本文選題：壬基酚 + 仔鼠　； 參考：《重慶醫(yī)科大學》2012年博士論文

【摘要】：壬基酚(Nonylphenol, NP)是環(huán)境雌激素樣化學物的典型代表，，作為乳化劑廣泛應用于工業(yè)、農業(yè)、日用品生產中，可由污水排入水體環(huán)境。NP在環(huán)境中難于降解，具有高度脂溶性和生物蓄積性，可經口腔、呼吸道、皮膚等多種途徑進入機體，對人群健康產生危害。 研究估計，非職業(yè)暴露人群通過各種途徑接受NP的暴露水平為3.6～31.4μg/kg/day。體內、外實驗顯示NP的雌激素活性約為雌二醇的10-4～10-5倍，可模擬雌激素與機體內多組織器官的雌激素受體結合發(fā)揮雌激素樣作用，目前較多關于NP生殖和發(fā)育毒性的研究表明，NP的毒性機制主要源于其對內分泌的干擾作用，可對魚類、兩棲動物及哺乳動物多種器官產生不良作用：包括影響生殖、內分泌、免疫、消化、泌尿等系統(tǒng)的功能，然而NP對子代神經行為發(fā)育的影響目前尚不清楚。 中樞神經系統(tǒng)在發(fā)育時期對體內多種激索水平的變化非常敏感，相對成人而言，胎兒在胚胎中后期和哺乳期，血腦屏障未發(fā)育成熟，中樞神經系統(tǒng)正值器官形成期，此時期最易受外來毒物損害，其神經系統(tǒng)器官發(fā)育和功能很可能受到影響。因此，若機體此期間若暴露于內分泌干擾物NP，可能導致胎兒神經系統(tǒng)所受的損害會比其它時期更為嚴重。以往研究大多是多種環(huán)境內分泌干擾物(EnvironmentalEndocrine Disrupters,EEDs)的聯合暴露，不能說明NP單獨的毒性作用，得出的結果也各不相同，因此結論尚具有不確定性，對機理的研究較片面，缺乏深入而系統(tǒng)的研究。 本課題以大鼠為研究對象，首次在神經系統(tǒng)胚胎發(fā)育敏感期暴露NP，觀察NP對仔鼠神經行為發(fā)育的影響，測試其學習記憶能力的變化，并從細胞凋亡、神經營養(yǎng)因子、膠質細胞纖維酸性蛋白、信號傳遞等角度進行研究，同時利用基因芯片從分子水平嘗試探討NP神經毒性的分子機制，進而可為NP在發(fā)育期間暴露的危害評價提供實驗數據，為制定相關環(huán)境污染標準提供理論依據。 第一部分NP對母鼠生殖和仔鼠生長發(fā)育的影響 目的:研究NP對雌性大鼠生產和仔鼠生長發(fā)育的影響。 方法：SD孕鼠28只隨機分為4組（對照組、50mg/kg NP、100mg/kgNP、200mg/kg NP），每組6～7只，妊娠第9～15天灌胃NP，觀察孕鼠的體重、進食、染毒后的一般情況以及生殖情況，觀察仔鼠的出生指標及體重變化，檢測仔鼠早期生理發(fā)育指標。 結果：（1）各實驗組孕鼠末見明顯中毒癥狀，100mg/kg（中劑量組）和200mg/kg（高劑量組）NP組孕鼠每窩平均胎數、活胎數降低，死胎數增加，p0.05。（2）高劑量組仔鼠身長、尾長、肛殖距縮短，p0.05。（3）各實驗組仔鼠出生臟器重量（腦，肝、腎、心等）與對照組比較差異無統(tǒng)計學意義，p0.05。（4）高劑量組體重出生后1、7、14、21、28天均低于對照組，p0.01。（5）高劑量組仔鼠早期生理發(fā)育指標（張耳、開眼、長毛、出牙）發(fā)育時間較對照組延長，p0.05。以上指標低劑量組與對照組比較差異均無統(tǒng)計學意義，p0.05。 結論:在本實驗的染毒方式、時間和劑量下，高劑量組NP對雌鼠的生殖能力有影響，同時可影響仔鼠的出生指標和生長發(fā)育指標。 第二部分NP對仔鼠神經行為發(fā)育的影響 目的:探討母鼠NP孕期暴露致子代神經行為發(fā)育及學習記憶的影響。 方法:孕鼠染毒及分組方法同第一部分。在出生后特定的時間，觀察仔鼠斷崖回避、平面翻正、前肢懸掛、空中翻正、聽覺驚愕和視覺定位等早期神經行為發(fā)育指標,選擇8周齡仔鼠進行Morris水迷宮和跳臺試驗，檢測NP對其學習記憶的影響；脫椎取腦組織做石蠟切片HE染色光鏡下觀察其病理變化；海馬組織透射電鏡觀察超微結構變化。 結果:（1）早期神經行為發(fā)育指標：高劑量組仔鼠（斷崖回避、平面翻正、前肢懸掛、空中翻正、聽覺驚愕和視覺定位等）時間較對照組延長（p0.05）；（2）Morris水迷宮試驗：高劑量組仔鼠水迷宮中逃避潛伏期延長(p005)；（3）跳臺試驗：反應時間延長，步下潛伏期縮短，錯誤次數增加(p005)；（4）病理：HE染色，光鏡可見高暴露組海馬組織充血水腫；（5）透射電鏡：高劑量組仔鼠海馬組織電鏡下見線粒體腫脹呈空泡樣變，染色質濃縮成塊狀聚集在核周圍。 結論: NP孕期暴露可阻礙仔鼠早期神經行為的發(fā)育，使空間學習記憶能力下降。 第三部分NP對斷乳期仔鼠海馬基因表達譜的影響 目的：應用基因芯片技術，考察NP暴露組和對照組仔鼠海馬組織差異基因的表達狀況，篩選部分與神經毒性相關的差異表達基因及通路進行進一步機制研究。方法：建立孕期和哺乳期暴露NP的仔鼠模型，提取暴露組和對照組出生1天仔鼠海馬組織mRNA，采用Roche Nimblegen公司生產的12×135位點的包含大鼠26,419個基因的表達譜基因芯片，檢測腦基因的表達，掃描儀進行掃描及處理數據。 結果：暴露組與對照組共有1,254個差異表達基因，其中619個基因上調，635個基因下調。部分與神經系統(tǒng)功能相關差異表達基因為：A.神經營養(yǎng)相關的基因表達：甘丙肽(Galanin，Gal)基因下調，神經生長因子(Nerve Growth Factor，NGF)基因下調；B.細胞凋亡的相關基因的表達：凋亡蛋白酶活化因子-1(Apoptotic Protease Activating Factor-1,Apaf-1)基因上調，凋亡抑制基因-1（Defender Against Apoptotic Death-1，DAD1）基因下調，半胱氨酸蛋白酶7(Cysteine-aspartic Acid Protease，Caspase7)基因上調；C.信號傳遞及離子通道相關基因的表達：谷氨酸鹽受體(Glutamate Receptor, Ionotropic,AMPA2)基因下調，鈣調素依賴性蛋白激酶Ⅱ (Calcium/calmodulin-dependent Protein Kinase II Delta,Camk2d)基因下調。 結論:芯片結果提示： NP能導致仔鼠海馬神經元信號傳導、免疫應答、細胞凋亡、炎癥反應因子、神經膠質細胞發(fā)育等相關基因的差異表達，以上改變有可能干擾神經系統(tǒng)的發(fā)育和功能的發(fā)揮。 第四部分NP暴露對仔鼠神經發(fā)育毒性的機制研究 目的：母鼠孕期及哺乳期暴露NP，觀察對子代神經細胞凋亡、神經遞質、膠質細胞以及神經生長相關基因的表達變化，探討NP對仔鼠神經毒性的可能機制。 方法：將交配成功的31只孕鼠根據妊娠日期分層后隨機分配到4組，即C、L、M、H組（NP0、25、50、100mg/kg/day），單籠飼養(yǎng)，空腹灌胃, NP暴露時間為受孕第6天到出生后21天哺乳期結束（GD6～PND21），放免法檢測21天仔鼠血清雌二醇(E2)和睪酮(TT)水平；分光比色法測仔鼠海馬組織膽堿乙酰轉移酶（ChAT）和膽堿酯酶（AchE）活性；免疫組化發(fā)觀察海馬組織即早基因c-fos和c-jun蛋白的表達；原位末端標記法(TUNEL)觀察PND21天和60天仔鼠海馬神經元凋亡發(fā)生情況；免疫組織化學法檢測海馬和皮質星形膠質細胞膠質原纖維酸性蛋白(GFAP)、神經生長相關因子(GAP-43)的蛋白的變化，RealTime PCR法檢測GFAP和GAP-43mRNA的變化，并分析上述指標變化與NP暴露劑量之間的關系。 結果：①NP對斷乳期仔鼠血清激素水平的影響：放免法檢測結果顯示，仔鼠出生后21天血清睪酮水平隨NP暴露劑量增加而降低，存在劑量-效應關系（r=-0.889，p 0.05），與對照組比較，M和H兩個劑量組睪酮明顯降低（p0.05）；雌激素水平與NP暴露劑量正相關（r=-0.462，p0.01），H劑量組雌激素水平與對照組比較差異有統(tǒng)計學意義（p 0.05）。②NP暴露對斷乳期及成熟期仔鼠神經細胞凋亡的影響：TUNEL法檢測結果顯示，仔鼠出生后21d和60d，H劑量組海馬細胞凋亡率顯著高于對照組(p 0.01)，且NP暴露劑量與凋亡率正相關（r=0.836、0.521，p 0.05）。從縱向比較，各暴露組21天仔鼠海馬組織凋亡率均高于60天（t=3.331，p0.05）③NP對仔鼠神經信號傳導的影響：A. NP對仔鼠海馬組織ChAT和AchE活性的影響：M、H劑量組仔鼠海馬組織ChAT活性明顯低于對照組；M劑量組AchE活性高于對照組（p 0.01）。海馬組織ChAT和AchE活性與NP暴露劑量有劑量效應關系（r=-0.821、0.757，p 0.05）。B.海馬組織c-fos和c-jun蛋白表達的變化：正常仔鼠海馬中c-jun和c-fos蛋白表達很低，L劑量組陽性細胞數少，著色淺；M和H劑量組仔鼠海馬c-jun和c-fos陽性細胞數量增多，尤其是高劑量組分布密集，胞體大、著色深。④NP對仔鼠海馬星形膠質細胞膠質原纖維酸性蛋白的影響：免疫組化技術檢測GFAP蛋白表達的結果顯示，H劑量組21d和60d齡的仔鼠海馬和皮質部GFAP免疫陽性反應細胞數目、積分光密度顯著高于同期對照組仔鼠(p 0.05)，熒光定量PCR檢測GFAP表達的結果顯示，H劑量組21d和60d齡的仔鼠海馬GFAP mRNA表達升高，與對照組比較有顯著性差異。GFAP蛋白與GFAP mRNA表達與NP暴露劑量有正相關關系(p 0.05)。⑤NP對仔鼠神經生長相關蛋白的影響：免疫組化技術檢測GAP-43蛋白表達的結果顯示，H劑量組21d和60d齡的仔鼠海馬和皮質部GAP-43免疫反應陽性細胞平均數目、積分光密度低于同期對照組仔鼠(p 0.05)，熒光定量PCR結果顯示，H劑量組21d和60d齡的仔鼠海馬GAP-43mRNA表達下降，差異有統(tǒng)計學意義。GAP-43蛋白和GAP-43mRNA表達與NP暴露劑量有負相關關系(p 0.05)。 結論：結合以上數據，推測NP誘導的神經毒性可能機制是：在胚胎期及哺乳期接觸NP， NP的弱雌激素樣作用通過競爭雌激素受體引起內分泌系統(tǒng)失衡，導致仔鼠體內雌激素水平升高，改變了子代大腦發(fā)育的內分泌環(huán)境，干擾神經細胞發(fā)育過程，降低神經營養(yǎng)因子GAP-43的表達水平，抑制神經細胞分化，包括神經突起生長和分支，突觸的形成，同時通過增加膠質細胞纖維酸性蛋白GFAP表達，并影響星形膠質細胞的形態(tài)、結構和功能，進一步影響膽堿能神經遞質Ach以及即早基因c-jun、c-fos的信息傳遞，并且誘導仔鼠海馬區(qū)神經細胞凋亡，最終導致子代發(fā)育期神經反射時間延遲，成熟期學習記憶障礙。
[Abstract]:Nonylphenol (NP) is a typical representative of environmental estrogenic chemicals. As a emulsifier, it is widely used in industrial, agricultural and daily necessities production. It can be discharged into the water environment by sewage and.NP is difficult to degrade in the environment. It has high fat solubility and bioaccumulation, and can enter the body through oral, respiratory, skin and other ways. Health is harmful.
It is estimated that the exposure level of non occupational exposures to NP is 3.6 to 31.4 micron g/kg/day. in various ways. The external experiment shows that the estrogen activity of NP is about 10-4 to 10-5 times as much as estradiol. Developmental toxicity studies have shown that the toxic mechanism of NP mainly originates from its endocrine disruption and has adverse effects on various organs of fish, amphibians and mammals, including the functions of reproductive, endocrine, immune, digestive, and urinary systems. However, the effects of NP on neurobehavioral development of the progeny are not yet clear.
The central nervous system is very sensitive to a variety of changes in the level of irritable cord in the body during the development period. Compared with the adult, the fetus is not mature in the middle and late embryo and lactation period, and the central nervous system is in the stage of organogenesis. This period is most vulnerable to foreign poison, and the development and function of the nervous system organs are likely to be affected. Therefore, if the body is exposed to the endocrine disruptor NP during this period, the damage to the fetal nervous system may be more serious than that of other periods. Previous studies were mostly combined exposure to a variety of environmental endocrine disruptors (EnvironmentalEndocrine Disrupters, EEDs), which could not explain the toxic effects of NP alone, and the results were also found. Therefore, the conclusion is still uncertain. The research on mechanism is rather one-sided and lacks in-depth and systematic research.
This subject takes rats as the research object, exposes NP in the sensitive stage of the embryonic development of the nervous system for the first time, observing the effect of NP on the neurobehavioral development of the offspring, testing the changes of learning and memory ability, and studying from the angle of cell apoptosis, neurotrophic factor, glial fibrillary acidic protein, signal signal transmission and so on, and using gene chip from the angle of gene chip. At the molecular level, we try to explore the molecular mechanism of NP neurotoxicity, and then provide experimental data for the risk assessment of NP exposure during development, and provide a theoretical basis for the formulation of related environmental pollution standards.
Part one the effect of NP on the growth and development of female rats and their offspring.
Objective: To study the effects of NP on the growth and development of female rats and offspring rats.
Methods: 28 SD pregnant rats were randomly divided into 4 groups (control group, 50mg/kg NP, 100mg/kgNP, 200mg/kg NP), 6~7 rats in each group, NP in each group for ninth to 15 days. The weight of pregnant rats, eating, general condition and reproductive status were observed. The birth index and weight change of the offspring were observed and the early physiological development indexes of the offspring were detected.
Results: (1) there were obvious poisoning symptoms at the end of the pregnant rats in the experimental groups. The average number of fetus per litter in 100mg/kg (medium dose group) and 200mg/kg (high dose group) NP group, the number of live births and the number of stillbirths increased, the length of the rats in the high dose group p0.05. (2), the tail length, the anal colonization shortened, and p0.05. (3) the weight of the viscera (brain, liver, kidney, heart, etc.) of the offspring rats of the experimental groups (3) and the control group. The difference was not statistically significant. The p0.05. (4) high dose group was lower than the control group at 1,7,14,21,28 days after birth, and the development time of early physiological development index (Zhang Er, eye opening, long hair, tooth) in the high dose group of p0.01. (5) high dose group was longer than that of the control group, and there was no statistical difference between the low dose group above the p0.05. index and the control group, p0.05.
Conclusion: at the time and dose of the experiment, the high dose group NP has an influence on the reproductive ability of the female rats, and it can also affect the birth index and the growth and development index of the offspring.
The effect of second part NP on the neurobehavioral development of offspring rats
Objective: To investigate the effects of NP pregnancy exposure on offspring's neurobehavioral development and learning and memory.
Methods: pregnant rats were infected and grouped in the same way as the first part. At the specific time after birth, the early neurobehavioral development indicators such as cliffs avoidance, plane reversal, forelimb suspension, air reversal, auditory consternation and visual orientation were observed and the effects of NP on the learning and memory of the 8 week old rats were tested by the Morris water fan palace and the platform test. The brain tissue was removed by paraffin section and stained with HE. The pathological changes were observed under light microscope. Ultrastructural changes were observed by transmission electron microscope.
Results: (1) early neurobehavioral development index: the time of high dose group (Cliffs avoidance, plane reversal, forelimb suspension, air reversal, auditory consternation and visual orientation) was longer than that of the control group (P0.05); (2) Morris water maze test: the escape latency prolonged (P005) in the water maze of high dose group rats (P005); (3) the jump test: reaction time delay Long, lower latency and increased number of errors (P005); (4) pathology: HE staining, light microscopy showed hyperemia in the hippocampus of high exposure group; (5) transmission electron microscopy: high dose group of hippocampus tissue under the electron microscope showed vacuolar like changes in mitochondria, chromatin concentrated around the nucleus.
Conclusion: exposure to NP during pregnancy can hinder the development of neural behavior and reduce the ability of spatial learning and memory.
The third part is the effect of NP on the gene expression profile in the hippocampus of weaning rats.
Objective: To investigate the expression of differentially expressed genes in the hippocampus of NP exposed group and control group by gene chip technology, and to select the differentially expressed genes and pathways related to neurotoxicity. Methods: to establish the offspring model of NP in pregnancy and lactation period, and to extract the 1 day offspring from the exposure group and the control group. The rat hippocampal tissue mRNA, using the 12 x 135 locus produced by Roche Nimblegen, contained the gene chip of 26419 genes of the rat, detected the expression of the brain gene, and scanned and processed the data by the scanner.
Results: there were 1254 differentially expressed genes in the exposure group and the control group, of which 619 genes were up-regulated and 635 genes were down. Some genes related to the function of the nervous system were expressed as: A. neurotrophic related gene expression: Galanin (Gal) gene downregulation, neural growth factor (Nerve Growth Factor, NGF) gene downregulation; B. The expression of apoptosis related genes: apoptotic protease activating factor -1 (Apoptotic Protease Activating Factor-1, Apaf-1) up-regulated, apoptosis inhibitory gene -1 (Defender Against Apoptotic Death-1, DAD1) gene regulation, cysteine protease 7 gene regulation; The expression of the ion channel related genes: the Glutamate Receptor (Ionotropic, AMPA2) gene was down regulated, and the calmodulin dependent protein kinase II (Calcium/calmodulin-dependent Protein Kinase II Delta, Camk2d) gene was downregulated.
Conclusion: the results of the chip suggest that NP can lead to differentially expressed genes such as signal transduction, immune response, apoptosis, inflammatory response factor, and glial cell development in the hippocampal neurons of the offspring, and the above changes may interfere with the development and function of the nervous system.
The fourth part is the mechanism of NP exposure on the neurodevelopmental toxicity of offspring rats.
Objective: To observe the changes of apoptosis, neurotransmitters, glial cells and nerve growth related genes in the pregnant and lactation period of NP rats, and to explore the possible mechanism of NP on the neurotoxicity of the offspring.
Methods: 31 pregnant mice were randomly assigned to 4 groups according to the date of pregnancy, namely, C, L, M, H group (NP0,25,50100mg/kg/day), single cage, fasting stomach, NP exposure time for sixth days of pregnancy to 21 days after birth (GD6 to PND21), and radioimmunoassay for the detection of serum estradiol (E2) and testosterone (TT) levels in the serum for 21 days. The activity of cholinesterase (ChAT) and cholinesterase (AchE) in hippocampal tissue of offspring was measured by colorimetric method. The expression of early gene c-fos and c-jun protein in hippocampus was observed by immunohistochemical staining. In situ terminal labeling method (TUNEL) was used to observe the apoptosis of hippocampal neurons in PND21 days and 60 days, and immunohistochemistry was used to detect hippocampus and cortex. The changes in the protein of glial glial fibrillary acidic protein (GFAP) and nerve growth related factor (GAP-43) in astrocytes and the changes of GFAP and GAP-43mRNA were detected by RealTime PCR method, and the relationship between the changes of these indexes and the exposure dose of NP was analyzed.
Results: (1) the effect of NP on serum hormone levels in weaning rats: the results of radioimmunoassay showed that the serum testosterone level decreased with the increase of NP exposure dose 21 days after birth, and there was a dose effect relationship (r=-0.889, P 0.05). Compared with the control group, the testosterone levels in two groups of M and H were significantly decreased (P0.05); estrogen level and NP exposure were also exposed. The dose positive correlation (r=-0.462, P0.01), the level of estrogen in the H dose group was significantly different from that of the control group (P 0.05). (2) the effect of NP exposure on the apoptosis of the nerve cells in the weaning and mature rats: the results of TUNEL assay showed that the apoptosis rate of hippocampal cells in 21d and 60d in the offspring was significantly higher than that in the control group (P 0.01), and the NP was NP. The exposure dose was positively correlated with the apoptosis rate (r=0.836,0.521, P 0.05). From the longitudinal comparison, the apoptosis rate of hippocampus tissue in the 21 day offspring of the exposed groups was higher than that of 60 days (t=3.331, P0.05). The effect of A. NP on the ChAT and AchE activity of the hippocampal tissues of the offspring: M, H dose group was significantly lower than that of the hippocampus. The activity of AchE in the M dose group was higher than that in the control group (P 0.01). The activity of ChAT and AchE in the hippocampus and the exposure dose of NP were in a dose-dependent manner (r=-0.821,0.757, P 0.05) and the expression of c-fos and c-jun protein in the.B. hippocampus tissue: the expression of c-jun and protein in the hippocampus of normal rats was very low, and the number of positive cells in the dose group was less and the pigment was shallow. The number of c-jun and c-fos positive cells in the hippocampus of the rats increased, especially in the high dose group. The effect of NP on the glial fibrillary acidic protein in the astrocytes of the hippocampus of the offspring: the results of the immunohistochemical technique for the expression of GFAP protein showed that the H dose group was 21d and the hippocampal and cortex of 60d old mice were GFAP free. The number of pestilence positive cells, the integral light density was significantly higher than that of the control group (P 0.05). The results of GFAP expression by fluorescence quantitative PCR showed that the expression of GFAP mRNA in the hippocampus of 21d and 60d age rats in the H dose group was significantly higher than that of the control group, and the expression of.GFAP protein and GFAP mRNA was positively related to the exposure dose of NP (0.05). The effect of NP on the nerve growth related protein in the offspring: the results of the immunohistochemical technique to detect the expression of GAP-43 protein showed that the average number of GAP-43 positive cells in the hippocampus and cortex of the H dose group was 21d and 60d, and the integral light density was lower than that of the control group (P 0.05), and the fluorescence quantitative PCR results showed 21d and 60d in the H dose group. The expression of GAP-43mRNA in hippocampus of aged rats was decreased, and the difference was statistically significant. There was a negative correlation between.GAP-43 protein and GAP-43mRNA expression and NP exposure dose (P 0.05).
Conclusion: combined with the above data, it is speculated that the possible mechanism of NP induced neurotoxicity is to contact NP in embryo and lactation period. The weak estrogen like action of NP causes the imbalance of endocrine system through competitive estrogen receptor, which leads to the increase of estrogen level in the offspring, changes the endocrine environment of the development of the offspring's brain and interferes with the hair cells. It reduces the expression level of neurotrophic factor GAP-43 and inhibits the differentiation of nerve cells, including neurite growth and branching, synapse formation, and increases the expression of glial fibrillary acidic protein GFAP, and affects the morphology, structure and energy of astrocytes, and further affects the cholinergic neurotransmitter Ach and the early basis. The information transmission of c-jun, c-fos and the induction of neuronal apoptosis in the hippocampus of the offspring led to the delay of the neural reflex time in the offspring's development and the learning and memory impairment at the mature stage.

【學位授予單位】：重慶醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R114

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