【摘要】：雙酚A (Bisphenol A, BPA)是一種廣泛使用于塑料制品的環(huán)境內(nèi)分泌干擾物。BPA能經(jīng)由食品以及飲料進(jìn)入到人體,也可以從垃圾滲析到周圍的生態(tài)環(huán)境中而對(duì)健康產(chǎn)生危害。大量研究發(fā)現(xiàn)BPA能夠影響激素的合成和代謝,受體的表達(dá)以及基因的活性,然而以往的研究多集中在其雌激素活性上。本實(shí)驗(yàn)室前期研究發(fā)現(xiàn)無論是圍生期、青春期還是成年期BPA暴露均性別依賴性地?fù)p傷雄性小鼠的空間學(xué)習(xí)記憶以及被動(dòng)回避記憶能力。與雌激素對(duì)雌性動(dòng)物的重要作用一樣,雄激素對(duì)雄性的認(rèn)知功能以及突觸形成具有重要的調(diào)節(jié)作用。近來研究發(fā)現(xiàn)BPA能拮抗雄激素受體(AR)介導(dǎo)的轉(zhuǎn)錄活性。所以,本實(shí)驗(yàn)旨在探究BPA暴露性別特異性地?fù)p傷雄性小鼠學(xué)習(xí)記憶行為是否與其干擾雄激素對(duì)雄鼠學(xué)習(xí)記憶的調(diào)節(jié)作用有關(guān)。突觸可塑性與空間學(xué)習(xí)記憶行為密切相關(guān)。性激素能通過影響海馬和前額葉皮層中樞神經(jīng)系統(tǒng)的突觸重塑而影響認(rèn)知行為。有研究發(fā)現(xiàn)睪丸摘除導(dǎo)致雄性小鼠海馬突觸密度降低,在補(bǔ)充丙酸睪酮(TP)或二氫睪酮(DHT)后,突觸密度顯著增加。突觸界面是一個(gè)對(duì)化學(xué)物質(zhì)非常敏感的結(jié)構(gòu),突觸間隙、突觸活性帶長度、突觸后致密物(postsynaptic density, PSD)和突觸界面曲率等可因外界刺激而發(fā)生改變。PSD上分布著大量的腳手架蛋白以及一些與突觸傳遞相關(guān)的調(diào)節(jié)蛋白,其中很多是與后膜上受體通道相關(guān)聯(lián),這些蛋白表達(dá)水平的改變以及彼此間的相互作用都能影響突觸的活性和突觸可塑性,同時(shí)也導(dǎo)致PSD厚度的變化。本研究通過建立成年去勢(shì)雄鼠模型,將性腺完整、去勢(shì)、去勢(shì)后補(bǔ)充雄激素的雄鼠分別暴露于BPA,研究長期BPA暴露對(duì)成年雄鼠學(xué)習(xí)記憶行為的影響,進(jìn)一步電鏡觀測(cè)雄鼠海馬CA1區(qū)神經(jīng)元的突觸密度以及突觸界面結(jié)構(gòu)的改變；最后通過Western blot檢測(cè)海馬突觸蛋白Synapsin Ⅰ和PSD-95,興奮性氨基酸NMDA受體以及信號(hào)通路蛋白ERK1/2、p38及其磷酸化表達(dá)的改變,探討B(tài)PA暴露影響雄鼠空間學(xué)習(xí)記憶行為和突觸可塑性的可能機(jī)制。研究方法：清潔級(jí)8周齡的ICR雄性小鼠,購買于浙江醫(yī)學(xué)科學(xué)院實(shí)驗(yàn)動(dòng)物中心。飼養(yǎng)的環(huán)境為自然光照和黑暗12h交替,飼養(yǎng)室的溫度控制在23±2℃，，50%-60%的濕度控制,水以及食物均能自由取食。適應(yīng)環(huán)境一周后,水合氯醛(400mg/kg)腹腔注射麻醉,然后進(jìn)行睪丸摘除術(shù)建立去勢(shì)模型。術(shù)后恢復(fù)2周之后,每天進(jìn)行頸背部皮下注射染毒：丙酸睪酮(TP,0.5 mg/kg/day), BPA(0.4,4 mg/kg/day), TP+BPA(0.4或4 mg/kg/day),金龍魚食用油(50μL/day),為期45天。給藥結(jié)束3天后,每組取14只進(jìn)行行為檢測(cè),6只制作海馬超薄切片進(jìn)行海馬突觸形態(tài)測(cè)定,4只用于測(cè)定相關(guān)蛋白,8只用于測(cè)定腦和血清雄激素水平。實(shí)驗(yàn)所有的數(shù)據(jù)以平均值士標(biāo)準(zhǔn)誤顯示,用SPSS 17.0統(tǒng)計(jì)軟件進(jìn)行統(tǒng)計(jì)分析。水迷宮4天訓(xùn)練結(jié)果采用重復(fù)三因素方差分析,水迷宮第5天結(jié)果、突觸形態(tài)測(cè)定結(jié)果采用雙因素方差分析,雄激素水平以及Western blot的蛋白結(jié)果采用單因素方差分析。研究結(jié)果：1.與假手術(shù)對(duì)照組相比,性腺摘除顯著降低血清和腦內(nèi)雄激素水平(p0.001；p0.001),當(dāng)補(bǔ)充TP后,血清和腦雄激素水平上升(p0.001；p0.001)。BPA(0.4,4mg/kg/day)暴露不影響性腺摘除鼠血清和腦中雄激素水平,但是顯著降低假手術(shù)組小鼠血清(p0.05；p0.01)和腦(p0.05；p0.01)雄激素的水平和TP補(bǔ)充小鼠血清(p0.05)和腦(p0.05；p0.01)雄激素水平。2.水迷宮4天的訓(xùn)練結(jié)果表明：與假手術(shù)對(duì)照組相比,性腺摘除顯著延長第4天小鼠找到平臺(tái)的潛伏期(p0.05),TP補(bǔ)充后,找到平臺(tái)的潛伏期縮短(p0.05),表明雄激素缺失明顯損傷空間學(xué)習(xí)能力。BPA暴露沒有延長去勢(shì)小鼠找到平臺(tái)的潛伏期(p0.05),但顯著延長假手術(shù)組(4 mg/kg/day, p0.01)和TP補(bǔ)充組(0.4 mg/kg/day, p0.05)小鼠找到平臺(tái)的潛伏期。水迷宮第5天的結(jié)果表明,BPA暴露降低假手術(shù)組小鼠(0.4 mg/kg/day, p0.05)和TP補(bǔ)充組小鼠(p0.001；p0.01)在目標(biāo)象限停留的時(shí)間百分比,但不影響睪丸摘除小鼠目標(biāo)象限停留的時(shí)間百分比。這些結(jié)果表明BPA損傷成年小鼠空間記憶能力,能抑制雄激素對(duì)性腺摘除誘導(dǎo)的空間記憶損傷的恢復(fù)作用。3.突觸密度結(jié)果顯示,性腺摘除顯著降低成年雄鼠海馬CA1區(qū)突觸密度(p0.001),TP補(bǔ)充后突觸密度顯著提高(p0.001)。BPA (0.4,4mg/kg/day)暴露降低假手術(shù)組海馬CA1區(qū)突觸密度(p0.001,p0.001),但對(duì)性腺摘除組沒有影響。BPA (0.4,4 mg/kg/day)暴露抑制TP誘導(dǎo)的突觸密度增多(p0.01,p0.001)。與假手術(shù)對(duì)照組相比,性腺摘除顯著縮短活性帶長度(p0.01),減小PSD厚度(p0.001),增大突觸間隙寬度(p0.001),但TP補(bǔ)充后這種變化被BPA逆轉(zhuǎn)(p0.05,p0.05,p0.001)。BPA暴露對(duì)假手術(shù)組突觸結(jié)構(gòu)的影響與TP補(bǔ)充組相似。這些結(jié)果表明BPA暴露能抑制雄激素的誘導(dǎo)的海馬突觸的形成和結(jié)構(gòu)修飾。4.進(jìn)一步的Western blot分析顯示,BPA尤其在4 mg/kg/day的劑量,顯著下調(diào)假手術(shù)組小鼠海馬synapsin Ⅰ (p0.05), PSD-95 (p0.01), NR2B (p0.05)的表達(dá)。性腺摘除微弱下調(diào)synapsin I,但顯著下調(diào)PSD-95 (p0.05), NR2B(p0.01)的表達(dá),在補(bǔ)充TP之后這些蛋白表達(dá)上調(diào)(p0.05,p0.05)。BPA暴露抑制TP誘導(dǎo)對(duì)synapsinⅠ (p0.01), PSD-95 (p0.05), NR2B (p0.05)的上調(diào)作用。進(jìn)一步分析發(fā)現(xiàn),性腺摘除和BPA暴露對(duì)p38和ERK1/2的表達(dá)沒有影響,但是4 mg/kg/day的BPA暴露顯著下調(diào)ERK1/2的磷酸化(p-ERK1/2)水平(p0.05)并上調(diào)p-p38的磷酸化(p-p38)(p0.001)。BPA暴露抑制TP誘導(dǎo)的p-ERK1/2上調(diào)(p0.01)和p-p38下調(diào)(p0.01)。這些結(jié)果表明BPA暴露抑制雄激素誘導(dǎo)的突觸蛋白和NR2B的表達(dá),抑制MAPK/ERKs并促進(jìn)MAPK/p38信號(hào)通路的活性。結(jié)論：長期暴露于BPA性別特異性地?fù)p傷雄性動(dòng)物的學(xué)習(xí)記憶功能可能與BPA的抗雄激素作用有關(guān)。該作用可能一方面通過降低腦內(nèi)雄激素水平,并干擾雄激素對(duì)ERKs和p38信號(hào)通路的活性而下調(diào)突觸蛋白和NMDA受體水平,負(fù)性改變海馬神經(jīng)元的突觸可塑性,最終損傷學(xué)習(xí)記憶功能。
[Abstract]:Bisphenol A (BPA) is a widely used environmental endocrine disruptor for plastic products. BPA can enter the human body via food and beverage, and can also be harmful to health by dialysis to the surrounding ecological environment. A large number of studies have found that BPA can affect the synthesis and metabolism of hormones, the expression of receptors, and the activity of genes, however, the previous studies have been focused on their estrogenic activity. The pre-laboratory study found that both perinatal, adolescent and adult-year BPA exposure had sex-dependent impairment of the spatial learning and memory of male mice and passive avoidance of memory. As with the important role of estrogen on female animals, androgens play an important role in the cognitive function of the male and the formation of synapses. Recent studies have found that BPA can antagonize androgen receptor (AR)-mediated transcriptional activity. Therefore, the purpose of this experiment is to explore whether the exposure of BPA to sex-specific damage to male mice is related to the effect of interfering with androgen on learning and memory of male rats. The synaptic plasticity is closely related to the spatial learning and memory behavior. Sex hormones can affect cognitive behavior by affecting the synaptic remodeling of the central nervous system in the hippocampus and the prefrontal cortex. It was found that testicular removal resulted in a decrease in synaptic density in the hippocampus of male mice, and a significant increase in synaptic density following the supplementation of testosterone (TP) or dihydrotestosterone (DHT). The synaptic interface is a very sensitive structure to chemical substances, synaptic cleft, synaptic active band length, postsynaptic density (PSD) and synaptic interface curvature can change due to external stimuli. A large number of scaffolding proteins and some regulatory proteins associated with synaptic transmission are distributed on the PSD, many of which are associated with the receptor channel on the back membrane, the changes in the level of expression of these proteins, and the interaction with each other, can affect the activity and synaptic plasticity of the synapse, And also results in a change in the PSD thickness. The effects of long-term BPA exposure on learning and memory behavior of adult male rats were studied by establishing an adult castrated male mouse model, exposing the male mice with complete, castrated and castrated androgen to BPA, respectively, and studying the effects of long-term BPA exposure on learning and memory behavior of adult male rats. The changes of the synaptic density and the synaptic interface structure of the neurons in the hippocampal CA1 region of the male rats were observed by electron microscopy, and the changes of the expression of the synapsin I and PSD-95, the excitatory amino acid NMDA receptor and the signaling pathway protein ERK1/2, p38 and the phosphorylation of the signal pathway proteins were detected by Western blot. To study the possible mechanism of BPA exposure to the learning and memory behavior and synaptic plasticity of male rats. The method of the study was to clean the ICR male mice at 8 weeks of age and to purchase the experimental animal center of Zhejiang Academy of Medical Sciences. The environment of the feeding is natural light and dark 12h, and the temperature of the feeding room is controlled at 23-2 & deg; C and 50-60% of the humidity control, and the water and the food can be freely fed. After a week of acclimation, a castrated model was established by intraperitoneal injection of chloral (400 mg/ kg). After 2 weeks of post-operation, the neck and back were injected subcutaneously each day: Testosterone Propionate (TP, 0.5 mg/ kg/ day), BPA (0.4,4 mg/ kg/ day), TP + BPA (0.4 or 4 mg/ kg/ day), and Golden Dragon Fish Oil (50.mu. L/ day) for a period of 45 days. Three days after the end of the administration,14 animals were tested for behavioral tests,6 of which were used for hippocampal synapse morphometry,4 for the determination of related proteins and 8 for the determination of brain and serum androgen levels. All the data of the experiment were misdisplayed by means of the mean value, and the statistical analysis was made with the SPSS 17.0 statistical software. The results of 3-factor analysis of variance and the fifth day of the water maze were used in the water maze. The results of the five-day analysis of the water maze and the results of the morphological measurement of the water maze were the two-factor analysis of variance, the level of androgens and the results of Western blot. Study results:1. Compared with the sham-operated control group, gonad removal significantly decreased the levels of androgen in serum and brain (p0.001; p0.001), and the levels of serum and brain androgen increased after supplementation of TP (p0.001; p0.001). The exposure of BPA (0.4,4 mg/ kg/ day) did not affect the levels of androgen in the serum and brain of the gonads, but significantly reduced the levels of androgen in the sham-operated group (p0.05; p0.01) and the brain (p0.05; p0.01), and the androgen levels in the brain (p0.05) and the brain (p0.05; p0.01). The results of the 4-day training of the water maze showed that, compared with the sham-operated control group, the latency of the platform was significantly prolonged on the 4th day after the gonad removal (p0.05), and the latency of the platform was shortened after the addition of TP (p0.05), indicating that the androgen deficiency obviously damaged the learning ability of the space. The exposure of BPA did not prolong the incubation period of the castrated mice (p0.05), but significantly prolonged the latency of the platform in the sham operation group (4 mg/ kg/ day, p0.01) and the TP supplementation group (0.4 mg/ kg/ day, p0.05). The results of the fifth day of the water maze showed that BPA exposure reduced the percentage of time that the sham-operated mice (0.4 mg/ kg/ day, p0.05) and TP-supplemented mice (p0.001; p0.01) remained in the target quadrant, but did not affect the percentage of time that the testicle removed the target quadrant of the mouse. These results show that the ability of BPA to damage the space memory of adult mice can inhibit the recovery of the spatial memory damage induced by androgen on the gonad removal. The results of synaptic density showed that the synaptic density (p0.001) in the CA1 region of the hippocampus of the adult male rats was significantly reduced, and the postsynaptic density was significantly increased after the addition of TP (p0.001). BPA (0.4,4 mg/ kg/ day) exposure reduced the synaptic density in the hippocampal CA1 region of the sham-operated group (p0.001, p0.001), but had no effect on the gonad removal group. The exposure of BPA (0.4,4 mg/ kg/ day) inhibited the increase in synaptic density induced by TP (p0.01, p0.001). Compared with the sham operation control group, gonad removal significantly shortened the length of the active band (p0.01), decreased the PSD thickness (p0.001), increased the synaptic cleft width (p0.001), but the change was reversed by the BPA after the addition of TP (p0.05, p0.05, p0.001). The effect of BPA exposure on the synaptic structure of the sham-operated group was similar to that of the TP-supplemented group. These results suggest that BPA exposure can inhibit the formation and structural modification of androgen-induced hippocampal synapses. Further Western blot analysis showed that the expression of p0.05, PSD-95 (p0.01), NR2B (p0.05) in the hippocampus of the sham-operated mice was significantly reduced, especially at the dose of 4 mg/ kg/ day. In addition, the expression of PSD-95 (p0.05) and NR2B (p0.01) was significantly reduced, and the expression of these proteins was up-regulated after the supplementation of TP (p0.05, p0.05). The exposure of BPA inhibited the up-regulation of synapsin I (p0.01), PSD-95 (p0.05), NR2B (p0.05). Further analysis found that the exposure of gonad and BPA did not affect the expression of p38 and ERK1/2, but the exposure of 4 mg/ kg/ day to BPA significantly reduced the phosphorylation of ERK1/2 (p-ERK1/2) (p0.05) and increased the phosphorylation of p-p38 (p-p38) (p0.001). BPA exposure inhibited TP-induced p-ERK1/2 up-regulation (p0.01) and p-p38 down-regulation (p0.01). These results suggest that the exposure of BPA inhibits the expression of the androgen-induced mutant and NR2B, inhibits the MAPK/ ERKs and promotes the activity of the MAPK/ p38 signaling pathway. Conclusion: Long-term exposure to BPA sex-specific damage to the learning and memory function of male animals may be related to the anti-androgenic effect of BPA. This effect may reduce the level of the synaptoprotein and the NMDA receptor by reducing the level of androgen in the brain and interfering with the activity of the androgen on the ERKs and p38 signaling pathways, negatively altering the synaptic plasticity of the hippocampal neurons, and eventually damaging the learning and memory function.
【學(xué)位授予單位】：浙江師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R114

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