本文選題：對羥基苯甲酸酯 + 鄰苯二甲酸酯�。� 參考：《浙江大學》2017年碩士論文

【摘要】：對羥基苯甲酸醋類(Parabens)和鄰苯二甲酸醋類(Phthalate esters,PAEs)物質(zhì)作為抗菌防腐劑和塑化劑被廣泛的添加到個人護理品、消費品中,其殘留在多種環(huán)境介質(zhì)和生物體內(nèi)被頻繁檢出,目前關(guān)于其人體健康和生態(tài)環(huán)境風險相關(guān)研究相對匱乏。本文選取不同側(cè)鏈結(jié)構(gòu)和類型Parabens和PAEs物質(zhì)為研究對象,分析了parabens對雄激素受體(Androgen receptor,AR)干擾效應(yīng),考察了污染物水解后干擾效應(yīng)的變化,探討了其雄激素受體干擾效應(yīng)的分子機制。以青海弧菌(Vibrio qinghaiensis sp.-Q67)為模式生物,研究了PAEs與鎘(Cadimum,Cd)的單一和二元聯(lián)合毒性,分析了重金屬Cd脅迫對PAEs急性毒性的影響,并利用經(jīng)典模型預測了PAEs與Cd的聯(lián)合毒性效應(yīng)。從構(gòu)效關(guān)系角度分析了parabens及PAEs的側(cè)鏈長度和基團類型對其毒性的影響。主要獲得如下研究結(jié)果:(1)采用酵母雙雜交方法研究了10種芳氧基和烷氧基側(cè)鏈parabens對AR的干擾效應(yīng)。發(fā)現(xiàn)parabens的烷氧基側(cè)鏈C原子數(shù)為1-4時,AR拮抗效應(yīng)隨側(cè)鏈增長而顯著降低;當側(cè)鏈C原子數(shù)為7,8和12時,parabens無顯著AR拮抗效應(yīng)。相比烷氧基側(cè)鏈,具有芳氧基側(cè)鏈的parabens如對經(jīng)基苯甲酸芐醋(Benzyl paraben,BzP)和對經(jīng)基苯甲酸苯醋(Phenyl paraben,PnP)具有相對較高的AR拮抗效應(yīng)。分子對接(Molecular docking)揭示與天然雄激素二氫睪酯(Dihydrotestosterone,DHT)具有相似的結(jié)合模式,parabens與AR受體配體結(jié)合域(Ligand binding domain,LBD)877號蘇氨酸和705號天冬酰胺形成氫鍵。Parabens與AR LBD的結(jié)合能量與其AR拮抗效應(yīng)顯著相關(guān)(R~2=0.84,P0.05)。為進一步分析parabens側(cè)鏈對AR拮抗活性的影響,采用豬肝醋酶將parabens水解,發(fā)現(xiàn)水解后parabens的AR拮抗活性完全消除。高效液相色譜串聯(lián)紫外檢測器(HPLC-UV)及超高效液相色譜串聯(lián)質(zhì)譜檢測器(UPLC-MS/MS)分析發(fā)現(xiàn)parabens水解后酯鍵斷裂,生成對羥基苯甲酸。相較于芳氧基側(cè)鏈parabens,烷氧基側(cè)鏈parabens是豬肝酯酶的最優(yōu)底物,更易于被水解。(2)以Vibrio qinghaiensis sp.-Q67為模式生物,研究了PAEs與Cd的單一和二元聯(lián)合毒性。發(fā)現(xiàn)六種PAEs包括鄰苯二甲酸二甲醋(Dimethyl phthalate,DMP)、鄰苯二甲酸二乙酯(Diethyl phthalate,DEP)、鄰苯二甲酸丁芐酯(Benzyl butyl phthalate,BBP)、鄰苯二甲酸二正丁酯(Dibutyl phthalate,DBP)、鄰苯二甲酸二異辛醋(Diisooctyl phthalate,DIOP)和鄰苯二甲酸二正辛酯(Di-n-octyl phthalate,DOP)對青海弧菌急性毒性的EC50值大于100mg/L(DMP:134.4mg/L;DEP:283.1 mg/L;DBP:895.1 mg/L),說明對青�；【毙远拘暂^弱;隨PAEs側(cè)鏈長度增加,其急性毒性顯著減小(R~2=0.8961,P0.05)。進一步測定了PAEs與Cd的二元聯(lián)合毒性,并結(jié)合獨立作用(Independent action,IA)和濃度加和(Concentration addition,CA)模型進行了預測探討。發(fā)現(xiàn)二元混合物DMP-DEP,DEP-DBP和DMP-DBP的毒性單位(Toxicunit,TU)值均大于1.2,聯(lián)合毒性表現(xiàn)為拮抗效應(yīng);二元混合物DMP-Cd,DEP-Cd和DBP-Cd的TU值介于0.8-1.2,聯(lián)合毒性表現(xiàn)為簡單相加效應(yīng)。重金屬Cd脅迫顯著增加了PAEs對青�；【毙远拘�。
[Abstract]:Parabens and Phthalate esters, PAEs, as antiseptic preservatives and plasticizers, are widely added to personal care products. In consumer products, their residues are frequently detected in a variety of environmental media and organisms, and the relative research on human health and ecological environment risks is relative. In this paper, the interference effects of parabens on androgen receptor (Androgen receptor, AR) were analyzed by selecting different side chain structures and types of substance Parabens and PAEs. The changes of interference effect after the hydrolysis of pollutants were investigated, and the molecular mechanism of the interference effect of androgen receptor was discussed, with Vibrio Qinghai (Vibrio qinghaiensis sp.-Q6). 7) for model organisms, the single and two element joint toxicity of PAEs and Cadimum (Cd) was studied. The effects of heavy metal Cd stress on the acute toxicity of PAEs were analyzed, and the combined toxicity of PAEs and Cd was predicted by the classical model. The effects of side chain length and group type on the toxicity of parabens and PAEs were analyzed from the point of view of structure-activity relationship. The results are as follows: (1) the interference effect of 10 aryl oxygen groups and alkoxy side chain parabens on the AR was studied by yeast two hybrid method. It was found that when the number of parabens alkoxy side chain C atoms was 1-4, the AR antagonistic effect decreased significantly with the side chain growth. When the number of side chain C atoms was 7,8 and 12, parabens had no significant AR antagonistic effect. The oxygen group side chain, with the aryl side chain parabens, has a relatively high AR antagonism to the Benzyl Paraben, BzP and Phenyl paraben (PnP). Molecular docking (Molecular docking) reveals a similar binding pattern with the natural androgen two hydrotestosterone (Dihydrotestosterone, DHT). The binding energy of Bens with AR receptor ligand binding domain (Ligand binding domain, LBD) 877 and No. 705 asparagine is significantly related to the AR antagonistic effect of the hydrogen bond.Parabens and AR LBD (R~2=0.84, P0.05). The AR antagonistic activity of rabens was completely eliminated. High performance liquid chromatography tandem UV detector (HPLC-UV) and ultra high performance liquid chromatography tandem mass spectrometry detector (UPLC-MS/MS) analysis found that the ester bond breaks after parabens hydrolysis and produces P hydroxybenzoic acid. Compared to the aryl side chain parabens, the alkoxy side chain parabens is the best substrate for porcine liver esterase, and the alkoxy side chain parabens is the best substrate. It is easy to be hydrolyzed. (2) a single and two element joint toxicity of PAEs and Cd is studied with Vibrio qinghaiensis sp.-Q67 as a model organism. Six kinds of PAEs include two methyl acetic acid (Dimethyl phthalate, DMP), two (Diethyl phthalate, DEP), phthalic two formate, and phthalic two a. Acid two n-butyl (Dibutyl phthalate, DBP), phthalic acid two isooctyl vinegar (Diisooctyl phthalate, DIOP) and ortho benzoate two n-octyl (Di-n-octyl phthalate, DOP) are more acute toxicities of Vibrio Qinghai than 100mg/L (DMP:134.4mg/L; The acute toxicity of PAEs and Cd was significantly reduced (R~2=0.8961, P0.05). The combined toxicity of PAEs and Cd was further measured, and the prediction was carried out in combination with the independent action (Independent action, IA) and concentration addition (Concentration addition, CA). The combined toxicity of DMP-Cd, DEP-Cd and DBP-Cd was higher than 1.2, and the TU value of two yuan mixture was 0.8-1.2, and the combined toxicity showed simple additive effect. Heavy metal Cd stress significantly increased the acute toxicity of PAEs to Vibrio Qinghai.
【學位授予單位】：浙江大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：X171.5

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相關(guān)期刊論文 前1條

1 王立鑫;楊旭;;鄰苯二甲酸酯毒性及健康效應(yīng)研究進展[J];環(huán)境與健康雜志;2010年03期

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