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タイトル: Studies on cardiovascular and autonomic nervous effects of trichothecene mycotoxin in the rat
その他のタイトル: トリコテセンマイコトキシンのラット心臓血管系および自律神経系に及ぼす影響に関する研究
著者: Suchitra, Ngampongsa
著者(別言語): スチトラ, ガンポンサ
発行日: 2013年3月25日
抄録: This study aimed to elucidate toxicities and the toxic mechanisms of representative trichothecene mycotoxins, i.e., T-2 toxin and deoxynivalenol (DON), to the cardiovascular and autonomic nervous system. In order to achieve this goal, the scheme was considered several experiments consisted of both in vivo and in vitro methods. In vivo studies a series of experiments were conducted in Wistar strain rats as experimental animals under the anesthetized or conscious condition, while in vitro study, the cardiomyocyte was obtained from neonatal SD strain rats. The cell culture assya was carried out to identify a direct toxicity to the rat cardiomyocyte due to the trichothecene mycotoxins. In in vivo study, changes in the electrocardiographic (ECG) parameters and the autonomic nervous activity that were affected by administration of trichothecene mycotoxin were mainly investigated by a telemetry method. In these experiments, possible contributions of baroreceptor reflex that result in changes of heart rate (HR) by responding to blood pressure (BP) changes as well as concurrent alterations in the autonomic nervous activity measuring from the heart rate variability (HRV) were examined. Moreover, the echocardiography was employed to investigate circulatory changes including cardiac functions and systemic vascular resistance after the toxin administration. In in vitro study, changes in mitochondrial respiratory function, which were measured as oxygen consumption rate (OCR), in cultured cardiomyocytes were investigated after direct application of T-2 toxin and DON to the cardiomyocytes. First, acute cardiovascular changes in response to subcutaneous administration of T-2 toxin (0.5 and 1.0 mg/kg) and DON (0.5, 1.0 and 2.0 mg/kg) were observed for 3 hours in anesthetized rats. T-2 toxin induced an increase in HR that begun at 60 min while especially QRS duration and QT interval in the ECG wave-components tended to increase at least 30 min after the administration. Moreover, the occurrence of arrhythmia was recognized within 3 hours of observation in the administration of T-2 toxin. As regards DON administration, a decrease of HR starting from 90 min with a prolongation of PR interval and QRS duration, being accompanied by the occurrence of arrhythmia, was observed. Furthermore, these two toxins induced a similar change of blood pressure characterized by an increase in the systolic, diastolic and mean arterial blood pressure after 30 min of the toxin administration. From these acute experiments, it was found that T-2 toxin and DON possess the toxicity to produce the functional alteration in the cardiovascular system. On the basis of the results described above, in the next step the experiments with long-term observation for toxicities by the two mycotoxins were conducted in order to clarify reversible or irreversible alterations of the cardiovascular functions in unanesthetized and unrestrained rats. In this study, telemetric measurements of ECG and the analysis of heart rate variability (HRV) were performed to record long-term responses to T-2 toxin and DON in freely moving rats with subcutaneous administrations of toxins. Subcutaneous injections of T-2 toxin (0.1 and 0.5 mg/kg) and DON (0.5, 1.0 and 2.0 mg/kg) were done twice at an interval of 3 days. A marked change in HR was observed in especially T-2 toxin administration, where T-2 toxin and DON both induced the increase in HR after 90 min following the administration. In this long-term observation, the cardiovascular toxicity due to T-2 toxin was found to be lasted for as long as 3 days, being identified by the increase in HR, significant decrease in HRV components and occurrences of various types of arrhythmia within 3 days of observation at dose of 0.5 mg/kg. The change in HR and HRV components by DON administration lasted for approximately 12 hours which was shorter than that in T-2 toxin. Moreover, DON-induced abnormalities, i.e., changes in HRV components, arrhythmias, seemed to be reversible changes since all the ECG parameters including HR could recover to its normal values within 3 days of observation. From the results of these studies in the section, it was elucidated that T-2 toxin has a potent and long-lasting toxicity which is represented by significant changes in HR, autonomic nervous activity and frequent occurrence of arrhythmia and also elucidated that such changes in T-2 toxin is significantly greater than those produced by DON. As for the mechanism of HR changes and the occurrence of arrhythmia induced by T-2 toxin and DON in the present study, the participation of the autonomic nervous activity and/or direct action of those toxins on the heart were assumed as casual factors of such cardiac alterations. Therefore, in the next step, the effect of autonomic nervous blockades on the HR change and occurrence of arrhythmia as well as changes of HRV was examined in rats in which the osmotic mini-pump containing atropine as a parasymphathetic nerve blockade or propranolol as a sympathetic nerve blockade was implanted and T-2 toxin (0.5 mg/kg, s.c.) or DON (2.0 mg/kg, s.c.) was injected. As a result, the increase of HR due to T-2 toxin and DON administration were inhibited by the continuous administration of propranolol (100 mg/kg/day). Moreover, the arrhythmias, especially second-degree AV block and sinus bradycardia, which responded to T-2 toxin were significantly reduced by both the blockades. On the other hand, the occurrence of ventricularextrasystole was significantly increase by the administration of atropine (20 mg/kg/day). In addition, the LF power and LF/HF ratio were reduced by the atropine administration in both toxins, while the HF power was also reduced by atropine in DON. According to these data, it was clarified that in unanesthetized rats T-2 toxin and DON produced the HR change, arrhythmia with a conduction disturbance and changes in HRV via the alteration of the autonomic nervous activity and some cardiac abnormalities such as ventricular extrasystoles may be provoked by not only the autonomic nervous system but also a possible direct action of toxins to the cardiac tissue. In in vivo study, the dynamic circulatory changes including cardiac contractility, blood flow velocity, cardiac output and peripheral vascular resistance were also examined in rats with administration of T-2 toxin (0.1 mg/kg, 0.5 mg/kg, s.c.) with the aid of echocardiogram equipped with B-mode, M-mode and pulse Doppler analysis. This echocardiographic observation revealed a tendency for increase in cardiac output and a significant increase in mean blood flow velocity in the common carotid artery and femoral artery in rats with administration of T-2 toxin at 48 h after the injection, accompanying by a tendency for increase in HR and fractional shortening and an increase or decrease in resistance index in the common carotid artery and femoral artery at the dose of 0.5 mg/kg. After the echocardiogram examination the blood serum sample was collected for measurement of oxidative stress. This measurement resulted in a significant increase of amount of reactive oxygen species (ROS) without a change of antioxidative parameter in rats administered with T-2 toxin. From these experiments, it was clarified that the dynamic change in the circulatory system was produced by T-2 toxin, accompanying by the concurrent increase in the oxidative stress in the blood. On the basis of the results described above and from the past reports, I assumed that these trichothecene mycotoxins may have a property of cellular toxicity through the direct action of the toxins to the cardiac muscle. The cultured primary cardiomyocyte isolated from newborn rats were assigned for in vitro experiments on the toxicity of T-2 toxin and DON to the mitochondria respiratory function in which the oxygen consumption rate (OCR) was measured at 24 h after the onset of T-2 toxin application. As a result, a significant decrease in baseline OCR was recognized at a concentration of 6×10^-4 μM of T-2 toxin and at 0.78 μM of DON. Furthermore, the TP-linked OCR in response to oligomycin was significantly decreased at 6×10^5 μM of T-2 toxin and at 0.78 μM of DON, while the similar OCR change was observed for the response to FCCP that indicated the reserve capacity of electron transport system in the mitochondria. In conclusion, the present study demonstrated that T-2 toxin and DON have considerable toxic properties for the cardiovascular system involving the appearance of potent arrhythmia, marked alterations in the autonomic nervous function, and cardiac cellular toxicity and that the extent of toxicity is much greater in T-2 toxin than that in DON.
内容記述: 報告番号: ; 学位授与年月日: 2013-03-25 ; 学位の種別: 課程博士 ; 学位の種類: 博士(獣医学) ; 学位記番号: 博農第3968号 ; 研究科・専攻: 農学生命科学研究科獣医学専攻
URI: http://hdl.handle.net/2261/56577
出現カテゴリ:021 博士論文
1162420 博士論文(獣医学専攻)

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