環境雌激素雙酚A暴露現狀及其雄性生殖毒性研究概況

蔣志惠，謝文艷，李新平，張小鶯

西北農林科技大學 動物醫學院，楊凌 712100

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環境雌激素雙酚A暴露現狀及其雄性生殖毒性研究概況

蔣志惠，謝文艷，李新平，張小鶯*

西北農林科技大學 動物醫學院，楊凌 712100

雙酚A(bisphenol A，BPA)作為典型的環境雌激素，在環境中廣泛存在，具有接觸機會頻繁、劑量累積、潛伏期長等特點，是對生殖系統危害極大的一類污染物。研究表明BPA可在地表水、野生動物體內檢測出，甚至在健康人群的體液中存在，尤其在嬰兒體內含量較高。BPA進入機體后可通過I相和II相代謝酶分解，其分解產物的毒性目前仍不清楚。BPA在體內發揮雌激素樣作用，與雌二醇競爭性地結合到雌激素受體上，阻礙雄激素受體的活性，促進促黃體生成素與催乳素的合成，最終抑制雄性激素的合成。BPA可破壞血睪屏障，直接刺激睪丸細胞的凋亡并導致精子質量下降，其中主要通過影響下丘腦-垂體-性腺軸(HPG)上促性腺激素釋放激素受體(GnRHR)、促黃體生成素受體(LHRβ)和促卵泡雌激素(Fshb)的表達和直接刺激睪丸和附睪細胞，降低睪酮合成酶的表達及活性，抑制與精子生成相關蛋白的表達，從而影響生殖能力。同時，BPA代謝過程中消耗大量的抗氧化酶，產生氧自由基，其氧化產物可能會對睪丸和附睪的損傷形成二次打擊。總之，雙酚A造成雄性生殖損傷障礙主要是損傷HPG軸正負反饋調節的平衡以及影響調節激素相關基因的表達和直接損傷睪丸細胞和精子質量。

雙酚A；生殖毒性；含量檢測；代謝

Received 27 October 2015 accepted 31 December 2015

雙酚A (bisphenol A，BPA，CAS no. 80-05-7)即是環境內分泌干擾物的一種，常作為增塑劑而被廣泛應用，包括嬰兒奶瓶、塑料和金屬材料的食品飲料容器的內壁涂層、牙套密封劑等。因其化學結構與雌激素類似(圖1)，具有弱雌激素和強抗雄激素活性，導致雄性生殖發育毒性。隨著塑料制品的廣泛應用，人們接觸BPA的機會也越來越多，經調查，平均每年排放到大氣中的BPA可達100 t[2]，另外，包括灰塵、水、紙也發現了BPA的污染[3-4]。美國疾控中心調研發現90%的美國人在尿液中檢測到BPA的存在[5]。當大部分塑料制品在有裂紋或長期應用造成磨損時，就會分解釋放出BPA，滲入食品或飲料，從而進入人體。BPA通過皮膚、呼吸道、消化道等進入動物或人體后，引起機體多系統損傷，如生殖系統、發育系統、免疫系統、神經系統、代謝系統，并具有基因毒性和氧化毒性，其中，對生殖系統的影響已成為當前研究的重中之重[1]。

圖1 雙酚A和雌二醇的化學結構Fig. 1 The chemical structure of BPA and estradiol

表1 地表水和野生動物體內BPA的含量

注：GC-ECD，氣相色譜-電子捕獲檢測器；HPLC，高效液相色譜法；GC-MS，氣相色譜-串聯質譜法；UPLC，超高效液相色譜法；ND，未檢測出。

Notes: ECD, GC-63Ni Electron Capture Detector; HPLC, High Performance Liquid Chromatography; GC-MS, Gas Chromatography-Mass Spectrometer; UPLC, Ultra Performance Liquid Chromatography; ND, Not-Detected.

1 雙酚A暴露標志物監測 (Monitoring of environmental exposure to BPA)

隨著人們對BPA的關注，專家學者監測了環境及野生動物中BPA的含量，發現在工廠附近河流水體存在大量BPA，甚至在一些地區的地表水中也檢測到了BPA的存在。同時，野生魚出現了雌雄同體的現象[6]，并發現BPA的存在(如表1)。2013年，美國疾病防控中心(CDC)監測人類血液或尿液中BPA的含量，發現2 594名美國成年人尿液樣本中，共有95%的樣品中能檢出BPA[12]。美國國家健康與營養調查(NHANES)報道，基于尿液中BPA的含量推測人類平均每天進食BPA約25 ng·kg-1[13]。值得注意的是，BPA可通過乳汁進入嬰兒體內[14]，且與其他年齡段相比含量最高[15]。另外，研究者采集曾接受牙齒矯正患者的唾液，結果表明使用牙齒密封劑患者均能檢測出BPA的含量。其他國家包括中國、德國、澳大利亞、西班牙、韓國和日本等也對人群尿液中BPA含量進行了檢測，發現各國均有不同程度的BPA污染(表2)。研究表明，健康人群中均可檢出BPA，BPA的EC50是3.24～34.85 μg·mL-1[16]，雖然目前研究結果表明體內含量未達到對機體損傷計量，但BPA可長期累積在機體內，當長期食用含雙酚A的食品和其他接觸將會存在相當大的隱患。

表2 人類體液中BPA的含量

注：GC-MS/MS，氣相色譜-串聯質譜法；HPLC-FD，高效液相-熒光色譜法；Online SPE-HPLC-MS/MS，在線固相萃取-高效液相色譜-串聯質譜法；LC/LC-MS/MS，液相色譜-串聯質譜法；SGIC-HPLC-FD，硅凝膠免疫柱-高效液相-熒光檢測法；CME-LC-FD，微萃取-液相色譜-熒光色譜法；ND，未檢測出；-，未說明。

Notes: GC-MS/MS, Gas Chromatography-Mass Spectrometer/Mass Spectrometer; HPLC-FD, High Performance Liquid Chromatography-Fluorescent Detection; Online SPE-HPLC-MS/MS, Online Solid Phase Extraction-High Performance Liquid Chromatography- Mass Spectrometer/Mass Spectrometer; SGIC-HPLC-FD, Silicon Gel Immune Column-High Performance Liquid Chromatography-Fluorescent Detection; CME-LC-FD, Coacervative Microextraction-Liquid Chromatography-Fluorescence Detection; ND, Not detected; -, Not shown.

2 雙酚A的代謝 (Metabolism of BPA)

BPA主要是通過肝臟和胃腸道中的I相代謝酶CYP450家族發生1位取代，生成2，2-雙(4-羥苯基)丙醇，o-羥基苯二酚或丙二酚-o-醌。在人類和大鼠中，90% I相代謝產物可通過II相結合酶-谷胱甘肽結合酶(GSTs)家族結合成無毒形式的單葡萄糖醛酸(如圖2)。BPA可影響多種I相代謝酶如表3所示，其中I相代謝酶主要是CYP3A家族[29]，當BPA刺激人源肝臟細胞時，可誘導CYP3A4基因的表達[30]。當不同濃度的BPA刺激細胞時，CYP3A4的表達呈現正相關[29]。BPA在體內的代謝過程主要有3個途徑。途徑一：BPA通過CYP450酶氧化生成羥乙基乙醇(HCA)和鏈有谷胱甘肽(GSH)的4-異丙苯酚[31]。途徑二：可通過羥基化反應形成間位羥基化的BPA(m-OH BPA)，然后氧化成對位鏈有苯醌基的BPA，GSH共價結合到苯醌基團上，另外GSH還可鏈在去除水分子后的羥基化的BPA上[32]。途徑三：BPA可通過C-C鍵斷開使其烷基鏈退化轉移，通過CYP450酶催化發生鄰位取代反應形成醌類化合物，產生的醌類化合物由于其化學鍵之間的范德華力小而不穩定，可釋放出正電荷，故可通過與水分子結合生成羥乙基乙醇[33]，或者與GSH結合生成4-異丙苯酚[32]。以上3種途徑的代謝產物均為無毒化合物，但有研究表明環境微生物體內代謝的BPA對石斑魚的毒性要高于BPA本身，其代謝產物可導致石斑魚胚胎在受精后的死亡率升高，同時增加石斑魚胚胎畸形的比例，提示BPA的代謝還存在其他未知途徑。

圖2 肝臟中BPA的生物代謝過程Fig. 2 Proposed metabolism of BPA in human liver

3 雙酚A對雄性生殖的毒性作用機理 (Mechanization of BPA induced reproduction injury)

隨著雙酚A在體內逐漸累積，發揮擬雌激素作用，可造成男性激素紊亂，生精細胞的損傷，最終導致雄性不育。精子的質量是評價雄性生殖能力的指標，刺激精子合成的激素的水平和生成精子的場所睪丸的質量是影響精子質量的主要因素。

3.1 雙酚A導致睪丸損傷的作用機理

在BPA的刺激下，可引起睪丸細胞凋亡、產生氧化應激，進而造成精子生成紊亂。病理學研究表明BPA可引起睪丸細胞出現空泡、細胞核消失、壞死、曲精小管中精子含量降低，精子凝集成團，間質細胞減少等變化。TUNEL法檢測表明BPA組熒光量增加，同時與凋亡信號相關的蛋白caspase-3和Bcl-2表達量升高，通過激活JNKs/p38 MAPK蛋白磷酸化，刺激c-jun和CHOP基因表達，說明BPA可引起睪丸細胞凋亡[43-44]。同時，BPA可刺激核轉錄因子NF-κB從細胞質進入細胞核進行轉錄，促進炎癥的產生。另外，BPA在體內代謝時消耗大量的谷胱甘肽還原酶，導致機體不能及時清除自由基，使其自由基含量增加，進而刺激睪酮細胞損傷。

哺乳動物體內95%雄激素(睪酮和雄烯二酮)是由睪丸間質細胞分泌，其利用血膽固醇或乙酸鹽，在其細胞器內質網、線粒體及微粒體中，經過一系列的生物學過程，合成睪酮。從膽固醇到睪酮的轉化過程中，主要涉及到下列步驟(圖3)：①膽固醇須從線粒體膜外由類固醇急性調節蛋白(StAR)和轉運蛋白(TSPO)轉運進入線粒體膜內。②線粒體內的膽固醇在CYP11A1催化下變為孕烯醇酮。③孕烯醇酮可經3β-類固醇脫氫酶(3β-HSD)脫氫成孕酮。④孕酮經CYP17A1代謝成雄烯二酮。⑤雄烯二酮經17β-類固醇脫氫酶(17β-HSD)脫氫生成睪酮。這一過程，影響其中的每一步驟都會影響睪酮的生成。研究發現，當睪丸細胞暴露在BPA時，可降低CYP11A1、3β-HSD、17β-HSD和CYP17A1的表達，表明BPA可通過抑制生成類固醇酶的表達進而影響睪酮的生成[40]。

表3 BPA對不同種屬和組織中CYP的表達

圖3 體內激素合成主要信號分子通路注：促黃體生成素可刺激類固醇生成急性調節蛋白(StAR)將膽固醇由細胞質轉運到細胞核，進而被膽固醇側鏈裂解酶(CYP11A1)、3β羥化類固醇脫氫酶(3β-HSD)、17，20裂解酶(CYP17A1)和17β羥化類固醇脫氫酶(17β-HSD)代謝生成睪酮。Fig. 3 Main molecular signaling pathways involved in the regulation of homeostasisNotes: Luteinizing hormone stimulates the sterodiogenic acute regulatory protein (StAR) conjunction with the CYP 11A1 in inner mitochondria membrane of testis, tethered to the outer mitochondrial membrane, and then the cholesterol were synthesized into testosterone by CYP11A1, 3β-HSD, CYP17A1 and 17β-HSD.

圖4 影響精子功能的相關蛋白注：該圖改編自Rahman等的文章[45]。Fig. 4 Pathways regulated by selected fertility-related proteins in spermatozoaNotes: Adapt from Rahman et al. ,2015[45]

3.2 雙酚A導致激素紊亂的作用機理

BPA可通過作用下丘腦-垂體-性腺軸，通過干擾雄激素受體(AR)活性，導致雄激素不能與受體結合而發揮功能。另外，在下丘腦或垂體中，BPA可與雌二醇競爭性結合在雌二醇激素受體(ER)上，抑制機體的負反饋調節作用，使正反饋持續刺激LH的分泌，進而刺激睪丸中雌二醇的產生，發揮雌激素樣作用，BPA還可促進催乳素、性激素結合蛋白的表達和分泌，降低抑制素B和雄烯二酮的水平，擾亂激素的平衡[46]。

3.3 雙酚A導致精子損傷的作用機理

BPA可破壞睪丸中的血睪屏障直接作用于精子，通過降低ATP的含量，導致精子的活性、數量、運動性降低，畸形率增加[44]。高劑量BPA(100 μmol·L-1)可引起參與精子生成的酪氨酸蛋白磷酸化導致頂體細胞早熟，影響受精質量和胚胎發育。通過生物信息學分析已篩選出BPA影響精子功能相關的蛋白，包括參與氧化應激、能量代謝、精子的運動與活化、頂體反應、細胞生長、精子生成和生育能力的蛋白[45](圖4)。其中GAPDH和GPX4分別是糖酵解和電子傳遞過程中參與酶，可調節精子的運動性。GPX4和PRDX5是精子生成過程中的抗氧化物酶，他們可清除體內99.9%的H2O2。Actin肌動蛋白可調節精子的運動。

4 小結 (Conclusions)

雙酚A作為主要的環境雌激素，可導致雄性激素水平下降，損傷睪丸功能，降低精子的質量，因此可成為典型的雄性生殖障礙模型的誘導劑，通過研究BPA在體內的代謝特點，損傷的作用靶點等內容，為研發雄性生殖保護的新藥提供思路。

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Bisphenol A Exposure and Male Reproductive Injury: An Review

Jiang Zhihui, Xie Wenyan, Li Xinping, Zhang Xiaoying*

College of Veterinary Medicine, Northwest A&F University,Yangling 712100, China

Bisphenol A (BPA) is one of the xenoestrogens and being used as agent for endocrine disruption. The impacts of BPA on male infertility have been investigated in several animal species including fish (in river and lake) as well as in humans. It is metabolized by phase I and phase II enzyme, as a substrate for the ipso-metabolism catalyzed by microsomal cytochrome P450 (CYP450). BPA interrupts the androgen receptor activity and competitively combines with estrogen receptor, thereby increasing the levels of prolactin and LH, decreasing the level of testosterone. BPA stimulates the testicular cell apoptosis and decreases the testosterone synthetase activity through the hypothalamus- pituitary- gonad (HPG) axis regulation. The relative gene expression reveals an increase in gonadotropin releasing hormone receptor (Gnrhr), luteinizing hormone beta (LHRβ) and follicle stimulating hormone beta (FSHβ), Continuous exposure to BPA can lead to impairing functioning in sexual development, reproduction and behavior. BPA also decreases sperm motility and motion kinematics by significantly decreasing ATP levels in spermatozoa and increases the phosphorylation of tyrosine residues on sperm proteins involved in protein kinase A-dependent regulation thus leading to a precocious acrosome reaction. One of the metabolites of BPA is ROS, which may cause “second hit” for testicle and epididymis injury. In conclusion, BPA exposure compromises sperm production and functionality, disrupts the HPG axis balance and redox pathways resulting in a state of hypogonadotropic hypogonadism.

bisphenol-A (BPA); reproductive toxicity; content evaluation; metabolism

教育部外國文教專家聘請計劃(X2015016)；陜西省國際科技合作基地建設項目(2015SD0018)；陜西省2011協同創新中心建設項目(陜西秦巴山區生物資源綜合開發)

蔣志惠(1987-)，女，博士研究生，研究方向為藥理毒理學，E-mail: jiangzhihui19870326@126.com；

*通訊作者(Corresponding author)， E-mail: zhang.xy@nwsuaf.edu.cn

10.7524/AJE.1673-5897.20151027003

2015-10-27 錄用日期：2015-12-31

1673-5897(2016)4-001-09

X171.5

A

簡介：張小鶯(1976—)，男，博士，教授，研究方向為藥理毒理學。

蔣志惠, 謝文艷, 李新平, 等. 環境雌激素雙酚A暴露現狀及其雄性生殖毒性研究概況[J]. 生態毒理學報，2016, 11(4): 1-9

Jiang Z H, Xie W Y, Li X P, et al. Bisphenol A exposure and male reproductive injury: An review [J]. Asian Journal of Ecotoxicology, 2016, 11(4): 1-9 (in Chinese)