环境雌激素双酚A暴露现状及其雄性生殖毒性研究概况

蒋志惠，谢文艳，李新平，张小莺

西北农林科技大学 动物医学院，杨凌 712100



环境雌激素双酚A暴露现状及其雄性生殖毒性研究概况

蒋志惠，谢文艳，李新平，张小莺*

西北农林科技大学 动物医学院，杨凌 712100

双酚A(bisphenol A，BPA)作为典型的环境雌激素，在环境中广泛存在，具有接触机会频繁、剂量累积、潜伏期长等特点，是对生殖系统危害极大的一类污染物。研究表明BPA可在地表水、野生动物体内检测出，甚至在健康人群的体液中存在，尤其在婴儿体内含量较高。BPA进入机体后可通过I相和II相代谢酶分解，其分解产物的毒性目前仍不清楚。BPA在体内发挥雌激素样作用，与雌二醇竞争性地结合到雌激素受体上，阻碍雄激素受体的活性，促进促黄体生成素与催乳素的合成，最终抑制雄性激素的合成。BPA可破坏血睾屏障，直接刺激睾丸细胞的凋亡并导致精子质量下降，其中主要通过影响下丘脑-垂体-性腺轴(HPG)上促性腺激素释放激素受体(GnRHR)、促黄体生成素受体(LHRβ)和促卵泡雌激素(Fshb)的表达和直接刺激睾丸和附睾细胞，降低睾酮合成酶的表达及活性，抑制与精子生成相关蛋白的表达，从而影响生殖能力。同时，BPA代谢过程中消耗大量的抗氧化酶，产生氧自由基，其氧化产物可能会对睾丸和附睾的损伤形成二次打击。总之，双酚A造成雄性生殖损伤障碍主要是损伤HPG轴正负反馈调节的平衡以及影响调节激素相关基因的表达和直接损伤睾丸细胞和精子质量。

双酚A；生殖毒性；含量检测；代谢

Received 27 October 2015 accepted 31 December 2015

双酚A (bisphenol A，BPA，CAS no. 80-05-7)即是环境内分泌干扰物的一种，常作为增塑剂而被广泛应用，包括婴儿奶瓶、塑料和金属材料的食品饮料容器的内壁涂层、牙套密封剂等。因其化学结构与雌激素类似(图1)，具有弱雌激素和强抗雄激素活性，导致雄性生殖发育毒性。随着塑料制品的广泛应用，人们接触BPA的机会也越来越多，经调查，平均每年排放到大气中的BPA可达100 t[2]，另外，包括灰尘、水、纸也发现了BPA的污染[3-4]。美国疾控中心调研发现90%的美国人在尿液中检测到BPA的存在[5]。当大部分塑料制品在有裂纹或长期应用造成磨损时，就会分解释放出BPA，渗入食品或饮料，从而进入人体。BPA通过皮肤、呼吸道、消化道等进入动物或人体后，引起机体多系统损伤，如生殖系统、发育系统、免疫系统、神经系统、代谢系统，并具有基因毒性和氧化毒性，其中，对生殖系统的影响已成为当前研究的重中之重[1]。

图1 双酚A和雌二醇的化学结构Fig. 1 The chemical structure of BPA and estradiol

表1 地表水和野生动物体内BPA的含量

注：GC-ECD，气相色谱-电子捕获检测器；HPLC，高效液相色谱法；GC-MS，气相色谱-串联质谱法；UPLC，超高效液相色谱法；ND，未检测出。

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 双酚A暴露标志物监测 (Monitoring of environmental exposure to BPA)

随着人们对BPA的关注，专家学者监测了环境及野生动物中BPA的含量，发现在工厂附近河流水体存在大量BPA，甚至在一些地区的地表水中也检测到了BPA的存在。同时，野生鱼出现了雌雄同体的现象[6]，并发现BPA的存在(如表1)。2013年，美国疾病防控中心(CDC)监测人类血液或尿液中BPA的含量，发现2 594名美国成年人尿液样本中，共有95%的样品中能检出BPA[12]。美国国家健康与营养调查(NHANES)报道，基于尿液中BPA的含量推测人类平均每天进食BPA约25 ng·kg-1[13]。值得注意的是，BPA可通过乳汁进入婴儿体内[14]，且与其他年龄段相比含量最高[15]。另外，研究者采集曾接受牙齿矫正患者的唾液，结果表明使用牙齿密封剂患者均能检测出BPA的含量。其他国家包括中国、德国、澳大利亚、西班牙、韩国和日本等也对人群尿液中BPA含量进行了检测，发现各国均有不同程度的BPA污染(表2)。研究表明，健康人群中均可检出BPA，BPA的EC50是3.24～34.85 μg·mL-1[16]，虽然目前研究结果表明体内含量未达到对机体损伤计量，但BPA可长期累积在机体内，当长期食用含双酚A的食品和其他接触将会存在相当大的隐患。

表2 人类体液中BPA的含量

注：GC-MS/MS，气相色谱-串联质谱法；HPLC-FD，高效液相-荧光色谱法；Online SPE-HPLC-MS/MS，在线固相萃取-高效液相色谱-串联质谱法；LC/LC-MS/MS，液相色谱-串联质谱法；SGIC-HPLC-FD，硅凝胶免疫柱-高效液相-荧光检测法；CME-LC-FD，微萃取-液相色谱-荧光色谱法；ND，未检测出；-，未说明。

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 双酚A的代谢 (Metabolism of BPA)

BPA主要是通过肝脏和胃肠道中的I相代谢酶CYP450家族发生1位取代，生成2，2-双(4-羟苯基)丙醇，o-羟基苯二酚或丙二酚-o-醌。在人类和大鼠中，90% I相代谢产物可通过II相结合酶-谷胱甘肽结合酶(GSTs)家族结合成无毒形式的单葡萄糖醛酸(如图2)。BPA可影响多种I相代谢酶如表3所示，其中I相代谢酶主要是CYP3A家族[29]，当BPA刺激人源肝脏细胞时，可诱导CYP3A4基因的表达[30]。当不同浓度的BPA刺激细胞时，CYP3A4的表达呈现正相关[29]。BPA在体内的代谢过程主要有3个途径。途径一：BPA通过CYP450酶氧化生成羟乙基乙醇(HCA)和链有谷胱甘肽(GSH)的4-异丙苯酚[31]。途径二：可通过羟基化反应形成间位羟基化的BPA(m-OH BPA)，然后氧化成对位链有苯醌基的BPA，GSH共价结合到苯醌基团上，另外GSH还可链在去除水分子后的羟基化的BPA上[32]。途径三：BPA可通过C-C键断开使其烷基链退化转移，通过CYP450酶催化发生邻位取代反应形成醌类化合物，产生的醌类化合物由于其化学键之间的范德华力小而不稳定，可释放出正电荷，故可通过与水分子结合生成羟乙基乙醇[33]，或者与GSH结合生成4-异丙苯酚[32]。以上3种途径的代谢产物均为无毒化合物，但有研究表明环境微生物体内代谢的BPA对石斑鱼的毒性要高于BPA本身，其代谢产物可导致石斑鱼胚胎在受精后的死亡率升高，同时增加石斑鱼胚胎畸形的比例，提示BPA的代谢还存在其他未知途径。

图2 肝脏中BPA的生物代谢过程Fig. 2 Proposed metabolism of BPA in human liver

3 双酚A对雄性生殖的毒性作用机理 (Mechanization of BPA induced reproduction injury)

随着双酚A在体内逐渐累积，发挥拟雌激素作用，可造成男性激素紊乱，生精细胞的损伤，最终导致雄性不育。精子的质量是评价雄性生殖能力的指标，刺激精子合成的激素的水平和生成精子的场所睾丸的质量是影响精子质量的主要因素。

3.1 双酚A导致睾丸损伤的作用机理

在BPA的刺激下，可引起睾丸细胞凋亡、产生氧化应激，进而造成精子生成紊乱。病理学研究表明BPA可引起睾丸细胞出现空泡、细胞核消失、坏死、曲精小管中精子含量降低，精子凝集成团，间质细胞减少等变化。TUNEL法检测表明BPA组荧光量增加，同时与凋亡信号相关的蛋白caspase-3和Bcl-2表达量升高，通过激活JNKs/p38 MAPK蛋白磷酸化，刺激c-jun和CHOP基因表达，说明BPA可引起睾丸细胞凋亡[43-44]。同时，BPA可刺激核转录因子NF-κB从细胞质进入细胞核进行转录，促进炎症的产生。另外，BPA在体内代谢时消耗大量的谷胱甘肽还原酶，导致机体不能及时清除自由基，使其自由基含量增加，进而刺激睾酮细胞损伤。

哺乳动物体内95%雄激素(睾酮和雄烯二酮)是由睾丸间质细胞分泌，其利用血胆固醇或乙酸盐，在其细胞器内质网、线粒体及微粒体中，经过一系列的生物学过程，合成睾酮。从胆固醇到睾酮的转化过程中，主要涉及到下列步骤(图3)：①胆固醇须从线粒体膜外由类固醇急性调节蛋白(StAR)和转运蛋白(TSPO)转运进入线粒体膜内。②线粒体内的胆固醇在CYP11A1催化下变为孕烯醇酮。③孕烯醇酮可经3β-类固醇脱氢酶(3β-HSD)脱氢成孕酮。④孕酮经CYP17A1代谢成雄烯二酮。⑤雄烯二酮经17β-类固醇脱氢酶(17β-HSD)脱氢生成睾酮。这一过程，影响其中的每一步骤都会影响睾酮的生成。研究发现，当睾丸细胞暴露在BPA时，可降低CYP11A1、3β-HSD、17β-HSD和CYP17A1的表达，表明BPA可通过抑制生成类固醇酶的表达进而影响睾酮的生成[40]。

表3 BPA对不同种属和组织中CYP的表达

图3 体内激素合成主要信号分子通路注：促黄体生成素可刺激类固醇生成急性调节蛋白(StAR)将胆固醇由细胞质转运到细胞核，进而被胆固醇侧链裂解酶(CYP11A1)、3β羟化类固醇脱氢酶(3β-HSD)、17，20裂解酶(CYP17A1)和17β羟化类固醇脱氢酶(17β-HSD)代谢生成睾酮。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.

图4 影响精子功能的相关蛋白注：该图改编自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 双酚A导致激素紊乱的作用机理

BPA可通过作用下丘脑-垂体-性腺轴，通过干扰雄激素受体(AR)活性，导致雄激素不能与受体结合而发挥功能。另外，在下丘脑或垂体中，BPA可与雌二醇竞争性结合在雌二醇激素受体(ER)上，抑制机体的负反馈调节作用，使正反馈持续刺激LH的分泌，进而刺激睾丸中雌二醇的产生，发挥雌激素样作用，BPA还可促进催乳素、性激素结合蛋白的表达和分泌，降低抑制素B和雄烯二酮的水平，扰乱激素的平衡[46]。

3.3 双酚A导致精子损伤的作用机理

BPA可破坏睾丸中的血睾屏障直接作用于精子，通过降低ATP的含量，导致精子的活性、数量、运动性降低，畸形率增加[44]。高剂量BPA(100 μmol·L-1)可引起参与精子生成的酪氨酸蛋白磷酸化导致顶体细胞早熟，影响受精质量和胚胎发育。通过生物信息学分析已筛选出BPA影响精子功能相关的蛋白，包括参与氧化应激、能量代谢、精子的运动与活化、顶体反应、细胞生长、精子生成和生育能力的蛋白[45](图4)。其中GAPDH和GPX4分别是糖酵解和电子传递过程中参与酶，可调节精子的运动性。GPX4和PRDX5是精子生成过程中的抗氧化物酶，他们可清除体内99.9%的H2O2。Actin肌动蛋白可调节精子的运动。

4 小结 (Conclusions)

双酚A作为主要的环境雌激素，可导致雄性激素水平下降，损伤睾丸功能，降低精子的质量，因此可成为典型的雄性生殖障碍模型的诱导剂，通过研究BPA在体内的代谢特点，损伤的作用靶点等内容，为研发雄性生殖保护的新药提供思路。

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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

教育部外国文教专家聘请计划(X2015016)；陕西省国际科技合作基地建设项目(2015SD0018)；陕西省2011协同创新中心建设项目(陕西秦巴山区生物资源综合开发)

蒋志惠(1987-)，女，博士研究生，研究方向为药理毒理学，E-mail: jiangzhihui19870326@126.com；

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

10.7524/AJE.1673-5897.20151027003

2015-10-27 录用日期：2015-12-31

1673-5897(2016)4-001-09

X171.5

A

简介：张小莺(1976—)，男，博士，教授，研究方向为药理毒理学。

蒋志惠, 谢文艳, 李新平, 等. 环境雌激素双酚A暴露现状及其雄性生殖毒性研究概况[J]. 生态毒理学报，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)