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

【摘要】：目的：肝臟毒性與氧化應(yīng)激相關(guān)機(jī)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(dòng)物肝臟功能。同時(shí)有研究報(bào)道BPA和4-NP可發(fā)揮類(lèi)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(biāo)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(jī)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(shí)驗(yàn)組),同時(shí)以同等劑量的玉米油為溶劑對(duì)照。組。給藥量為0.1ml/10g,每48小時(shí)注射1次,實(shí)驗(yàn)周期為30天。我們就BPA和4-NP對(duì)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(biāo)記物的影響進(jìn)行了相關(guān)研究：同時(shí)也研究了BPA和4-NP暴露所誘導(dǎo)凋亡、肝毒性和氧化應(yīng)激相關(guān)基因表達(dá)的改變。此外,根據(jù)修正版BattsLudwig評(píng)分系統(tǒng)(評(píng)價(jià)壞死)和Brunt等制定的NASH分級(jí)和分期系統(tǒng)(評(píng)價(jià)脂肪變性、膨脹和小葉炎癥),對(duì)肝損傷發(fā)病率和嚴(yán)重程度進(jìn)行了定量分析。 結(jié)果：BPA處理組與對(duì)照組比較,大鼠體重和肝臟重量差異無(wú)統(tǒng)計(jì)學(xué)意義。4-NP處理組肝的絕對(duì)重量和相對(duì)重量與對(duì)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(guò)氧化氫(H202)水平均增加,但BPA處理組的抗氧化酶過(guò)氧化氫酶(CAT)、超氧化物歧化酶(SOD)和谷胱甘肽過(guò)氧化物酶(GSH-PX)水平均降低,且與對(duì)照組比較,差異均具有統(tǒng)計(jì)學(xué)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(duì)內(nèi)分泌干擾物BPA和4-NP所誘導(dǎo)的細(xì)胞凋亡、肝毒性和氧化應(yīng)激(OS)相關(guān)基因進(jìn)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(dá)(P0.05或P0.01)：結(jié)果亦顯示BPA顯著性降低Bcl-2mRNA表達(dá),增加凋亡關(guān)鍵基因iNOS, TNF-α, Casp-3和Casp-9mRNA表達(dá)。4-NP可誘導(dǎo)氧化應(yīng)激相關(guān)基因SOD1和GPx mRNA表達(dá)降低,與此同時(shí),50mg/kg4-NP處理組的HSP70mRNA表達(dá)顯著性增加(P0.05)。肝細(xì)胞凋亡可促進(jìn)NAFLD進(jìn)展,Fas/FasL、TNF-a和Caspase-9mRNA的激活在肝脂肪變性過(guò)程具有重要作用。此外,4-NP可顯著性降低Bcl-2mRNA表達(dá),同時(shí)誘導(dǎo)Bax mRNA表達(dá)增加。 結(jié)論我們的研究結(jié)果證實(shí)細(xì)胞凋亡、壞死和NAFLD進(jìn)展與肝損害密切相關(guān)。此外,BPA所誘導(dǎo)的肝臟抗氧化系統(tǒng)的毒性反應(yīng)可能導(dǎo)致細(xì)胞凋亡和壞死,引起長(zhǎng)效肝毒性。同時(shí),我們首次報(bào)道4-NP可干擾肝毒性效應(yīng)相關(guān)基因異常表達(dá),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(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R114

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