ABSTRACT
To investigate the optimal administration period for evaluating ovarian toxicity that reflects abnormal female fertility in the repeated dose toxicity study, atrazine, a potent herbicide with endocrine-disrupting activity, was administered to female Sprague-Dawley (Slc:SD) rats for two or four weeks at doses of 3, 30 or 300 mg/kg for the repeated dose toxicity study, and at doses of 3, 30 or 100 mg/kg for the female fertility study from two weeks before mating to Day 7 of gestation. In the two-week repeated dose toxicity study, prolongation of diestrus and histopathological findings such as loss of the currently formed corpora lutea, decrease in the numbers of previously formed corpora lutea, increase in large-sized atretic follicles, and swelling of the previously formed luteal cells were observed in the 300 mg/kg group, suggesting that atrazine had an anovulatory effect through suppression of the luteinizing hormone surge. In the female fertility study, copulation failure caused by prolongation of diestrus was observed in one animal in the 100 mg/kg group, which could be due to the anovulatory effect of atrazine. It is demonstrated that the effect of atrazine on female fertility can be assessed by detailed histopathological examination of ovaries in a two-week repeated dose toxicity study, provided the appropriate dose levels are selected.
Subject(s)
Atrazine/toxicity , Fertility/drug effects , Herbicides/toxicity , Ovary/drug effects , Toxicity Tests/methods , Animals , Atrazine/administration & dosage , Body Weight/drug effects , Copulation/drug effects , Corpus Luteum/drug effects , Corpus Luteum/metabolism , Corpus Luteum/pathology , Drug Administration Schedule , Estrous Cycle/drug effects , Female , Herbicides/administration & dosage , Japan , Male , Organ Size/drug effects , Ovarian Follicle/drug effects , Ovarian Follicle/metabolism , Ovarian Follicle/pathology , Ovary/pathology , Ovary/physiopathology , Pregnancy , Proliferating Cell Nuclear Antigen/metabolism , Public-Private Sector Partnerships , Rats , Rats, Sprague-Dawley , Societies, Scientific , Weight Gain/drug effectsABSTRACT
The tomato saponin alpha-tomatine has been proposed to kill sensitive cells by binding to cell membranes followed by leakage of cell components. However, details of the modes of action of the compound on fungal cells are poorly understood. In the present study, mechanisms involved in alpha-tomatine-induced cell death of fungi were examined using a filamentous pathogenic fungus Fusarium oxysporum. alpha-Tomatine-induced cell death of F. oxysporum (TICDF) occurred only under aerobic conditions and was blocked by the mitochondrial F(0)F(1)-ATPase inhibitor oligomycin, the caspase inhibitor D-VAD-fmk, and protein synthesis inhibitor cycloheximide. Fungal cells exposed to alpha-tomatine showed TUNEL-positive nuclei, depolarization of transmembrane potential of mitochondria, and reactive oxygen species (ROS) accumulation. These results suggest that TICDF occurs through a programmed cell death process in which mitochondria play a pivotal role. Pharmacological studies using inhibitors suggest that alpha-tomatine activates phosphotyrosine kinase and monomeric G-protein signaling pathways leading to Ca(2+) elevation and ROS burst in F. oxysporum cells.
Subject(s)
Apoptosis/drug effects , Fusarium/drug effects , Reactive Oxygen Species/pharmacology , Tomatine/analogs & derivatives , Antifungal Agents/pharmacology , Calcium Signaling/drug effects , Cell Death/drug effects , Enzyme Activation/drug effects , Fusarium/metabolism , GTP-Binding Proteins/metabolism , Solanum lycopersicum/chemistry , Protein-Tyrosine Kinases/metabolism , Reactive Oxygen Species/metabolism , Saponins/chemistry , Saponins/pharmacology , Signal Transduction/drug effects , Tomatine/pharmacologyABSTRACT
The induction of chromosome aberration of Ca-type Garcinia cambogia extract containing about 65% (-)-hydroxycitric acid was investigated by use of the chromosome aberration test in cultured Chinese hamster lung cells (CHL/IU) and the micronucleus test in mice. In the chromosome aberration test, Ca-type Garcinia cambogia extract did not increase the number of cells with structural aberration and/or numerical aberrations. The micronucleus test was carried out with bone marrow cells of Slc : ddY male mice after single oral administration of up to 2,000 microg/kg. There was no significant increase in the frequency of micronucleated polychromatic erythrocytes. These results indicate that Ca-type Garcinia cambogia extract does not induce chromosome aberration.
