We demonstrated that trophoblastic apoptosis occurs in the placentas of a mouse model with preterm delivery induced by lipopolysaccharide. We postulated that apoptosis may lead to placental abruption, and its development may be prevented by treatment with urinary trypsin inhibitor.
Huge vacuoles in the follicular epithelial cells distributing diffusely in the thyroid gland were seen in 2 out of 36 males and 8 out of 82 females of BrlHan: WIST@Jcl (GALAS) rats examined histopathologically. The vacuoles showed negative reactivity by periodic acid-Schiff reaction and thyroglobulin-immunohistochemistry. Corresponding to the vacuoles, remarkable dilatation of rough endoplasmic reticulum was seen in electron microscopic observation. The animals in which the thyroid lesion was found had shown no abnormalities in behavior, body weight, food consumption, or hematological and biochemical examinations. Plasma concentrations of thyroid-stimulating hormone (TSH) and thyroid hormones (T3 and T4) were not different from those of normal rats. From these results, thyroid functions seemed to be kept normal in spite of the severe morphological change. Based on the character and incidence of the thyroid lesion, it was presumed to be related with a certain genetic factor of one or several parents of breeding rats rather than food contamination or infection. ( BrlHan: WIST@Jcl (GALAS) rats, so called Wistar Hannover GALAS rats, have been used in toxicity studies in Europe. This strain has several beneficial characters such as a higher survival rate and a smaller body weight than those of other strains, for instance, Sprague-Dawley, Wistar, and Fischer 344 rats. A higher survival rate (about 80% for 2 years) is advantageous for long term-toxicity studies, and a smaller body weight is worthy to use in preliminary toxicity studies of new drugs when the quantity of compounds is limited. In our laboratory, this strain has been recently used in preliminary toxicity studies. In the studies, we found a lesion of the thyroid gland in 2 out of 36 males and 8 out of 82 females. One female bearing the lesion was from nontreated groups. We considered the lesion as a spontaneous change since the quality and the degree were similar to that in the non-treated animal.All animals were supplied from CLEA, Japan, Inc. at 5 weeks of age. Animals examined were from 6 lots (4 lots for 4 preliminary toxicity studies and 2 lots for the accumulation of background data at 8 weeks of age). They were housed in stainless steel cages in a room maintained at 23 ± 2°C, 55 ± 15% relative humidity and a 12-hr-light and -dark cycle, and had free access to a standard laboratory diet (CRF-1, Oriental Yeast Co., Ltd., Tokyo) and tap water. Blood samples were withdrawn from the abdominal aorta under sodium pentobarbital anesthesia and the animals were killed by exsanguination at 8 weeks of age.Many organs including the thyroid gland were removed and weighed (the organs of one rat was not weighed). The organs were fixed in 10% neutral-buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin (H.E.) for light microscopic observation. In addition, sections of the thyroid and pituitary glands were processed for periodic acid-Schiff (PAS) reaction. In 6 normal rats and 8 rats with thyroid lesion, immunohistochemi...
The Eisai hyperbilirubinemic rat (EHBR) should be a useful animal model for studies on the toxicity of organic anions which are substrates of multidrug resistance-associated protein 2 (Mrp2), since the systemic exposure to these compounds is expected to be increased in EHBR. In this study, we tested the value of EHBR for this purpose, using pravastatin (PV) and methotrexate (MTX) as model compounds. In the case of a single oral dose of PV (200 mg/kg), C(max) in plasma was 4.0-fold higher and AUC(0-infinity) was 3.6-fold larger than those of normal Sprague-Dawley rats (SDR), respectively. When multiple doses of PV were given to EHBR without co-administration of any other compound, drug-induced skeletal muscle toxicity (myopathy/rhabdomyolysis) and increased creatine phosphokinase (CPK) level were observed, whereas a control experiment using SDR did not show any toxic change. When a single dose of MTX (0.6 mg/kg) was given to EHBR orally, C(max) was 1.7-fold higher and AUC(0-infinity) was 1.6-fold larger than those of SDR, respectively. When multiple doses of MTX were given to EHBR, the changes in bone marrow, spleen and intestines were more severe than those in SDR. These findings support the view that EHBR would be a valuable animal model for toxicity studies on organic anion compounds which are substrates of Mrp2.
Altered gene expression of the DNA repair-and cell proliferationassociated proteins/enzymes was examined during the process of tamoxifen-induced hepatocarcinogenesis in female Sprague-Dawley rats. When rats were treated by gavage with a single dose of tamoxifen (20 mg/kg body weight) or with the same dose given at 24-h intervals for 2, 12 or 52 weeks, no histopathological change was observed in the liver after 2 weeks. Pathologically altered cell foci and placental form of glutathione-S-transferase (GST-P)-positive foci were observed in the liver after 12 weeks of treatment. Treatment for 52 weeks resulted in the formation of liver hyperplastic nodules that strongly expressed GST-P. During the process of carcinogenesis, changes in hepatic gene expression of DNA repair proteins/enzymes (XPA and XPC, xeroderma pigmentosum complementation groups A and C, respectively; APE, apurinic/apyrimidinic endonuclease) and of cell proliferation-associated proteins (c-myc; PCNA, proliferating cell nuclear antigen; cyclin D1, cyclin B, and p34cdc2) were examined by RT-PCR. The gene expression of XPA and APE was increased by the tamoxifen treatment for 2 or 12 weeks, but no increase was observed after the 52-week treatment. In addition, no significant change in XPC gene expression occurred at any period examined. The gene expression of c-myc, PCNA, and cyclin D1 was increased in a timedependent fashion up to 12 weeks of treatment, and this increase was maintained up to 52 weeks of treatment. The gene expression of cyclin B and p34cdc2 was increased after the 1-day treatment, reverted to the control level at 2 and 12 weeks of treatment, and was remarkably increased after the 52-week treatment. In the present study, we demonstrate the altered gene expression of various proteins/enzymes involved in DNA repair, cell growth and the cell cycle during the process of tamoxifen-induced hepatocarcinogenesis. We discuss the relationship between the altered gene expression and hepatocarcinogenesis. (Cancer Sci 2003; 94: 582-588) otent hepatocarcinogenicity of the antiestrogen tamoxifen in rats has been reported, [1][2][3][4] although tamoxifen is widely used not only as an anticancer drug, 5,6) but also as a chemopreventive agent 7) for breast cancer. This hepatocarcinogenesis is thought to occur through the chemical modification of DNA by tamoxifen metabolites.8-13) α-(N 2 -Deoxyguanosinyl)tamoxifen is detected as a major DNA adduct of tamoxifen in the rat liver, and the adduct has been shown to be formed through metabolic activations, α-hydroxylation and O-sulfation, of tamoxifen. [14][15][16][17][18][19][20][21] Although N-desmethyltamoxifen, tamoxifen N-oxide, and 4-hydroxytamoxifen are major metabolites of tamoxifen, DNA adducts of these metabolites are hardly detected in the liver, 19,22) suggesting that these metabolites might be considered primarily as detoxification forms.Recently, we 23) have investigated changes in the drug-metabolizing enzymes involved in forming tamoxifen metabolites during the process of tamoxifen-induced hepa...
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