李欣洋(綜述)，王　曄(審校)

(四川大學(xué)華西公共衛(wèi)生學(xué)院，成都 610041)

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鄰苯二甲酸二(2-乙基己)酯中毒機(jī)制研究進(jìn)展

李欣洋(綜述)，王曄※(審校)

(四川大學(xué)華西公共衛(wèi)生學(xué)院，成都 610041)

摘要：鄰苯二甲酸二(2-乙基己)酯是使用十分廣泛的塑化劑，為人類內(nèi)分泌干擾物。目前對(duì)其致病機(jī)制尚不清楚?，F(xiàn)有研究認(rèn)為，其可能具有內(nèi)分泌干擾、氧化損傷、免疫紊亂和遺傳物質(zhì)改變等多系統(tǒng)、多途徑的毒性。其內(nèi)分泌干擾主要表現(xiàn)為可能通過(guò)多途徑干擾雄性生殖系統(tǒng)發(fā)育及功能，對(duì)雌性生殖系統(tǒng)也可能有影響，表現(xiàn)出擬雌激素作用；氧化損傷主要可能的靶器官為肝臟；由于其體內(nèi)代謝分布特性，免疫干擾表現(xiàn)在多器官中，表現(xiàn)多樣；對(duì)神經(jīng)毒性的相關(guān)研究發(fā)現(xiàn)，鄰苯二甲酸二(2-乙基己)酯可上調(diào)或下調(diào)多種神經(jīng)因子，可能有多器官的廣泛毒性。

關(guān)鍵詞：鄰苯二甲酸二(2-乙基己)酯； 毒性； 病理機(jī)制

鄰苯二甲酸二(2-乙基己)酯[di-(2-ethylhexyl)phthalate，DEHP]是使用最為廣泛的塑化劑，被世界衛(wèi)生組織確定為環(huán)境內(nèi)分泌干擾物之一，甚至被列為人類可能致癌物(IARC分類為Group 2B)[1]。其毒性作用具體機(jī)制至今尚未完全清楚，大量學(xué)者在DEHP有關(guān)人體內(nèi)代謝和多種可能的靶器官以及靶細(xì)胞的作用機(jī)制等方面進(jìn)行了相關(guān)研究。該文綜述國(guó)內(nèi)外近年來(lái)的相關(guān)研究，供相關(guān)領(lǐng)域?qū)W者參考。

1DEHP在體內(nèi)的代謝

DEHP主要經(jīng)口攝入[2]，在腸道和肝臟中代謝。在腸道中經(jīng)過(guò)水解酶的作用后DEHP大部分代謝為鄰苯二甲酸單乙基己基酯[Mono(2-ethylhexyl) phthalate，MEHP][3]。Carbone 和Velkov[4]發(fā)現(xiàn)MEHP與腸細(xì)胞內(nèi)固有脂質(zhì)結(jié)合蛋白或腸-肝-脂肪酸結(jié)合蛋白結(jié)合后，就可輕易進(jìn)入腸上皮細(xì)胞，進(jìn)而被吸收入血。而后在肝臟水解酶和細(xì)胞色素P450的介導(dǎo)下發(fā)生葡萄糖醛酸化，代謝為5-OH MEHP 和5-Oxo MEHP[5-6]，最終以葡萄糖醛酸結(jié)合體形式排出體外；在腸道中未被水解的DEHP多以原型從糞中排出。Choi等[7]發(fā)現(xiàn)，DEHP 在人的腸道的清除率是肝臟的2~4倍；然而肝臟對(duì)MEHP的細(xì)胞色素P450介導(dǎo)的氧化反應(yīng)速度很快。研究表明，人體清除進(jìn)入體內(nèi)的DEHP速度比較快，一般不在體內(nèi)蓄積[8]。除經(jīng)口攝入外，Hopf等[9]發(fā)現(xiàn)DEHP也可以通過(guò)皮膚接觸方式進(jìn)入人體，并在皮膚局部代謝為5-Oxo MEHP。

2內(nèi)分泌干擾作用

DEHP主要通過(guò)雌激素樣作用、干擾內(nèi)分泌調(diào)節(jié)來(lái)作用于生殖器官。目前研究較多的是雄性子代的胚胎生殖毒性，對(duì)雌性生殖系統(tǒng)以及胰腺內(nèi)分泌功能的影響也有研究。

Gray等[10]對(duì)母鼠進(jìn)行DEHP染毒后發(fā)現(xiàn)子代雄鼠睪丸與附睪出現(xiàn)高度畸形，主要為萎縮和發(fā)育不全。F1代多數(shù)雄性后代肛門生殖器距離縮短，精子數(shù)量下降，生殖器官重量減少。此外，雄性胚胎出生率下降，突變概率增加。Howdeshell等[11]通過(guò)生化檢測(cè)發(fā)現(xiàn)鄰苯二甲酸酯染毒的子代雄鼠睪酮、雌二醇水平下降，胰島素樣因子3(僅由成熟的Leydig細(xì)胞產(chǎn)生)表達(dá)減少，他們認(rèn)為鄰苯二甲酸酯干擾睪丸間質(zhì)細(xì)胞(Leydig細(xì)胞)和睪丸支持細(xì)胞(Sertoli細(xì)胞)的成熟，導(dǎo)致成年時(shí)雄鼠生精小管畸形，進(jìn)而導(dǎo)致精細(xì)胞畸形、多核。Carbone等[12]以胎鼠后代為觀察對(duì)象，發(fā)現(xiàn)較低劑量DEHP染毒后，血液中促性腺激素水平未觀察到明顯變化，且雌雄后代氨基酸神經(jīng)遞質(zhì)水平降低；隨染毒劑量的升高，在子代雄胎鼠中出現(xiàn)抑制性神經(jīng)遞質(zhì)γ-氨基丁酸水平下降，興奮性神經(jīng)遞質(zhì)天冬氨酸水平增加，同時(shí)伴有外周促性腺激素水平增加；在子代雌鼠中，γ-氨基丁酸和天冬氨酸同時(shí)增加，伴有典型的促性腺激素增加，他們認(rèn)為DEHP改變下丘腦-垂體-性腺軸的功能，興奮性氨基酸系統(tǒng)對(duì)促性腺激素釋放激素具有刺激作用，進(jìn)而促性腺激素釋放，而γ-氨基丁酸對(duì)此有抑制作用。Sekiguchi等[13]先對(duì)未成熟的雌鼠先誘導(dǎo)過(guò)度排卵，然后用大劑量DEHP處理，發(fā)現(xiàn)其外周循環(huán)中甲狀腺素水平明顯下降。

Takai 等[14]發(fā)現(xiàn)雌鼠卵巢暴露于DEHP后形成空泡，大劑量時(shí)還發(fā)現(xiàn)新生黃體減少以及發(fā)情周期延長(zhǎng)且不規(guī)律。Carnevali等[15]對(duì)斑馬魚(yú)進(jìn)行DEHP染毒發(fā)現(xiàn)，DEHP暴露后排卵與胚胎數(shù)均下降，幾種特殊的調(diào)節(jié)因子如黃體生成素受體、膜孕激素受體β水平也下降；此外環(huán)氧合酶-2的表達(dá)也下降。Zhou等[16]將MA-10 Leydig細(xì)胞暴露于MEHP后，發(fā)現(xiàn)黃體酮刺激型環(huán)磷酸腺苷和孕激素水平下降；而當(dāng)使用二丁基-環(huán)磷酸腺苷、22-羥基膽固醇或孕激素來(lái)消除孕激素減少的影響后，環(huán)磷酸腺苷則不減少，同時(shí)發(fā)現(xiàn)MEHP還可使細(xì)胞活性氧類水平上升。Ambruosi 等[17]對(duì)馬卵母細(xì)胞進(jìn)行體外DEHP 染毒實(shí)驗(yàn)，發(fā)現(xiàn)低劑量的DEHP明顯抑制卵母細(xì)胞的成熟，而高劑量時(shí)則誘導(dǎo)卵細(xì)胞凋亡伴有卵丘細(xì)胞活性氧類水平上升，但不影響其成熟。然而，已經(jīng)成熟的卵細(xì)胞暴露于DEHP，其線粒體功能及超氧化物歧化酶雖未見(jiàn)異常，但其ATP水平增高。

Zhang等[18]研究發(fā)現(xiàn)，DEHP對(duì)精細(xì)胞有絲分裂過(guò)程沒(méi)有影響，但精子的質(zhì)量和數(shù)量均下降；與精子質(zhì)量有關(guān)的基因DDx3Y、Usp9Y、RBM 和E1F1AY表達(dá)下調(diào)，黃體生成素受體、表皮生長(zhǎng)因子(epidermal growth factor，EGF)和EGF受體水平下調(diào)，Cyp17a1和 Cyp19a1表達(dá)上調(diào)；他們還發(fā)現(xiàn)DEHP對(duì)精子生成過(guò)程中基因重組有干擾作用，干擾染色體互換，MLH1蛋白表達(dá)增加。Richburg等[19]研究表明，用實(shí)驗(yàn)動(dòng)物暴露于MEHP后，Sertoli細(xì)胞介導(dǎo)生殖細(xì)胞凋亡，其中與Fas/FasL信號(hào)通路有密切關(guān)系。

Lin 等[20]通過(guò)大鼠實(shí)驗(yàn)發(fā)現(xiàn)，DEHP暴露會(huì)導(dǎo)致胰島B細(xì)胞超微結(jié)構(gòu)異常，細(xì)胞量下降，胰腺胰島素水平、相關(guān)基因表達(dá)均受影響，鼠成年后，雌性鼠血糖水平上升，血清中胰島素水平下降，糖耐受能力和胰島素分泌功能受損；雄性后代則出現(xiàn)血清胰島素水平上升。所有后代均有出生后體質(zhì)量減輕。

3肝臟的損傷

有流行病學(xué)研究發(fā)現(xiàn)，使用DEHP的注射用品與新生兒膽汁淤積關(guān)系密切，其機(jī)制不明[21]。Zheng 等[22]通過(guò)腹膜內(nèi)注射法將金魚(yú)暴露于DEHP后發(fā)現(xiàn)鄰苯二甲酸酯作用于魚(yú)會(huì)使其肝臟內(nèi)超氧化物歧化酶、過(guò)氧化氫酶和還原型谷胱甘肽等3種抗氧化酶的活性明顯降低。Hayashi 等[23]將鼠野生型肝過(guò)氧化物酶體增殖物激活受體α(hepatic peroxisome proliferator-activated receptor α，PPARα)與人樣PPARα進(jìn)行對(duì)比研究發(fā)現(xiàn)，野生型鼠宮內(nèi)暴露DEHP后未發(fā)現(xiàn)子代鼠肝質(zhì)量變化，但血清中三酰甘油水平明顯低于對(duì)照組；但在人樣PPARα鼠中并未觀察到三酰甘油水平下降，他們認(rèn)為這是由于在脂肪酸β氧化過(guò)程中PPARα的種間特異性所致。Nakashima等[24]研究也表明，DEHP可降低血漿中四種脂肪酸水平，而這僅在野生型PPARα鼠中表現(xiàn)明顯。而Satake等[25]對(duì)成年獼猴進(jìn)行DEHP 染毒后發(fā)現(xiàn)大劑量DEHP對(duì)肝的形態(tài)未發(fā)生明顯改變，對(duì)肝過(guò)氧化酶體的影響也很輕微。此外，還有鼠體內(nèi)實(shí)驗(yàn)表明，宮內(nèi)暴露會(huì)增加肝脂肪變，減少肝糖原蓄積，并且增加雌性后代細(xì)β聯(lián)蛋白等[26]。

4神經(jīng)毒作用

Shiue[27]通過(guò)對(duì)中風(fēng)患者尿中鄰苯二甲酸酯類水平的隊(duì)列研究，發(fā)現(xiàn)中風(fēng)患者尿中鄰苯二甲酸酯類水平顯著于正常人，認(rèn)為鄰苯二甲酸酯類可能會(huì)增加中風(fēng)的發(fā)病風(fēng)險(xiǎn)。Testa 等[28]通過(guò)對(duì)48例孤獨(dú)障礙的兒童尿中MEHP及其代謝物質(zhì)水平的研究發(fā)現(xiàn)，孤獨(dú)障礙與尿中5-Oxo MEHP水平呈正相關(guān)。此外，男孩在玩耍中“男子氣概”與其母親DEHP的暴露情況呈負(fù)相關(guān)[6]。

Smith等[29]研究表明，出生前暴露于DEHP的胎鼠其腦部海馬CA3區(qū)遠(yuǎn)端多形細(xì)胞層軸突標(biāo)志物減少，并且DEHP使雄性鼠后代的成熟及未成熟的齒狀回神經(jīng)元細(xì)胞的密度均減少。Win-Shre等[30]通過(guò)對(duì)過(guò)敏體質(zhì)的鼠用DEHP處理后發(fā)現(xiàn)下丘腦白細(xì)胞介素(interleukin，IL)1β、腫瘤壞死因子α、生長(zhǎng)因子、趨化因子C-C motif ligand 3(CCL3 )、核因子κB、Ⅰ型血紅素氧合酶、神經(jīng)生長(zhǎng)因子等的信使RNA表達(dá)明顯上調(diào)，他們認(rèn)為DEHP暴露可能引起神經(jīng)炎癥。

5干擾免疫

流行病學(xué)研究發(fā)現(xiàn)，低劑量DEHP暴露會(huì)引起粒細(xì)胞集落刺激因子、IL-5、IL-6和嗜酸性陽(yáng)離子蛋白在鼻腔分泌量的增加；而高劑量DEHP暴露會(huì)引起粒細(xì)胞集落刺激因子和IL-6 分泌的減少[31]。

Shin 等[32]研究發(fā)現(xiàn)，暴露于DEHP的雌鼠后代，其肺灌洗液中炎細(xì)胞數(shù)目、IL-4、IL-13和嗜酸性細(xì)胞趨化因子減少，血漿中IgE水平下降，他們認(rèn)為母體暴露于DEHP，其子代鼠的肺炎癥反應(yīng)下降，黏液分泌功能降低，哮喘發(fā)生風(fēng)險(xiǎn)下降。但也有相反的研究報(bào)道，Bornehag和Nanberg[33]在關(guān)于小兒哮喘與鄰苯二甲酸酯的關(guān)系的研究中發(fā)現(xiàn)鼠鄰苯二甲酸酯暴露可能在Th2分化中起輔助作用，同時(shí)會(huì)引起Th2相關(guān)細(xì)胞因子和免疫球蛋白(主要是IgG1和IgE)產(chǎn)量增加，并增強(qiáng)細(xì)胞脫顆粒和嗜酸性細(xì)胞的募集與浸潤(rùn)。動(dòng)物實(shí)驗(yàn)表明，DEHP暴露可以提高實(shí)驗(yàn)鼠對(duì)2-甲氧基-4-異氰酸硝基苯和苯乙基異氰酸酯的接觸敏感性，同時(shí)伴有干擾素γ的升高和IL-4的降低，DEHP與半抗原結(jié)合可明顯提高接觸過(guò)敏反應(yīng)[34]。

Oh和Lim[35]的體外試驗(yàn)結(jié)果表明，DEHP可以促進(jìn)Th1和Th2在脾中的分化，同時(shí)IL-4水平提高。Kuo 等[36]發(fā)現(xiàn)，DEHP 可以抑制漿細(xì)胞樣樹(shù)突狀細(xì)胞(plasmacytoid dendritic cells, pDC)干擾素α/干擾素β表達(dá)；DEHP還能抑制H3K4特異的三甲基轉(zhuǎn)移酶WDR5從胞質(zhì)轉(zhuǎn)移至細(xì)胞核的過(guò)程，抑制干擾素調(diào)節(jié)因子-7基因的啟動(dòng)子區(qū)域的H3K4的甲基化，從而抑制干擾素調(diào)節(jié)因子-7的表達(dá)；此外DEHP還能抑制pDC表達(dá)干擾素γ，同時(shí)通過(guò)CD4+T細(xì)胞提高IL-13水平。

6其他基因改變

Wu等[37]在鼠體內(nèi)實(shí)驗(yàn)發(fā)現(xiàn)，DEHP暴露組的重要的甲基轉(zhuǎn)移酶Dnmt1 mRNA的表達(dá)是對(duì)照組的5倍，他們認(rèn)為，睪丸發(fā)育不全綜合征的機(jī)制可能是由于胎鼠宮內(nèi)暴露于DEHP，引起DNA甲基化，同時(shí)DNA甲基轉(zhuǎn)移酶表達(dá)增強(qiáng)；隨著甲基化程度增加，DNA可能會(huì)發(fā)生基因沉默，引起組織特異性基因表達(dá)。Macejová等[38]對(duì)體外培養(yǎng)的乳腺癌細(xì)胞進(jìn)行DEHP染毒，發(fā)現(xiàn)DEHP可以提高維甲酸X受體α表達(dá)，也能提高維甲酸X受體β型的mRNA水平。

7總結(jié)

盡管對(duì)于DEHP暴露對(duì)機(jī)體損傷的可能機(jī)制尚未完全明確，但現(xiàn)有研究表明，DEHP及其代謝產(chǎn)物MEHP對(duì)人體可能的損傷主要有以下4種途徑：①干擾多種激素的合成途徑，發(fā)揮抗雄激素內(nèi)分泌干擾作用；②直接作用于細(xì)胞呼吸鏈，發(fā)生氧化應(yīng)激，損傷機(jī)體；③與多種細(xì)胞因子作用，造成免疫紊亂，妨礙生長(zhǎng)；④直接損傷DNA，影響其甲基化過(guò)程。因此，DEHP對(duì)機(jī)體的損傷機(jī)制不是簡(jiǎn)單的某一種機(jī)制，應(yīng)有多種物質(zhì)通過(guò)多種途徑最終造成機(jī)體損傷，詳盡的機(jī)制有待于更深一步研究。隨著分子生物學(xué)研究技術(shù)的進(jìn)步，基因組學(xué)、蛋白組學(xué)、代謝組學(xué)技術(shù)日益成熟，因此，在后來(lái)的研究中，這些技術(shù)也必然會(huì)應(yīng)用到DEHP中毒的研究中。

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Research Advances in Intoxication Mechanism of Di-(2-ethylhexyl)PhthalateLIXin-yang,WANGYe. (WesternChinaSchoolofPublicHealth,SichuanUniversity,Chengdu610041,China)

Abstract:Di-(2-ethylhexyl)phthalate,a ubiquitous plasticizer,is an endocrine disruptor with its pathological mechanism unclear yet.Studies have proposed that it is likely to have the toxicities of endocrine disruption,oxidative damage,immunological disorders and genetic changes，which may have certain pathways and target organs.Endocrine disruption may refers to certain pathways contributing to the development and functions of male reproductive systems,as well as the development and functions of female reproductive systems, which indicates that di-(2-ethylhexyl)phthalate acts like estrogens;oxidative damage targets livers;immunological disorders appear at multi-organs in various ways due to the metabolism of di-(2-ethylhexyl)phthalate;and certain neural factors may be up-regulated or down-regulated by di-(2-ethylhexyl)phthalate. Above all, di-(2-ethylhexyl)phthalate may have extensive toxicities in many organs.

Key words:Di-(2-ethylhexyl)phthalate; Toxicity; Pathological mechanisms

收稿日期：2014-05-28修回日期：2014-09-29編輯：相丹峰

doi：10.3969/j.issn.1006-2084.2015.09.017

中圖分類號(hào):R595.9

文獻(xiàn)標(biāo)識(shí)碼：A

文章編號(hào)：1006-2084(2015)09-1581-04