Course of Apoptotic Changes in the Rat Gastric Mucosa Caused by Oral Administration of Fusarenon-X.

Abstract

ABSTRACT. Male 5-week-old Wistar rats orally (po) administered with fusarenon-X (FX) 1.5 mg/kg and control rats po-treated with distilled water were sacrificed at 0-48 hr after gavage. FX-administered rats showed significant dilatation of the stomach with increased fluid contents at 1-24 hr postadministration (PA). Histopathologically, karyopyknosis of chief cells in the basal region of the gastric glands began to appear at 1 hr, and nuclear fragments were seen in the neck cell region at 1.5 hr PA. At 2-4 hr PA, apoptotic cells appeared diffusely in the neck region and focally in the basal region. Electron microscopy revealed that cells phagocytosing apoptotic bodies were the surface epithelia, undifferentiated neck cells, parietal cells and chief cells. No evidence was detected to show that parietal cells underwent apoptotic changes. The apoptotic lesions peaked at 4-6 hr PA, gradually subsided at 12 hr PA, and became minimal leaving apoptotic remnants in the basal region at 24 hr PA. At 48 hr PA, however, diffuse apoptotic lesions reappeared in the basal region at a level similar to that at 2-3 hr PA. This might be attributable to absorption of FX retaining in the stomach for 24 hr. In situ detection of DNA breaks by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) reaction was consistent with the histopathologic findings. Agarose gel electrophoresis of DNA fragments isolated from the gastric mucosae of FX-administered rats showed a ladder pattern after 1.5 hr PA and the pattern became more distinct at 2-4 hr PA. -KEY WORDS: apoptosis, DNA fragmentation, fusarenon-X, oral administration, rat stomach.J. Vet. Med. Sci. 59(3): 191-199, 1997 MATERIALS AND METHODS Animals:A hundred and four male 5-week-old Wistar rats weighing 140 ± 10.0 g purchased from the Kumamoto Agency of Japan SLC Co., Ltd., Shizuoka, Japan were randomly divided into the respective experimental and control groups for examination of pathomorphological changes and DNA fragmentation of the glandular stomach in rats po-treated with FX. They were kept in cages each containing 4 or 5 animals. Commercial breeder pellets for rats and mice (Japan Agricultural Products Co., Ltd., Yokohama) and tap water were given ad libitum. The room temperature and humidity during the experiment were conditioned 24 ± 1.0°C and 50-60%.Toxin administration: Each rat of the experimental group was po administered with 1.5 mg/kg of FX (purity 97.4%, Wako Pure Chemical Industries Ltd., Osaka) dissolved in distilled water at 0.5 mg/ml. The control group received po 0.5 ml of distilled water.Pathomorphological examination: Eighty rats, consisting of the equal number of FX-treated and control groups were sacrificed at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hr PA of the toxin by exsanguinating from the jugular vein under light ether anesthesia: each 4 animals for 0 to 4 hr and each 3 for 6 to 48 hr PA. The stomach with contents was removed and weighed using Mettler P1200 (Mettler Inc., Darmstadt, Germany). Data were analyzed using Stude...

Acute Parietal and Chief Cell Changes Induced by a Lethal Dose of Lipopolysaccharide in Mouse Stomach before Thrombus Formation

“…Steroids and nonsteroidal antiinflammatory drugs alter cytoprotective mechanisms and the mucosal barrier through inhibition of prostaglandin synthesis, resulting in erosions and ulcers (4). An oral dose of trichothecene mycotoxin Fusarenon-X causes apoptosis mainly in the chief cells and to a lesser extent in the surface epithelial cells and undifferentiated neck cells at 3 hours PI and degenerative changes in chief and parietal cells at 48 hours PI (8). Thus, the changes observed in the mice in the present study probably were caused by mechanisms other than these.…”

“…The first change was seen in the parietal cells, with vacuolar formation evident PI; very few of these cells were found in the control group and in the 4-and 6-hour groups. Electron microscopy revealed many cells with condensed chromatin of the nucleus, secretory granules of various electron densities, and abundant stacks of rough endoplasmic reticulum in the cytoplasm (Figure 8) (8). Thus, the changes observed in the mice in the present study probably were caused by mechanisms other than these.…”

Intestinal toxicity of the type B trichothecene mycotoxin fusarenon-X: whole transcriptome profiling reveals new signaling pathways

“…In line with the ex vivo observations presented here, a marked shortening of the intestinal villi in the jejunum and the ileum has been reported 24 hours following a single intra-peritoneal injection of 1 mg/kg of FX to rats 33 . FX also induced extensive hemorrhaging in the intestine with cellular destruction and karyorrhexis of the intestinal mucosa in mice, and apoptotic cell death in the rat gastric mucosa, in acute and sub-acute toxicity studies 9 , 34 , 35 . Our results emphasize that the intestine is a front-line target organ after dietary exposure to FX.…”

An overview of the toxicology and toxicokinetics of fusarenon-X, a type B trichothecene mycotoxin

“…FX (1.5 mg/kg BW) induced apoptosis in basal chief and parietal cells of rat gastric mucosa 1 hr after i.p. administration [ 29 ] and 1.5 hr after ingestion [ 28 ]. FX disrupted glycolysis and induced intestinal malabsorption by causing hypoglycemia and inhibiting mitosis of intestinal crypt cells [ 53 ].…”