citreoviridin and Body-Weight

Citreoviridin (CIT), a mycotoxin and ATP synthase inhibitor, is regarded as one of aetiology factors of cardiac beriberi and Keshan disease. Thiamine (VB1) and selenium (Se) improve the recovery of these two diseases respectively. The underlying mechanisms of cardiotoxic effect of CIT and cardioprotective effect of VB1 and Se have not been fully elucidated. In this study, we found that ectopic ATP synthase was more sensitive to CIT treatment than mitochondrial ATP synthase in H9c2 cardiomyocytes. CIT inhibited the transcriptional activity of peroxisome proliferator activated receptor gamma (PPAR-γ) in mice hearts and H9c2 cells. PPAR-γ agonist attenuated the inhibitory effect of CIT on mechanistic target of rapamycin complex 2 (mTORC2) and stimulatory effect of CIT on autophagy in cardiomyocytes. CIT induced apoptosis through lysosomal-mitochondrial axis in cardiomyocytes. PPAR-γ agonist and autophagy inhibitor alleviated CIT-induced apoptosis and accelerated cardiac biomarker. VB1 and Se accelerated the basal transcriptional activity of PPAR-γ in mice hearts and H9c2 cells. Furthermore, VB1 and Se reversed the effect of CIT on PPAR-γ, autophagy and apoptosis. Our findings defined PPAR-γ-mTORC2-autophagy pathway as the key link between CIT cardiotoxicity and cardioprotective effect of VB1 and Se. The present study would shed new light on the pathogenesis of cardiomyopathy and the cardioprotective mechanism of micronutrients.

Topics: Animals; Apoptosis; Aquaporins; Aurovertins; Autophagy; bcl-2-Associated X Protein; Body Weight; Cell Line; Male; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Inbred ICR; Myocardium; PPAR gamma; Protective Agents; Proto-Oncogene Proteins c-bcl-2; Rats; Selenium; Thiamine

Vascular endothelial dysfunction and inflammatory response are early events during initiation and progression of atherosclerosis. In vitro studies have described that CIT markedly upregulates expressions of ICAM-1 and VCAM-1 of endothelial cells, which result from NF-κB activation induced by CIT. In order to determine whether it plays a role in atherogenesis in vivo, we conducted the study to investigate the effects of CIT on atherosclerotic plaque development and inflammatory response in apolipoprotein E deficient (apoE-/-) mice. Five-week-old apoE-/- mice were fed high-fat diets and treated with CIT for 15 weeks, followed by assay of atherosclerotic lesions. Nitric oxide (NO), vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were detected in serum. Levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), VEGF, and ET-1 in plaque areas of artery walls were examined. NF-κB p65 expression and NF-κB activation in aorta also were assessed. CIT treatment significantly augmented atherosclerotic plaques and increased expressions of ICAM-1, VCAM-1, VEGF and ET-1 in aorta. Mechanistic studies showed that activation of NF-κB was significantly elevated by CIT treatment, indicating the effect of CIT on atherosclerosis may be regulated by activation of NF-κB.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Aurovertins; Body Weight; Diet, High-Fat; Endothelin-1; Endothelium, Vascular; Hypercholesterolemia; Inflammation; Intercellular Adhesion Molecule-1; Lipids; Male; Mice, Inbred C57BL; NF-kappa B; Nitric Oxide; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

The mycotoxin citreoviridin (CIT) isolated from Penicillium citreoviride was studied to elucidate the mechanism of its toxic actions. In CF#1 mice, near lethal doses of CIT decreased motor activities, body temperature and had cataleptic effects. Male mice appeared to be more susceptible to CIT and had lower subcutaneous (sc) LD50 values and longer CIT-induced hypothermia and hypokinesia. In CIT-treated mice the weights and histology of liver, kidneys and adrenals were normal one week after sc treatment, except for the increased adrenal weights in female mice. Single doses of CIT (sc), given on either day 4 or 5 of pregnancy (perinidation period), had no adverse effect on the rates of pregnancy, implantation of ova and embryonal resorptions in those mice examined on day 12 of pregnancy. CIT (40 mg/kg ip) produced a brief electro-encephalographic (EEG) activation, cardiac sinus arrhythmias and tachypnea in the rabbit. Intravenous (iv) lethal doses of CIT (greater than or equal to 5 mg/kg) caused an EEG activation followed by high voltage delta waves, increased the T wave in the electrocardiogram (ECG) and depressed the respiratory amplitude. The death caused by iv CIT started with the respiratory arrest, followed by isoelectric EEG and ECG was the last to stop. In urethane-anesthetized rabbits CIT decreased the blood pressure, and in succession it lowered, flattened and inverted the T wave of ECG suggesting heart ischemia. These observations indicated that the toxic effects of CIT resulted from respiratory and cardiovascular failures (apnea, delta EEG waves, sinus arrhythmia, hypotension) leading to central nervous system depression due to systemic hypoxia.

Topics: Adrenal Glands; Animals; Aurovertins; Body Temperature; Body Weight; Cardiovascular System; Electroencephalography; Female; In Vitro Techniques; Kidney; Lethal Dose 50; Liver; Male; Mice; Mice, Inbred Strains; Motor Activity; Mycotoxins; Myocardial Contraction; Organ Size; Pregnancy; Pyrans; Rabbits; Rana pipiens; Reaction Time; Respiration

Citreoviridin produced by the fungus Penicillium citreo-viride was administered by gavage to groups of 9-16 pregnant Fisher 344 rats either on days 8-11 (group A) or on days 12-15 (group B) of gestation. Doses of 0, 5, 10 or 15 mg/kg body weight were given daily in a constant volume of 1 ml/kg body weight in dimethylsulphoxide. Six rats in each high-dose group died during the dosing period. Compared with control groups, mean daily feed consumption was significantly reduced in the 10- and 15-mg/kg animals in both groups A and B. Weight gain during pregnancy in both groups was reduced with increasing dosage; dams in control groups gained an average of 75 g/rat compared with 30 g overall gain in group A, or 9 g overall gain in group B, both at a dose of 15 mg/kg. Male and female pup weights were reduced with increasing dosage for both groups A and B. The post-implantation foetal loss rate was significantly increased to 33% in group A high-dose animals. The main effect of citreoviridin on skeletal development in both groups A and B was one of retardation. No internal abnormalities were observed in group A pups. Some smaller than average pups from dams in group B that were treated with the high dose of citreoviridin had slightly dilated lateral ventricles of the brain and, in some cases, a palate defect. The foetotoxicity induced by citreoviridin was observed only at doses that also induced maternal toxicity.

Topics: Abnormalities, Drug-Induced; Animals; Aurovertins; Body Weight; Embryonic and Fetal Development; Female; Fetal Resorption; Fetus; Pregnancy; Pyrans; Rats; Rats, Inbred F344; Sex Ratio