本文選題：正己烷 + 妊娠期暴露�。� 參考：《福建醫(yī)科大學(xué)》2013年博士論文

【摘要】：正己烷是一種廣泛用于食品、藥品和有機(jī)合成的溶劑。因其常溫下易揮發(fā)職業(yè)暴露多通過呼吸道途徑，暴露人群中育齡女性比例較高。正己烷早期被認(rèn)為低毒或微毒物而廣泛應(yīng)用于各行業(yè)，但近年來的研究表明正己烷及其代謝產(chǎn)物對(duì)雌性生殖內(nèi)分泌有明顯的干擾，同時(shí)基礎(chǔ)毒理學(xué)資料表明妊娠期正己烷暴露有可能造成子代生長發(fā)育障礙，且正己烷無明顯的致DNA突變效應(yīng)。因此我們通過建立妊娠Wista大鼠正己烷暴露模型來研究妊娠期正己烷暴露對(duì)子代成年后卵巢生長發(fā)育、卵巢顆粒細(xì)胞DNA甲基化狀態(tài)及卵巢顆粒細(xì)胞激素分泌功能的影響，明確胚胎發(fā)育期正己烷暴露對(duì)子代雌性生殖系統(tǒng)發(fā)育的影響，有利于進(jìn)一步提高對(duì)正己烷職業(yè)暴露的防控和危險(xiǎn)人群的干預(yù)。 目的： 通過建立Wista大鼠妊娠期正己烷暴露模型，研究妊娠期正己烷暴露對(duì)子代成年后卵巢生長發(fā)育、卵巢顆粒細(xì)胞DNA甲基化狀態(tài)及卵巢顆粒細(xì)胞激素分泌功能的影響，進(jìn)一步從機(jī)制上闡明妊娠期正己烷暴露對(duì)于子代卵巢發(fā)育和功能的影響。為正己烷卵巢發(fā)育毒性及機(jī)制研究提供科學(xué)依據(jù)�；谝陨夏康�，我們將研究分為以下三個(gè)部分： （一）妊娠期正己烷暴露對(duì)F1代大鼠卵巢發(fā)育和激素分泌功能的影響 方法： 清潔級(jí)成年Wistar大鼠，雌性體重210-230g，雄性300-320g，合籠受孕后，每組5只。GD1-20分別暴露于0、100、500、2500和12500ppm正己烷，靜式吸入染毒，4h/d，F(xiàn)1代雌鼠PD56取卵巢。觀察大鼠的出生性別比、F1代雌鼠的體重增長、陰道開放時(shí)間和動(dòng)情周期；HE染色連續(xù)切片測量各級(jí)卵泡數(shù)并觀察卵巢病理改變；分離F1代雌鼠卵巢顆粒細(xì)胞，競爭性電化學(xué)發(fā)光法測定F1代雌鼠卵巢顆粒細(xì)胞培養(yǎng)液雌二醇和孕酮水平。 結(jié)果： （1）出生活胎數(shù)和性別比：12500ppm組的出生活胎數(shù)顯著低于其他各組（p0.05）；隨著暴露劑量的增加，雌/雄性別比有下降的趨勢。 （2）體重增長和陰道開放時(shí)間：各正己烷暴露組體重和對(duì)照組總體上無顯著性差異（p0.05），但d36日之后有增長減緩的趨勢；正己烷暴露組陰道開放時(shí)間與對(duì)照組比較無顯著差異（p0.05）。 （3）動(dòng)情周期：與對(duì)照組比較，100，500和2500ppm組的動(dòng)情前期顯著延長（p0.05），500ppm和2500ppm組動(dòng)情期顯著延長（p0.05），12500ppm組動(dòng)情間期顯著縮短（p0.05）。 （4）卵泡數(shù)目構(gòu)成比：12500ppm組的次級(jí)卵泡比例顯著低于對(duì)照組（p0.05），閉鎖卵泡比例顯著高于對(duì)照組（p0.05）。 （5）卵巢顆粒細(xì)胞培養(yǎng)液雌二醇、孕酮水平：2500和12500ppm雌二醇分泌水平顯著低于對(duì)照組（p0.05）；100和500ppm組孕酮分泌水平顯著高于對(duì)照組，而12500ppm組孕酮分泌水平顯著低于對(duì)照組（p0.05）。 （二）妊娠期正己烷暴露對(duì)F1代大鼠卵巢顆粒細(xì)胞啟動(dòng)子區(qū)差異甲基化全基因組研究 方法： 分離F1代大鼠的卵巢顆粒細(xì)胞，DNeasyBloodTissueKit提取基因組DNA，超聲破碎后與5-mC抗體免疫共沉淀，再與Nimblegen385KPromoterPlusCpGIslandArrays雜交，以啟動(dòng)子區(qū)探針PeakScore2并和對(duì)照組有差別為標(biāo)準(zhǔn)篩選差異甲基化基因。將差異甲基化基因?qū)隓AVID數(shù)據(jù)庫進(jìn)行以下分析：GeneOntologyConsortium方法注釋差異性甲基化基因、差異性甲基化基因DAVID聚類分析、DAVID聚類基因Pmvalue值二項(xiàng)聚類分析組間甲基化模式差異、差異甲基化基因KEGG信號(hào)通路分析。 結(jié)果： （1）基因組DNA無明顯的降解并裂解充分，甲基化免疫沉淀特異性高，，甲基化芯片信號(hào)清楚，陽性對(duì)照信號(hào)清晰。 （2）正己烷暴露組共同基因中，去甲基化基因多于高甲基化基因。 （3）基因注釋表明正己烷的效應(yīng)主要與細(xì)胞過程、代謝過程、細(xì)胞內(nèi)基因和磷酸轉(zhuǎn)移酶活性基因有關(guān)。 （4）細(xì)胞死亡、細(xì)胞生長和激素調(diào)控三個(gè)DAVID聚類結(jié)果pm值分析結(jié)果表明，對(duì)照和500ppm組的甲基化模式比較接近，2500和12500ppm組的甲基化模式相對(duì)接近。 （5）KEGG信號(hào)通路分析結(jié)果的表明：凋亡通路中12500ppm組促凋亡基因Bad啟動(dòng)子區(qū)低甲基化，500ppm組凋亡促進(jìn)基因NFKBIA，Bid，Casp7，Dffb啟動(dòng)子區(qū)高甲基化。在激素合成通路，2500和12500ppm組Cyp11a1,Cyp17a1,Hsd3b1和Srd5a1基因啟動(dòng)子區(qū)的高甲基化。 （三）妊娠期正己烷暴露對(duì)F1代大鼠卵巢顆粒細(xì)胞激素分泌相關(guān)基因啟動(dòng)子甲基化研究 方法： 測定MeDIP-Chip芯片譜中激素合成基因相關(guān)基因啟動(dòng)子區(qū)差異甲基化峰及探針位點(diǎn)，MS-HRM法驗(yàn)證篩選出激素合成相關(guān)基因啟動(dòng)子區(qū)甲基化狀態(tài)，RealtimePCR法測定篩選基因的mRNA表達(dá)水平。 結(jié)果： （1）激素合成基因相關(guān)基因啟動(dòng)子區(qū)差異甲基化峰測量：Star基因，500ppm組的甲基化程度低于對(duì)照組，而12500ppm組明顯高于對(duì)照組（p0.05）；Cyp11a1基因，2500ppm和12500ppm組的甲基化程度明顯高于對(duì)照組（p0.05）；Cyp17a1基因，2500ppm和12500ppm組的甲基化程度明顯高于對(duì)照組（p0.05）；Hsd3b基因，12500ppm組的甲基化程度顯著高于對(duì)照組（p0.05）。 （2）MS-HRM驗(yàn)證甲基化程度：Star基因啟動(dòng)子局部區(qū)域甲基化程度從高到低排列為：12500ppm2500ppmcontrol500ppm100ppm；Cyp11a1基因啟動(dòng)子局部區(qū)域甲基化程度從高到低排列為：12500ppm2500ppmcontrol500ppm和100ppm；Cyp17a1啟動(dòng)子局部區(qū)域甲基化程度從高到低排列為：12500ppm和2500ppmcontrol500ppm和100ppm；Hsd3b啟動(dòng)子局部區(qū)域基因甲基化程度從高到低排列為：12500ppm2500ppm和Control100ppm和500ppm。 （3）RT-PCR結(jié)果：Star、Cyp11a1、Cyp17a1和Hsd3bmRNA表達(dá)量與對(duì)照組比較出現(xiàn)了明顯改變，具體如下：與對(duì)照組比較，Star基因，500ppm組表達(dá)量顯著增高（p0.05），12500ppm組表達(dá)量顯著下降（p0.05）；Cyp11a1基因，500ppm組表達(dá)量顯著增高（p0.05），12500ppm表達(dá)量顯著下降（p0.05）；Cyp17a1基因，500ppm組顯著增高（p0.05），2500ppm和12500ppm顯著下降（p0.05）；Hsd3b基因，12500ppm組顯著下降（p0.05）。 結(jié)論： 根據(jù)以上結(jié)果，可得出如下結(jié)論 1.妊娠期高濃度正己烷暴露具有明顯的胚胎毒性，并能影響F1代雌性大鼠的卵巢發(fā)育和激素分泌功能。 2.妊娠期正己烷暴露會(huì)改變子代卵巢顆粒細(xì)胞的DNA啟動(dòng)子區(qū)甲基化狀態(tài)，高劑量的正己烷暴露（2500和12500ppm）能明顯改變顆粒細(xì)胞凋亡基因和激素合成基因的甲基化狀態(tài)。 3.妊娠期正己烷暴露后，卵巢顆粒細(xì)胞中激素合成相關(guān)基因Star、Cyp11a1、Cyp17a1和Hsd3b的啟動(dòng)子局部區(qū)域的甲基化狀態(tài)改變與對(duì)應(yīng)基因mRNA水平表達(dá)異常，性激素分泌能力改變可能存在一定的聯(lián)系。
[Abstract]:n - hexane ( n - hexane ) is a widely used solvent for food , medicine and organic synthesis .

Purpose :

The effects of n - hexane exposure during pregnancy on the growth and development of ovary , the DNA methylation status of ovary granular cells and the function of ovarian granular cell hormone secretion were studied by establishing a normal hexane exposure model in pregnancy . The effects of n - hexane exposure during pregnancy on the development and function of ovary were further elucidated .

The effects of n - hexane exposure during pregnancy on ovarian development and hormone secretion in F1 generation rats

Method :

Male Wistar rats weighing 210 - 230g and male 300 - 320g were exposed to 0 , 100 , 500 , 2500 , and 12500ppm n - hexane respectively .
HE stained continuous sections to measure the number of follicles at all levels and observe the pathological changes of the ovary ;
The levels of estradiol and progesterone in the ovary granular cells of F1 generation female mice were determined by competitive electrochemical luminescence .

Results :

( 1 ) The number of live fetuses and sex ratio were significantly lower than those in other groups ( p < 0.05 ) .
With the increase of exposure dose , the ratio of female / male sex ratio decreased .

( 2 ) Body weight gain and vaginal opening time : There was no significant difference between the body weight of each n - hexane exposure group and the control group ( p < 0.05 ) , but there was a tendency of slowing down after d36 days .
The vaginal opening time of n - hexane exposed group was not significantly different from that of the control group ( p < 0.05 ) .

( 3 ) The estrus cycle : Compared with the control group , the estrus period of the 100 , 500 and 2500 ppm groups was significantly prolonged ( p < 0.05 ) , the dynamic period of 500 ppm and 2500 ppm group was significantly prolonged ( p < 0.05 ) , and the estrus interval in the 12500 ppm group was significantly shortened ( p < 0.05 ) .

( 4 ) The proportion of follicles in the follicles was significantly lower than that in the control group ( p < 0.05 ) , and the proportion of follicles in the follicles was significantly higher than that of the control group ( p < 0.05 ) .

( 5 ) The levels of estradiol and progesterone in ovarian granular cell culture fluid were significantly lower than those in control group ( p < 0.05 ) .
The levels of progesterone secretion in the 100 and 500 ppm groups were significantly higher than those in the control group , while the level of progesterone secretion in the 12500 ppm group was significantly lower than that of the control group ( p < 0.05 ) .

( 2 ) Whole - gene group of differential methylation of normal hexane exposure during pregnancy on the promoter region of ovary granular cell in F1 generation rat

Method :

The genomic DNA was isolated from F1 generation rats . The genomic DNA was extracted by DNeaster TissueKit , and then hybridized with 5 - mC antibody after ultrasonic disruption . The differential methylated gene was introduced into DAVID database . The difference methylation gene was introduced into DAVID database . The difference of methylation patterns between the two cluster analysis groups was analyzed by GeneOntologyConsortium method .

Results :

( 1 ) the genome DNA has no obvious degradation and lysis , the methylation immunoprecipitation specificity is high , the methylation chip signal is clear , and the positive control signal is clear .

( 2 ) In the common gene of the n - hexane exposure group , the demethylation gene was more than the hypermethylated gene .

( 3 ) Gene annotation indicates that the effect of n - hexane is mainly related to cellular process , metabolic process , intracellular gene and phosphotransferase activity gene .

( 4 ) Three DAVID cluster results of cell death , cell growth and hormone regulation showed that the methylation patterns of the control and 500 ppm groups were relatively close , and the methylation patterns of 2500 and 12500 ppm groups were relatively close .

( 5 ) The results of the signal pathway analysis showed that the apoptosis promoting gene in the apoptotic pathway was low methylation in the promoter region of the promoter region of the promoter region , and the apoptosis promoted the methylation of the promoter region of NFKBIA , Bid , Casp7 and Dffb in the 500 ppm group .

( 3 ) Study on the methylation of the gene promoter involved in the secretion of hormone in the ovary granular cells of F1 generation rats by n - hexane exposure during pregnancy

Method :

The methylation peak and the probe site of the promoter region of the gene related to the hormone synthesis in the MeDIP - Chip chip were determined . The methylation status of the promoter region of the hormone synthesis related gene was verified by the MS - MS method , and the mRNA expression level of the screening gene was determined by the RealtimePCR method .

Results :

( 1 ) The methylation peak of the promoter region of the gene related to hormone synthesis was measured : Star gene , the degree of methylation of 500 ppm group was lower than that of the control group , while the 12500ppm group was significantly higher than that of the control group ( p < 0.05 ) ;
The methylation degree of Cyp11a1 gene , 2500ppm and 12500ppm group was higher than that of control group ( p < 0.05 ) .
The methylation degree of Cyp17a1 gene , 2500ppm and 12500ppm group was higher than that of control group ( p < 0.05 ) .
The methylation degree of Hsd3b gene and 12500ppm group was significantly higher than that of control group ( p < 0.05 ) .

( 2 ) the degree of methylation of the local region of the Star gene promoter from high to low was 12500ppm2500ppmcontrol500ppm100 ppm ;
the degree of methylation of the partial region of the promoter of the Cyp11a1 gene ranges from 12500ppm to 2500ppm control500ppm and 100 ppm ;
The degree of methylation of the partial region of the Cyp17a1 promoter ranged from 1250 ppm to 2500 ppm control500 ppm and 100 ppm ;
The degree of methylation of the local region gene of the Hsd3b promoter ranged from 12500 ppm to 2500 ppm and Control100 ppm and 500 ppm .

( 3 ) RT - PCR results showed that the expression of Star , Cyp11a1 , Cyp17a1 and Hsd3bmRNA was significantly different from that of the control group , which was as follows : Compared with the control group , the expression level of the Star gene and the 500ppm group was significantly increased ( p < 0.05 ) , and the expression level in the 12500ppm group was significantly decreased ( p < 0.05 ) ;
The expression of Cyp11a1 gene and 500 ppm group was significantly increased ( p < 0.05 ) , and the expression level of Cyp11a1 gene was significantly decreased ( p < 0.05 ) .
The Cyp17a1 gene , 500 ppm group increased significantly ( p0.05 ) , 2500 ppm and 12500 ppm decreased significantly ( p < 0.05 ) .
Hsd3b gene , 12500ppm group decreased significantly ( p < 0.05 ) .

Conclusion :

Based on the above results , the following conclusions can be drawn :

1 . High - concentration n - hexane exposure during pregnancy has obvious embryotoxicity and can affect the ovarian development and hormone secretion function of F1 generation female rats .

2 . Normal hexane exposure during pregnancy alters the methylation status of the DNA promoter region of the ovary granular cells in the ovary , and the high - dose n - hexane exposure ( 2500 and 12500ppm ) can significantly change the methylation state of the apoptosis gene and the hormone synthesis gene of the granular cell .

3 . After the exposure of n - hexane in pregnancy , the methylation status of the local region of the promoter of the hormone synthesis related genes Star , Cyp11a1 , Cyp17a1 and Hsd3b in the ovary granular cells changed with the level expression of the corresponding gene mRNA , and the change in the secretion ability of the sex hormone may have a certain relationship .

【學(xué)位授予單位】：福建醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類號(hào)】：R114

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