本文選題：雙酚A + 4-壬基酚��； 參考：《華中科技大學》2015年博士論文

【摘要】：目的：肝臟毒性與氧化應(yīng)激相關(guān)機制密切相關(guān)。相關(guān)研究表明內(nèi)分泌干擾物如雙酚A (bisphenol A, BPA)和4-壬基酚(4-nonylphenol,4-NP)可干擾哺乳動物肝臟功能。同時有研究報道BPA和4-NP可發(fā)揮類雌激素作用且具有肝毒性。本研究旨在研究BPA和4-NP暴露與肝臟相關(guān)效應(yīng)生物標記物、肝臟抗氧化防御系統(tǒng)和肝臟毒性的關(guān)聯(lián)性. 方法：48只SD雄性大鼠隨機分成4組,每組6只,腹腔皮下注射2,10,50mg/kg(以玉米油為溶劑)的BPA和4-NP(實驗組),同時以同等劑量的玉米油為溶劑對照。組。給藥量為0.1ml/10g,每48小時注射1次,實驗周期為30天。我們就BPA和4-NP對肝臟和血清中相關(guān)抗氧化酶(SGOT、SGPT. LDH和γ-GT)及肝損害的效應(yīng)生物標記物的影響進行了相關(guān)研究：同時也研究了BPA和4-NP暴露所誘導凋亡、肝毒性和氧化應(yīng)激相關(guān)基因表達的改變。此外,根據(jù)修正版BattsLudwig評分系統(tǒng)(評價壞死)和Brunt等制定的NASH分級和分期系統(tǒng)(評價脂肪變性、膨脹和小葉炎癥),對肝損傷發(fā)病率和嚴重程度進行了定量分析。 結(jié)果：BPA處理組與對照組比較,大鼠體重和肝臟重量差異無統(tǒng)計學意義。4-NP處理組肝的絕對重量和相對重量與對照組比較,差異具有顯著性。BPA處理組與4-NP處理組的丙二醛(MDA)和過氧化氫(H202)水平均增加,但BPA處理組的抗氧化酶過氧化氫酶(CAT)、超氧化物歧化酶(SOD)和谷胱甘肽過氧化物酶(GSH-PX)水平均降低,且與對照組比較,差異均具有統(tǒng)計學意義(P0.05)。2mg/kg b.wt的4-NP處理組抗氧化劑CAT和GSH-Px活性顯著性增加(P0.01),但10和50mg/kg b.wt的4-NP處理組CAT和GSH-Px活性顯著性降低(P0.001)。4-NP處理組的血清SGOT、SGPT、LDH和γ-GT水平均增加,BPA處理組SGOT、SGPT和LDH的水平亦增加,但γ-GT水平減少。我們也對內(nèi)分泌干擾物BPA和4-NP所誘導的細胞凋亡、肝毒性和氧化應(yīng)激(OS)相關(guān)基因進行了研究。研究發(fā)現(xiàn)BPA可顯著性增加氧化應(yīng)激相關(guān)基因SODl、GPx和Txnrdl mRNA表達(P0.05或P0.01)：結(jié)果亦顯示BPA顯著性降低Bcl-2mRNA表達,增加凋亡關(guān)鍵基因iNOS, TNF-α, Casp-3和Casp-9mRNA表達。4-NP可誘導氧化應(yīng)激相關(guān)基因SOD1和GPx mRNA表達降低,與此同時,50mg/kg4-NP處理組的HSP70mRNA表達顯著性增加(P0.05)。肝細胞凋亡可促進NAFLD進展,Fas/FasL、TNF-a和Caspase-9mRNA的激活在肝脂肪變性過程具有重要作用。此外,4-NP可顯著性降低Bcl-2mRNA表達,同時誘導Bax mRNA表達增加。 結(jié)論我們的研究結(jié)果證實細胞凋亡、壞死和NAFLD進展與肝損害密切相關(guān)。此外,BPA所誘導的肝臟抗氧化系統(tǒng)的毒性反應(yīng)可能導致細胞凋亡和壞死,引起長效肝毒性。同時,我們首次報道4-NP可干擾肝毒性效應(yīng)相關(guān)基因異常表達,此改變與肝脂肪變性密切相關(guān)。
[Abstract]:Objective: liver toxicity is closely related to oxidative stress. Related studies have shown that endocrine disruptors such as bisphenol A (BPAA) and 4-nonylphenolophane (4-NPP) interfere with liver function in mammals. At the same time, it has been reported that BPA and 4-NP can play an estrogenic role and have hepatotoxicity. The aim of this study was to investigate the relationship between BPA and 4-NP exposure and liver related biomarkers, liver antioxidant defense system and liver toxicity. Methods Forty-eight Sprague-Dawley male rats were randomly divided into 4 groups, 6 rats in each group. BPA and 4-NPP (n = 6) were injected subcutaneously with 210g / kg (corn oil as solvent) and 4-NPP (experimental group), and the same dose of corn oil was used as solvent control. Group. A dose of 0.1 ml / 10 g was given once every 48 hours for 30 days. We studied the effects of BPA and 4-NP on liver and serum related antioxidant enzymes SGOTN SGPTs. The effects of LDH and 緯 -GT) and the effect biomarkers of liver damage were studied. The changes of apoptosis, hepatotoxicity and oxidative stress-related gene expression induced by BPA and 4-NP exposure were also studied. In addition, the incidence and severity of liver injury were quantitatively analyzed according to the revised BattsLudwig scoring system (evaluation of necrosis) and Brunt's Nash grading and staging system (evaluation of steatosis, swelling and lobular inflammation). Results there was no significant difference in body weight and liver weight between the control group and the control group. The absolute and relative weight of liver in the 4-NP treatment group was higher than that in the control group. The levels of MDA and H202) in BPA group and 4-NP group were increased, but the levels of antioxidant enzyme catalase (CATX), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were decreased in BPA treatment group. And compared with the control group, The activities of cat and GSH-Px increased significantly in 4-NP treatment group, but the cat and GSH-Px activities in 10 and 50mg/kg b.wt 4-NP groups were significantly lower than those in 4-NP treatment group, but the levels of serum SGOTSGPTPTLDH and 緯 -GT in 4-NP treatment group were significantly lower than those in 4-NP treatment group (P 0.001). 4-NP treatment group increased the levels of serum SGOTSGPTPTLDH and 緯 -GT in BPA-treated group, but the activities of cat and GSH-Px activity in 4-NP treatment group were significantly lower than those in 4-NP treatment group (P 0.001g 路4-NP group). The levels of SGPT and LDH in SGOT group were also increased. But the level of 緯 -GT decreased. We also studied genes associated with apoptosis, hepatotoxicity and oxidative stress induced by endocrine disruptors BPA and 4-NP. It was found that BPA could significantly increase the expression of oxidative stress-related genes (SODlGPx and Txnrdl mRNA) (P0.05 or P0.01). The results also showed that BPA significantly decreased the expression of Bcl-2 mRNA. Increasing the expression of iNOS, TNF- 偽, Casp-3 and Casp-9 mRNA. 4-NP could induce the decrease of SOD1 and GPX mRNA expression, while the HSP70 mRNA expression in 50 mg / kg 4-NP group increased significantly (P 0.05). Hepatocyte apoptosis can promote the progression of NAFLD. The activation of Fas-FasL mRNA, TNF-a and Caspase-9 mRNA plays an important role in the process of hepatic steatosis. In addition, 4-NP significantly decreased Bcl-2 mRNA expression and increased Bax mRNA expression. Conclusion our results confirm that apoptosis, necrosis and NAFLD progression are closely related to liver damage. In addition, the toxic response of liver antioxidant system induced by BPA may lead to apoptosis and necrosis, and cause long-term hepatotoxicity. At the same time, we report for the first time that 4-NP interferes with the abnormal expression of genes associated with hepatotoxicity, which is closely related to hepatic steatosis.
【學位授予單位】：華中科技大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R114

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