, are neurotoxic and blocking the neurotoxicity may lead to...     

Heated Leaf Extract of Coriandrum sativum L. Protects Nigral Dopaminergic Degeneration in Rats

Coriandrum sativum L. (coriander), which is an annual herb of the Apiaceae family, has been traditionally used as a remedy. Here we tested whether heated extract of coriander leaf protects nigral dopaminergic neurodegeneration after exposure to 6-hydroxydopamine (6-OHDA). After injection of 6-OHDA into the rat substantia nigra pars compacta (SNpc), dopaminergic degeneration, which was determined by tyrosine hydroxylase immunostaining, was rescued by co-injection of CaEDTA, an extracellular Zn²⁺ chelator, suggesting that extracellular Zn²⁺ influx is involved in neurodegeneration. Both intracellular Zn²⁺ dysregulation determined by ZnAF-2 fluorescence and dopaminergic degeneration in the SNpc induced by 6-OHDA were rescued by co-injection of 0.25% coriander extract, which also reduced reactive oxygen species (ROS) production in the SNpc determined by aminophenyl fluorescein fluorescence. The present study suggests that coriander leaf extract protects nigral dopaminergic neurodegeneration induced by intracellular Zn²⁺ dysregulation. It is likely that the nutraceutical property of coriander leaf extract contributes to the protection via reducing ROS production.

     

Promotion of liver and kidney carcinogenesis by ethyl tertiary-butyl ether (ETBE) in male Wistar rats

Tumor-promoting effects of ethyl tertiary-butyl ether (ETBE) were investigated in a 2-stage carcinogenesis bioassay with regard to hepatic and renal carcinogenesis in rats. Male 6-week-old Wistar rats were given drinking water containing N-ethyl-N-(2-hydroxyethyl)nitrosamine (EHEN), as an initiator, at a dose of 500 ppm for 2 weeks. Starting one week thereafter, the animals were administered ETBE at dose levels of 0 (control), 100, 300, 500 or 1,000 mg/kg/day by gavage for 19 weeks from week 4 to 22. Necropsy of all rats was performed at week 23, and livers and kidneys were examined histopathologically. Incidences of hepatocellular adenomas, and those of combined hepatocellular adenomas and carcinomas were significantly elevated in rats given 1,000 mg/kg/day ETBE, but not 100‒500 mg/kg/day ETBE, and there was a significant increase in the average numbers of lesions. No significant differences in incidences and average numbers of renal tubule neoplasms were found in rats administered 100‒1,000 mg/kg/day ETBE. However, the average numbers of atypical tubule hyperplasias, considered to be preneoplastic lesions, were significantly increased in rats given ETBE at 1,000 mg/kg/day, but not in rats given 500 mg/kg/day or lower doses. Thus, these results imply that ETBE has hepatic and renal tumor-promoting activities that affect EHEN-induced carcinogenesis in male rats, and the no-observed-effect level is 500 mg/kg/day under the present experimental conditions.     

Effect of long-term exposure to sulfides on taurine transporter gene expression in the gill of the deep-sea mussel Bathymodiolus platifrons,which harbors a methanotrophic symbiont

Seawater around deep-sea hydrothermal vents and cold seeps contain high levels of hydrogen sulfide, which is toxic to most animals. Invertebrates inhabiting these environments have been reported to accumulate high levels of thiotaurine, a sulfur-containing amino acid. Thiotaurine is likely to play an important role in sulfide detoxification, but its functions in the detoxification process are still unknown. We cloned methane-seep mussel Bathymodiolus platifrons cDNA encoding the taurine transporter (TAUT), which transports thiotaurine and its precursors across the cell membrane. Phylogenetic analyses revealed that the predicted peptide formed a clade with the TAUTs of shallow-water mussel Mytilus galloprovincialis and the hydrothermal vent mussel Bathymodiolus septemdierum that harbors thioautotrophic bacteria. We then reared B. platifrons in the presence or absence of Na₂S and quantified TAUT mRNA using a real-time PCR system. The amount of TAUT mRNA in the gills of B. platifrons increased with rearing in the presence of Na₂S for 69 days, but no change was observed in the absence of sulfide. These results suggest that TAUT plays an important role in sulfide detoxification, even in species that do not harbor thioautotrophic bacteria. The TAUT mRNA level was variable in the mantle and low in the foot throughout the entire rearing period, regardless of the presence/absence of sulfide, suggesting that TAUT gene expression is regulated differentially in each tissue.     

Intake of Heated Leaf Extract of Coriandrum sativum Contributes to Resistance to Oxidative Stress via Decreases in Heavy Metal Concentrations in the Kidney

Plant Foods for Human Nutrition - Coriandrum sativum (coriander) is an annual herb of the Apiaceae family and has been used as a traditional remedy. Here we examined whether heated leaf extract of...     

Metallothionein expression and tumor growth in the transplantable pregnancy-independent mouse mammary tumor.

In various human tumors, a metal binding protein, metallothionein (MT) is reported to play an important role in carcinogenesis. In the present preliminary study, MT expression and tumor growth were investigated in transplantable pregnancy-independent mammary tumors (TPIMT) derived from pregnancy-independent mammary tumors (PIMT) in GR/A mice, in order to study the possible role of MT in mammary carcinogenesis. TPIMT as well as PIMT showed MT expression in tumor cells in all of the successive transplantations. A negative correlation was observed between MT expression in transplanted tumor tissues and their growth in the hosts (r=-0.53, p<0.05). The present study indicates that MT is a useful marker of tumor progression in TPIMT.