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农药类内分泌干扰物对无尾两栖动物影响的研究进展

刘蕊 刘春晓 刁金玲 周志强

引用本文:
Citation:

农药类内分泌干扰物对无尾两栖动物影响的研究进展

    作者简介: 刘蕊,女,硕士研究生,E-mail:rayliu@cau.edu.cn.
    通讯作者: 刁金玲, jinling@cau.edu.cn
  • 中图分类号: Q959.5;X592

Research progress on the effects of pesticides endocrine disrupting chemicals on anura amphibians

    Corresponding author: Jinling DIAO, jinling@cau.edu.cn ;
  • CLC number: Q959.5;X592

  • 摘要: 农药类内分泌干扰物 (endocrine disrupting chemicals, EDCs) 对人类健康和生态环境造成了一定威胁。无尾两栖动物因其处于水生生态系统和陆生生态系统的过渡阶段,在食物链中具有重要位置,同时也是经济合作与发展组织 (OECD) 和美国环保局 (USEPA) 识别和评估化合物影响的常见模式生物。因此开展农药类EDCs对无尾两栖动物影响的研究可进一步评价农药的生态风险,有助于全面认识农药类EDCs。本文综述了农药类内分泌干扰物对无尾两栖动物甲状腺及性腺干扰的研究进展,并展望了研究农药类EDCs对无尾两栖动物影响的深远意义,旨在为全面的农药生态风险评价及为农药安全性评价体系引入更加全面、科学的试验方法和评价标准提供科学依据。
  • 图 1  生物体甲状腺激素信号传导[30, 35-36]

    Figure 1.  Thyroid hormone signal transduction in organisms[30, 35-36]

    图 2  生物体性激素的生物合成途径[60-61]

    Figure 2.  Biosynthetic pathways of sexual hormones in organisms[60-61]

    表 1  对无尾两栖动物甲状腺具有干扰效应的农药

    Table 1.  Pesticides that interfere with the thyroid gland of anura amphibians

    种类
    Species
    暴露物  
    Chemicals  
    剂量  
    Dosage  
    暴露时间 
    Exposure durations 
    效应
    Observed effects
    参考文献Reference
    非洲爪蟾
    Xenopus laevis
    三唑酮
    triadimefon
    0, 0.112, 1.12 mg/L NF 51 期,暴露 21 d
    Nieuwkoop-Faber stage
    51, exposure 21 days
    1.12 mg/L 处理组甲状腺激素浓度显著降低,甲状腺球蛋白下调
    Thyroid hormone concentration decreased significantly in 1.12 mg/L treatment group, thyroglobulin decreased
    [40]
    黑斑蛙
    Rana nigromaculata
    三唑酮,三唑醇
    triadimefon, triadimenol
    0.1, 1, 10 mg/L Gosner 26 期,暴露 28 d
    Gosner stage 26, exposure
    28 days
    各处理组甲状腺激素信号受到破坏,10 mg/L 三唑酮比三唑醇对HPT轴产生更多的影响
    The thyroid hormone signal was destroyed in each treatment group, 10 mg/L triadimefon had more significant effects on the HPT axis than triadimenol
    [41]
    北美牛蛙
    North American bullfrog (Rana catesbeiana)
    三氯生
    triclosan
    0.15-0.03 μg/L 预变态蝌蚪,暴露 96 h
    Pre-metamorphic tadpoles,
    exposure 96 hours
    各处理组变态前蝌蚪脑部甲状腺激素受体 α 的转录水平改变
    Each treatment group changed the transcription level of thyroid hormone receptor alpha in tadpole brain before metamorphosis
    [42]
    黑斑蛙
    Rana nigromaculata
    环丙唑醇
    cyproconazole
    1, 10 mg/L Gosner 24 期,
    暴露 14、28、42、90 d
    Gosner stage 24, exposure
    14, 28, 42, 90 days
    各处理组甲状腺在组织学上显著改变,且 10 mg/L 处理组甲状腺相关基因和激素水平受影响
    Thyroid gland was changed significantly in each treatment group, 10 mg/L treatment group affected thyroid-related genes and hormone levels
    [43]
    非洲爪蟾
    Xenopus laevis
    丁草胺
    butachlor
    1, 10, 100 mg/L NF 51 期,暴露 7、14、
    21 d Nieuwkoop-Faber
    stage 51, exposure 7, 14,
    21 days
    3 个处理组甲状腺激素含量升高,100 mg/L处理组下丘脑-垂体-甲状腺 (HPT) 轴相关基因表达受影响
    The thyroid hormone levels in the three treatment groups were elevated, and the expression of the hypothalamic-pituitary-thyroid (HPT) axis-related genes was affected in the 100 mg/L treatment group
    [44]
    非洲爪蟾
    Xenopus laevis
    乙草胺
    acetochlor
    2.7 μg/L NF 52-54 期 暴露 48、72 h
    Nieuwkoop-Faber stage,
    52-54, exposure 48, 72 hours
    乙草胺处理组非洲爪蟾尾部的甲状腺相关基因表达发生改变
    Thyroid-related gene expression was changed in the tail of Xenopus laevis in the acetochlor treatment group
    [45]
    木蛙蝌蚪
    Wood frog tadpoles (Lithobates sylvaticus)
    草甘膦
    glyphosate
    0.21 mg/L, 2.89 mg/L 受精卵至 Gosner 36/37 期
    Fertilized eggs to Gosner stage 36/37
    高浓度处理组影响甲状腺相关基因的mRNA 水平
    High concentration treatment group affected mRNA levels of thyroid related genes
    [46]
    黑斑蛙
    Rana nigromaculata
    异丙甲草胺,精异丙
    甲草胺
    metolachlor, S-metolachlor
    0.1, 1, 5 mg/L Gosner 26 期,暴露 28 d
    Gosner stage 26, exposure
    28 days
    各处理组均抑制TH响应基因的表达,且对黑斑蛙蝌蚪甲状腺组织学均产生影响,异丙甲草胺和精异丙甲草胺处理组差异不明显
    All the treatment groups inhibited the expression of TH-responsive genes, and affected thyroid histology, the difference between the metolachlor and the S-metolachlor treatment group was not obvious
    [47]
    绿蛙蝌蚪
    Green frog tadpoles (Lithobates clamitans)
    甲萘威
    carbaryl
    1 mg/L 孵化后约 14、28、56、112 d,
    暴露 3 d
    About 14, 28, 56, 112 days after hatching, exposure 3 days
    甲萘威处理组改变绿蛙蝌蚪发育过程中 Th 调节基因的 mRNA 丰度分布
    The carbaryl treatment group altered the mRNA abundance distribution of Th regulatory genes
    [48]
    非洲爪蟾
    Xenopus laevis
    联苯菊酯 (外消旋及
    两个异构体)
    bifenthrin (racemate and two enantiomers)
    rac-bifenthrin 0.001 μg/L, S-bifenthrin 0.1 μg/L, R-bifenthrin 0.1 μg/L. NF 46 期,暴露 28、35 d
    Nieuwkoop-Faber stage 46,
    exposure 28, 35 days
    R-联苯菊酯处理组TH含量受到抑制,且 tshβdio2 等相关基因受到明显影响
    R-bifenthrin treatment group inhibited TH content, related genes was affected such as tshβ and dio2
    [51]
    下载: 导出CSV

    表 2  对无尾两栖动物性腺具有干扰效应的农药

    Table 2.  Pesticides that interfere with the gonad of anura amphibians

    种类
    Species
    暴露物
    Chemicals
    剂量  
    Dosage  
    暴露时间
    Exposure durations
    效应
    Observed effects
    参考文献
    Reference
    雄性非洲爪蟾
    Xenopus laevis, male
    戊唑醇
    tebuconazole
    0.1, 1, 10, 500 μg/L 成年雄性,暴露 27 d
    Adult males, exposure
    27 days
    500 μg/L 处理组血浆和性腺中类固醇激素水平改变
    Steroid hormone levels in plasma and gonads were changed in 500 μg/L treatment group
    [65]
    雄性非洲爪蟾
    Xenopus laevis, male
    乙烯菌核利
    vinclozolin
    10−6, 10−8, 10−10 mol/L 成年雄性,暴露 96 h
    Adult males, exposure
    96 hours
    10−6 mol/L 处理组雄性性唤起降低,处于性冷淡状态
    Male sexual arousal, sexually apathetic was reduced in 10−6 mol/L treatment group
    [66]
    雄性非洲爪蟾
    Xenopus laevis, male
    咪鲜胺
    prochloraz
    0, 6.7, 20, 60, 180 μg/L 非洲爪蟾胚胎 (受精后<1 d), 暴露至变态完成后 2 个月
    Xenopus embryos (<1 d after fertilization), exposure to two months after completion of metamorphosis
    180 μg/L 处理组雄性苗勒氏管受到抑制且睾丸功能相关基因表达水平受到影响
    Male Mullerian tube was inhibited in 180 μg/L treatment group, affected testicular function-related gene
    [67]
    雄性非洲爪蟾
    Xenopus laevis, male
    莠去津
    atrazine
    2.5 μg/L 孵化后的幼虫,暴露3年
    Hatched larvae, exposure
    3 years
    莠去津处理组雄性睾酮水平降低、生殖腺减小,交配行为受抑制,生育能力下降
    In the carbaryl treatment group male testosterone level and gonad size decreased, mating behavior was inhibited, and fertility decreased
    [69]
    雄性非洲爪蟾
    Xenopus laevis, male
    莠去津
    atrazine
    0.1, 1, 10, 100 μg/L NF 47 期,暴露 90 和 180 d
    Nieuwkoop-Faber stage 47, exposure 90, 180 days
    100 μg/L 处理组睾丸变性相关基因表达显著受到抑制
    Gene expression of testicular degeneration in 100 μg/L treatment group was significantly inhibited
    [70]
    雄性非洲爪蟾
    Xenopus laevis, male
    西玛津
    simazine
    0.1, 1.2, 11.0, 100.9 μg/L NF 46 期,暴露 100 d
    Nieuwkoop-Faber stage 46, exposure 100 days
    11.0 μg/L 和100.9 μg/L 处理组雄性腺重量显著减少,并且导致精原细胞肥大和睾丸形状不规则
    Male gland weight was significantly reduced in 11.0 μg/L and 100.9 μg/L treatment groups, lead to hypertrophy of spermatogonia and irregular testicular shape
    [71]
    非洲爪蟾
    Xenopus laevis
    利谷隆
    linuron
    9, 45 μg/L NF 40 期,暴露至 NF51/53, 55/58, 66期 Nieuwkoop-Faber stage 40, exposure
    to Nieuwkoop-Faber stage 51-53, 55-58, 66
    低浓度处理组导致性别比例雌性化,雄性生育力降低
    Low concentration treatment group resulted in feminization, male fertility decreased
    [73]
    雄性非洲爪蟾
    Xenopus laevis, male
    p,p′-DDE
    p,p′-dichlordi-phenyldichloroethylene
    3.18 ng/L, 318.0 ng/L 成年雄性,暴露 96 h
    Adult males, exposure
    96 hours
    318.0 ng/L 处理组雄性性唤起降低
    In the 318.0 ng/L treatment group, male arousal decreased
    [75]
    林蛙蝌蚪
    Rana dalmatina
    毒死蜱
    chlorpyrifos
    0.025 mg/L, 0.05 mg/L Gosner 25 期,暴露至 46 期Gosner stage 25, exposure
    to stage 46
    各处理组损害性腺发育,通过诱导睾丸间质状况和睾丸形态改变而影响性腺分化
    Each treatment group impaired gonadal development and affected gonadal differentiation by inducing testicular interstitial status and testicular morphology
    [76]
    雌性非洲爪蟾
    Xenopus laevis, female
    甲氧滴滴涕
    methoxychlor
    0.5, 5, 50, 500 μg/L 成年雌性,暴露 30 d
    Adult females, exposure
    30 days
    雌性产卵延迟,500 μg/L 处理组产卵数量显著减少,不可受精卵数量增加
    Female oviposition was delayed, number of oviposition decreased significantly and the number of unfertilized eggs increased in 500 μg/L treatment group
    [77]
    下载: 导出CSV
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出版历程
  • 收稿日期:  2019-07-18
  • 网络出版日期:  2019-09-29
  • 刊出日期:  2019-12-01

农药类内分泌干扰物对无尾两栖动物影响的研究进展

    通讯作者: 刁金玲, jinling@cau.edu.cn
    作者简介: 刘蕊,女,硕士研究生,E-mail:rayliu@cau.edu.cn
  • 中国农业大学 理学院,北京 100193

DOI: 10.16801/j.issn.1008-7303.2019.0102

摘要: 农药类内分泌干扰物 (endocrine disrupting chemicals, EDCs) 对人类健康和生态环境造成了一定威胁。无尾两栖动物因其处于水生生态系统和陆生生态系统的过渡阶段,在食物链中具有重要位置,同时也是经济合作与发展组织 (OECD) 和美国环保局 (USEPA) 识别和评估化合物影响的常见模式生物。因此开展农药类EDCs对无尾两栖动物影响的研究可进一步评价农药的生态风险,有助于全面认识农药类EDCs。本文综述了农药类内分泌干扰物对无尾两栖动物甲状腺及性腺干扰的研究进展,并展望了研究农药类EDCs对无尾两栖动物影响的深远意义,旨在为全面的农药生态风险评价及为农药安全性评价体系引入更加全面、科学的试验方法和评价标准提供科学依据。

English Abstract

  • 内分泌系统是机体重要的调节系统,参与调节机体的生长发育及各种代谢,维持内环境稳态,并影响机体行为和控制生殖等,起着不可或缺的作用[1]。1991年7月在研究低剂量接触环境中化学物质对激素的影响会议中,科学家们首次提出了内分泌干扰物 (EDCs) 一词[2]。美国环保局 (USEPA) 定义,EDCs为环境中存在的能够干扰天然激素产生、释放、转运、代谢、结合及消除的外源因子[3]。其通过模拟或阻断内源激素对完整的生物体或其后代群体造成不利影响[4]

    饮食、皮肤和呼吸是内分泌干扰物进入体内的主要途径,EDCs模拟激素行为或与激素竞争受体来干扰内分泌系统。这种干扰会使激素水平发生改变、激素的产生与代谢受到抑制以及激素在体内的转运方式发生变化,从而导致激素控制的功能受到影响[5]。根据作用终点,EDCs可分为雌激素、雄激素和甲状腺激素等内分泌干扰物[6-8]

    内分泌干扰物的作用机制主要分为3种:1) 受体介导反应。EDCs能通过模拟和拮抗内源性激素来介入内源性激素的介导反应,从而影响生物体的内分泌系统[9]。如莠去津和滴滴涕类物质可阻止睾丸激素与雄激素受体结合[9];多氯联苯 (PCBs) 类物质与甲状腺激素结构相似,能够干扰甲状腺激素的功能[10]。2) 非受体介导反应。EDCs通过破坏内源性激素及其受体的生成和代谢来干扰生物正常的内分泌功能[9]。3) 影响内分泌系统、神经系统与免疫系统的综合效应。由于环境中的EDCs通常以多种不同化合物的混合物形式存在,当这些混合物进入生物体后,由于其作用机制的相似性往往会表现出复合效应[10]。现有的研究表明,EDCs能对多种脊椎动物的各种行为产生此类综合效应[11-12],如暴露于过甲氧DDT的雄性小鼠在发情期对雌性小鼠没有任何繁殖行为和欲望[10],低浓度氯氰菊酯会使雄性大西洋大马哈鱼对雌鱼排卵期信息素的嗅觉反应能力大幅降低[10]

    一些研究表明,某些农药可能会影响实验动物、野生动物甚至是人类的正常内分泌功能[13-17],例如:氯苯嘧啶醇和三唑酮处理会使大鼠激素水平受到影响[13];DDT对秃鹰胚胎存活具有破坏性影响[16],且DDT及其代谢物、灭虫威等具有或潜在干扰人类和动物内分泌系统的危害[17]。无尾两栖动物对环境的变化较为敏感,且具有水生和陆地生命阶段的双相生命周期,是环境质量的良好指示生物[19]。然而,目前尚未见系统性地介绍农药类内分泌干扰物对无尾两栖动物影响的相关综述。鉴于此,笔者综述了农药类内分泌干扰物对无尾两栖类动物甲状腺及性腺干扰的研究进展,旨在全面评价农药的生态风险,并为农药安全评价体系中引入更加全面、科学的试验方法和评价标准提供科学依据。

    • 在无尾两栖动物繁殖季节,许多农药被用于杂草、真菌和害虫防治,使得无尾两栖动物极易受到威胁,这些农药的使用被认为是无尾两栖动物发育受损的不利因素之一[18]。此外,无尾两栖动物是联系水生和陆生环境的代表[19],由于其发育阶段被严格定义并对化学品引起的发育效应高度敏感,已成为识别和评估化合物影响的常见模式生物,如非洲爪蟾、黑斑蛙等[20-21]。评价化合物对无尾两栖动物的安全性主要是从化合物对其早期发育和甲状腺激素依赖的变态的影响入手,为了得到科学准确的化合物对无尾两栖动物安全性评价结果,不同的国家和组织制定了一系列的测试准则。

      OECD制定了3个相关测试指南:1) 爪蟾胚胎甲状腺试验 (XETA)。使用含有THb/ZIP-GFP转录因子的转基因非洲爪蟾蝌蚪,利用荧光测定技术检测供试化学品暴露72 h后对蝌蚪甲状腺活性的潜在调节[22];2) 两栖动物变态测定 (AMA)。将非洲爪蟾Xenopus laevis蝌蚪暴露于供试化学品21d,观察并记录后肢长度、发育阶段及每日死亡率等,并对甲状腺组织病理学进行评估,旨在鉴定可能干扰下丘脑-垂体-甲状腺 (HPT) 轴正常功能的物质[23];3) 两栖动物幼虫生长和发育测定 (LAGDA)。将非洲爪蟾胚胎暴露于供试化学品70 d (10周) 后进行生长 (体重和长度)、遗传/表型性别比的测定及甲状腺和性腺的组织病理学评估,以便对潜在的EDCs或其他类型的发育和生殖毒性物质进行评估[24]

      USEPA制定了蝌蚪/沉积物亚慢性毒性试验准则,将牛蛙蝌蚪在不同浓度的供试化学品中暴露30 d后计算其半致死浓度 (LC50) 值、半最大效应浓度 (EC50) 值及行为异常等数据,以评估化学品对无尾两栖动物的危害[25]。此外,USEPA还制定了关于两栖动物变态分析指南。非洲爪蟾蝌蚪在测试化学品中暴露21 d后测定其发育阶段、后肢长度、体长、体重及甲状腺激素等,旨在筛选可能干扰甲状腺功能的物质[26]

      中国根据自身的农药管理政策,在结合OECD及USEPA测试指南的基础上制定了农药对天敌两栖动物的急性毒性试验准则,选择泽蛙或非洲爪蟾蝌蚪暴露于供试农药,在24、48、72和96 h时观察并记录蝌蚪的中毒症状及死亡率,并计算每一观察时间的LC50值及95%置信区间,为化学农药的登记提供了科学依据[23, 25, 27]。2014年中国生态环境部发布了关于两栖动物的生物多样性观测技术导则,利用栅栏陷阱法、人工覆盖法和标记重捕法等方法对两栖动物的种类、个体数、性别及疾病状况等进行观测,以了解两栖动物多样性的现状和变化趋势[28],但中国关于农药对两栖动物甲状腺及变态等的相关试验准则还有所欠缺,有必要进一步制定相关试验准则以全面科学的评价农药安全性,为合理使用农药及其相应的环境管理提供科学依据。

    • 甲状腺对无尾两栖动物的变态反应调控及蛋白质合成有重要作用,甲状腺激素 (TH) 对正常脑和体细胞发育至关重要[29]

      无尾两栖动物在变态发育过程中,下丘脑-垂体-甲状腺轴 (HPT轴) 可调控多个组织和器官的重构,如腿芽的发生、尾吸收、颅面和消化系统的重构等[30]。HPT轴负责控制甲状腺激素的合成、释放和代谢[31]。下丘脑合成的促甲状腺激素释放激素 (TRH) 被释放到垂体,在垂体前叶刺激促甲状腺激素 (TSH) 的合成和释放。TSH调节甲状腺细胞的增殖以及甲状腺激素的合成和分泌。TH在甲状腺中产生,通常以甲状腺素 (T4) 的形式产生,并且在较小程度上产生三碘甲状腺原氨酸 (T3)[32],T4和T3对垂体TSH的释放和下丘脑TRH神经元的活性产生负反馈作用[33]。跨细胞膜的TH转运需要特异性转运蛋白 (TTR),这有助于TH的摄取和外排。2型脱碘酶 (Dio2) 是局部TH的主要激活剂,它可将T4转化为活性激素T3[34]。3型脱碘酶 (Dio3) 将T3和T4转化为不与TH受体相互作用的无活性代谢物——反三碘甲状腺原氨酸 (rT3) 或二碘甲状腺原氨酸 (T2),该酶被认为是TH作用的主要生理灭活剂。所有与TH代谢相关的机制,如TH转运蛋白、脱碘酶 (Dio2和Dio3) 等都存在于人和啮齿动物中,因此TH在调节生长发育中起重要作用。图1总结了生物体甲状腺激素的信号传导[30, 35-36]

      图 1  生物体甲状腺激素信号传导[30, 35-36]

      Figure 1.  Thyroid hormone signal transduction in organisms[30, 35-36]

      某些农药通过抑制甲状腺激素的合成、分泌、转运,或干扰甲状腺激素受体结合来干扰甲状腺系统,从而影响生物体正常的生长发育过程[37]。因此水环境中的农药残留可能会对无尾两栖动物的甲状腺产生内分泌干扰效应,从而影响到无尾两栖动物的正常生长发育[38]。下面总结了近年来对无尾两栖动物甲状腺系统具有干扰效应的农药,同时根据这些农药的种类、剂量、暴露时间和效应,将研究结果整理成表1

      表 1  对无尾两栖动物甲状腺具有干扰效应的农药

      Table 1.  Pesticides that interfere with the thyroid gland of anura amphibians

      种类
      Species
      暴露物  
      Chemicals  
      剂量  
      Dosage  
      暴露时间 
      Exposure durations 
      效应
      Observed effects
      参考文献Reference
      非洲爪蟾
      Xenopus laevis
      三唑酮
      triadimefon
      0, 0.112, 1.12 mg/L NF 51 期,暴露 21 d
      Nieuwkoop-Faber stage
      51, exposure 21 days
      1.12 mg/L 处理组甲状腺激素浓度显著降低,甲状腺球蛋白下调
      Thyroid hormone concentration decreased significantly in 1.12 mg/L treatment group, thyroglobulin decreased
      [40]
      黑斑蛙
      Rana nigromaculata
      三唑酮,三唑醇
      triadimefon, triadimenol
      0.1, 1, 10 mg/L Gosner 26 期,暴露 28 d
      Gosner stage 26, exposure
      28 days
      各处理组甲状腺激素信号受到破坏,10 mg/L 三唑酮比三唑醇对HPT轴产生更多的影响
      The thyroid hormone signal was destroyed in each treatment group, 10 mg/L triadimefon had more significant effects on the HPT axis than triadimenol
      [41]
      北美牛蛙
      North American bullfrog (Rana catesbeiana)
      三氯生
      triclosan
      0.15-0.03 μg/L 预变态蝌蚪,暴露 96 h
      Pre-metamorphic tadpoles,
      exposure 96 hours
      各处理组变态前蝌蚪脑部甲状腺激素受体 α 的转录水平改变
      Each treatment group changed the transcription level of thyroid hormone receptor alpha in tadpole brain before metamorphosis
      [42]
      黑斑蛙
      Rana nigromaculata
      环丙唑醇
      cyproconazole
      1, 10 mg/L Gosner 24 期,
      暴露 14、28、42、90 d
      Gosner stage 24, exposure
      14, 28, 42, 90 days
      各处理组甲状腺在组织学上显著改变,且 10 mg/L 处理组甲状腺相关基因和激素水平受影响
      Thyroid gland was changed significantly in each treatment group, 10 mg/L treatment group affected thyroid-related genes and hormone levels
      [43]
      非洲爪蟾
      Xenopus laevis
      丁草胺
      butachlor
      1, 10, 100 mg/L NF 51 期,暴露 7、14、
      21 d Nieuwkoop-Faber
      stage 51, exposure 7, 14,
      21 days
      3 个处理组甲状腺激素含量升高,100 mg/L处理组下丘脑-垂体-甲状腺 (HPT) 轴相关基因表达受影响
      The thyroid hormone levels in the three treatment groups were elevated, and the expression of the hypothalamic-pituitary-thyroid (HPT) axis-related genes was affected in the 100 mg/L treatment group
      [44]
      非洲爪蟾
      Xenopus laevis
      乙草胺
      acetochlor
      2.7 μg/L NF 52-54 期 暴露 48、72 h
      Nieuwkoop-Faber stage,
      52-54, exposure 48, 72 hours
      乙草胺处理组非洲爪蟾尾部的甲状腺相关基因表达发生改变
      Thyroid-related gene expression was changed in the tail of Xenopus laevis in the acetochlor treatment group
      [45]
      木蛙蝌蚪
      Wood frog tadpoles (Lithobates sylvaticus)
      草甘膦
      glyphosate
      0.21 mg/L, 2.89 mg/L 受精卵至 Gosner 36/37 期
      Fertilized eggs to Gosner stage 36/37
      高浓度处理组影响甲状腺相关基因的mRNA 水平
      High concentration treatment group affected mRNA levels of thyroid related genes
      [46]
      黑斑蛙
      Rana nigromaculata
      异丙甲草胺,精异丙
      甲草胺
      metolachlor, S-metolachlor
      0.1, 1, 5 mg/L Gosner 26 期,暴露 28 d
      Gosner stage 26, exposure
      28 days
      各处理组均抑制TH响应基因的表达,且对黑斑蛙蝌蚪甲状腺组织学均产生影响,异丙甲草胺和精异丙甲草胺处理组差异不明显
      All the treatment groups inhibited the expression of TH-responsive genes, and affected thyroid histology, the difference between the metolachlor and the S-metolachlor treatment group was not obvious
      [47]
      绿蛙蝌蚪
      Green frog tadpoles (Lithobates clamitans)
      甲萘威
      carbaryl
      1 mg/L 孵化后约 14、28、56、112 d,
      暴露 3 d
      About 14, 28, 56, 112 days after hatching, exposure 3 days
      甲萘威处理组改变绿蛙蝌蚪发育过程中 Th 调节基因的 mRNA 丰度分布
      The carbaryl treatment group altered the mRNA abundance distribution of Th regulatory genes
      [48]
      非洲爪蟾
      Xenopus laevis
      联苯菊酯 (外消旋及
      两个异构体)
      bifenthrin (racemate and two enantiomers)
      rac-bifenthrin 0.001 μg/L, S-bifenthrin 0.1 μg/L, R-bifenthrin 0.1 μg/L. NF 46 期,暴露 28、35 d
      Nieuwkoop-Faber stage 46,
      exposure 28, 35 days
      R-联苯菊酯处理组TH含量受到抑制,且 tshβdio2 等相关基因受到明显影响
      R-bifenthrin treatment group inhibited TH content, related genes was affected such as tshβ and dio2
      [51]
    • 三唑酮 (triadimefon) 是一种三唑类衍生物杀菌剂,在环境和目标农产品中均有检出,因此人们广泛关注其对野生动物和人类健康的风险[39]。Li等用不同浓度的三唑酮 (0、0.112和1.12 mg/L) 对Nieuwkoop-Faber (NF) 51期的非洲爪蟾蝌蚪展开试验,结果发现,暴露21 d后爪蟾变态前的发育速率受到影响,且甲状腺激素 (T4和T3) 浓度显著降低,甲状腺球蛋白下调,导致甲状腺内分泌紊乱,从而延缓了甲状腺激素依赖的变态发育[40]。此外,Zhang等还研究了黑斑蛙Rana nigromaculata蝌蚪暴露于三唑酮及其代谢物三唑醇后对甲状腺的影响,结果表明,三唑酮和三唑醇均可破坏甲状腺激素信号,并对蝌蚪的脑发育有明显的抑制作用[41]。有研究表明,杀菌剂三氯生可改变变态前蝌蚪脑部甲状腺激素受体α的转录水平,并导致其体重瞬间下降,同时可改变甲状腺激素介导的胚胎后期无尾两栖动物的发育速度[42]。将Gosner 24期的黑斑蛙蝌蚪暴露于环丙唑醇90 d后,黑斑蛙蝌蚪的甲状腺在组织学上发生显著变化,甲状腺相关基因 (tshβ, trh, trα, dio2, dio3) 和激素水平也受环丙唑醇暴露的影响而发生改变[43]

    • 丁草胺在中国水稻生态系统中有着广泛的应用,已成为水体环境中广泛存在的污染物。有研究表明,暴露于丁草胺7和14 d会引起非洲爪蟾蝌蚪畸形且甲状腺激素 (THs、T3和T4) 含量显著升高,且丁草胺可影响HPT轴相关基因 (tshα, tshβ, tg, tpo, dio1, dio2, ttr, trβ) 的表达量,并与剂量和暴露时间相关,导致甲状腺内分泌紊乱,从而导致发育毒性[44]。有研究表明,环境浓度的乙草胺暴露后可加速T3诱导的非洲爪蟾的变态,且蝌蚪尾部的甲状腺相关基因 (trα, trβ) 表达发生改变,表明乙草胺具有内分泌干扰作用[45]。草甘膦是目前世界上最常用的除草剂,在实验室条件下将蝌蚪暴露于草甘膦中,发现蝌蚪的生存和发育受到一定程度的影响。Lanctôt等研究了草甘膦对自然湿地中木蛙蝌蚪变态的影响,发现草甘膦暴露显著影响了木蛙蝌蚪甲状腺相关基因 (trβ, grII, dio2, dio3, crf) 的mRNA水平,表明草甘膦可能改变蝌蚪发育过程中的激素通路,从而引发内分泌干扰效应[46]。程程等研究了精异丙甲草胺与外消旋体异丙甲草胺对黑斑蛙蝌蚪发育的影响,表明这2种化合物对黑斑蛙蝌蚪的 TH 响应基因 (tshβ, trh, dio2, dio3) 的表达有抑制作用,且外消旋体抑制作用最为明显,异丙甲草胺及精异丙甲草胺暴露均使黑斑蛙蝌蚪甲状腺组织发生变化[47]

    • 研究发现,一些无尾两栖动物在幼虫发育后期接触杀虫剂甲萘威后,发育速度加快,这表明甲萘威可能影响了其与甲状腺激素相关的生物通路。Boone等分析了变态后暴露于甲萘威3 d对蝌蚪甲状腺的影响,发现其可作为内分泌干扰剂改变绿蛙蝌蚪发育过程中TH调节基因 (trα, trβ, dio2) 的mRNA丰度分布[48]。由于具有良好的光稳定性和杀虫活性,联苯菊酯 (bifenthrin) 一直被广泛应用[49]。USEPA基于暴露资料,已将联苯菊酯列入第一批进入内分泌干扰物一级筛选的最终名单[50]。Zhang等将非洲爪蟾蝌蚪暴露于顺式联苯菊酯对映体28和35 d后,发现TH含量受到抑制,且tshβ, trh, trβA, dio2等相关基因受到明显影响[51]

    • 性激素对性腺发育和分化的调控是影响无尾两栖动物性别分化的主要内在因素[52]。性激素属于类固醇激素,而血浆胆固醇是类固醇激素合成的前体[53-54]。内膜细胞在黄体生成素 (LH) 的作用下,使胆固醇转变为雄烯二酮,雄烯二酮可通过芳香酶直接转化为雌酮,或转化为睾酮[55]。雌激素主要由卵巢卵泡和黄体产生。雌激素的3个主要类型是雌酮 (E1)、17-β-雌二醇 (E2) 和雌三醇 (E3)[56]。在无尾两栖动物中,E2可被转运到肝脏中与雄激素受体结合并促进卵黄原蛋白的生成,为卵子发育提供必需营养物质[57]。17-α-雌二醇 (EE2) 是衍生自天然雌激素E2的合成激素[58]。睾酮是无尾两栖动物主要的雄激素,通过与雄激素受体介导核应答元件转录调控产生雄激素效应,在性别发育中起重要作用[57]。广泛分布于血液中的二氢睾酮是由睾酮与5α还原酶反应后生成的一种雄性激素。大量的研究证实,性激素影响无尾两栖动物的性腺分化和发育,雌二醇可诱导雄性转为雌性,睾酮可诱导雌性转为雄性[59]图2显示了生物体性激素的生物合成途径[60-61]

      图 2  生物体性激素的生物合成途径[60-61]

      Figure 2.  Biosynthetic pathways of sexual hormones in organisms[60-61]

      无尾两栖动物性别决定的多样性及其起源一直是生物学领域的研究热点。研究显示,性激素可能是无尾两栖动物性别的重要决定因子[62],而环境因素对其早期胚胎发育具有重要影响[59]。农药可能会抑制无尾两栖动物性激素的合成,导致性腺发育异常、性别比例异常和不寻常的交配行为[63]。因此农药对无尾两栖动物性腺的影响引发人们广泛的关注。下面按照农药类别总结了近年来不同农药对无尾两栖动物性腺系统的影响,同时根据农药的种类、剂量、暴露时间和效应,将农药对无尾两栖动物性腺干扰的研究结果整理成表2

      表 2  对无尾两栖动物性腺具有干扰效应的农药

      Table 2.  Pesticides that interfere with the gonad of anura amphibians

      种类
      Species
      暴露物
      Chemicals
      剂量  
      Dosage  
      暴露时间
      Exposure durations
      效应
      Observed effects
      参考文献
      Reference
      雄性非洲爪蟾
      Xenopus laevis, male
      戊唑醇
      tebuconazole
      0.1, 1, 10, 500 μg/L 成年雄性,暴露 27 d
      Adult males, exposure
      27 days
      500 μg/L 处理组血浆和性腺中类固醇激素水平改变
      Steroid hormone levels in plasma and gonads were changed in 500 μg/L treatment group
      [65]
      雄性非洲爪蟾
      Xenopus laevis, male
      乙烯菌核利
      vinclozolin
      10−6, 10−8, 10−10 mol/L 成年雄性,暴露 96 h
      Adult males, exposure
      96 hours
      10−6 mol/L 处理组雄性性唤起降低,处于性冷淡状态
      Male sexual arousal, sexually apathetic was reduced in 10−6 mol/L treatment group
      [66]
      雄性非洲爪蟾
      Xenopus laevis, male
      咪鲜胺
      prochloraz
      0, 6.7, 20, 60, 180 μg/L 非洲爪蟾胚胎 (受精后<1 d), 暴露至变态完成后 2 个月
      Xenopus embryos (<1 d after fertilization), exposure to two months after completion of metamorphosis
      180 μg/L 处理组雄性苗勒氏管受到抑制且睾丸功能相关基因表达水平受到影响
      Male Mullerian tube was inhibited in 180 μg/L treatment group, affected testicular function-related gene
      [67]
      雄性非洲爪蟾
      Xenopus laevis, male
      莠去津
      atrazine
      2.5 μg/L 孵化后的幼虫,暴露3年
      Hatched larvae, exposure
      3 years
      莠去津处理组雄性睾酮水平降低、生殖腺减小,交配行为受抑制,生育能力下降
      In the carbaryl treatment group male testosterone level and gonad size decreased, mating behavior was inhibited, and fertility decreased
      [69]
      雄性非洲爪蟾
      Xenopus laevis, male
      莠去津
      atrazine
      0.1, 1, 10, 100 μg/L NF 47 期,暴露 90 和 180 d
      Nieuwkoop-Faber stage 47, exposure 90, 180 days
      100 μg/L 处理组睾丸变性相关基因表达显著受到抑制
      Gene expression of testicular degeneration in 100 μg/L treatment group was significantly inhibited
      [70]
      雄性非洲爪蟾
      Xenopus laevis, male
      西玛津
      simazine
      0.1, 1.2, 11.0, 100.9 μg/L NF 46 期,暴露 100 d
      Nieuwkoop-Faber stage 46, exposure 100 days
      11.0 μg/L 和100.9 μg/L 处理组雄性腺重量显著减少,并且导致精原细胞肥大和睾丸形状不规则
      Male gland weight was significantly reduced in 11.0 μg/L and 100.9 μg/L treatment groups, lead to hypertrophy of spermatogonia and irregular testicular shape
      [71]
      非洲爪蟾
      Xenopus laevis
      利谷隆
      linuron
      9, 45 μg/L NF 40 期,暴露至 NF51/53, 55/58, 66期 Nieuwkoop-Faber stage 40, exposure
      to Nieuwkoop-Faber stage 51-53, 55-58, 66
      低浓度处理组导致性别比例雌性化,雄性生育力降低
      Low concentration treatment group resulted in feminization, male fertility decreased
      [73]
      雄性非洲爪蟾
      Xenopus laevis, male
      p,p′-DDE
      p,p′-dichlordi-phenyldichloroethylene
      3.18 ng/L, 318.0 ng/L 成年雄性,暴露 96 h
      Adult males, exposure
      96 hours
      318.0 ng/L 处理组雄性性唤起降低
      In the 318.0 ng/L treatment group, male arousal decreased
      [75]
      林蛙蝌蚪
      Rana dalmatina
      毒死蜱
      chlorpyrifos
      0.025 mg/L, 0.05 mg/L Gosner 25 期,暴露至 46 期Gosner stage 25, exposure
      to stage 46
      各处理组损害性腺发育,通过诱导睾丸间质状况和睾丸形态改变而影响性腺分化
      Each treatment group impaired gonadal development and affected gonadal differentiation by inducing testicular interstitial status and testicular morphology
      [76]
      雌性非洲爪蟾
      Xenopus laevis, female
      甲氧滴滴涕
      methoxychlor
      0.5, 5, 50, 500 μg/L 成年雌性,暴露 30 d
      Adult females, exposure
      30 days
      雌性产卵延迟,500 μg/L 处理组产卵数量显著减少,不可受精卵数量增加
      Female oviposition was delayed, number of oviposition decreased significantly and the number of unfertilized eggs increased in 500 μg/L treatment group
      [77]
    • 有研究表明,杀菌剂戊唑醇可能属于内分泌干扰物[64]。Poulsen等将成年雄性非洲爪蟾暴露于戊唑醇进行了为期27d的研究。结果显示,戊唑醇引起了血浆和性腺中类固醇激素水平的改变,从而抑制了暴露组的类固醇生成[65]。乙烯菌核利 (vinclozolin) 为二甲酰亚胺类杀菌剂,通过抑制雄激素受体与雄激素结合而表现出抗雄激素作用,可以影响脊椎动物的内分泌系统。有研究表明,成年 (5年) 雄性非洲爪蟾暴露于乙烯菌核利96 h后,雄性性唤起降低,处于性冷淡的状态。因此,抗雄激素乙烯菌核利可能通过改变非洲爪蟾的配偶呼唤行为而导致繁殖成功率降低[66]。Haselman等利用两栖幼虫动物生长发育试验 (LAGDA) 评估了非洲爪蟾多生命期暴露于咪鲜胺的影响。结果显示出咪鲜胺暴露抑制了雄性的苗勒氏管 (Mullerian duct),而雌性的苗勒氏管成熟加速,这是雌性化作用的特征,且睾丸功能相关基因 (cyp17a1, rflcii) 表达水平受到影响,表明睾丸间质细胞成熟和睾酮信号传导受损,体现出咪鲜胺的抗雄激素作用模式[67]

    • 莠去津也是一种强效的内分泌干扰物,可以对雄性两栖动物进行化学阉割和雌性化,其可破坏正常的性腺发育,使发育中的雄性性腺雌性化[68]。暴露于莠去津的雄性非洲爪蟾睾酮水平降低、生殖腺减小、喉部发育不明显/女性化,交配行为受到抑制、精子发生减少和生育能力下降[69]。此外,Sai等进一步研究发现,莠去津诱导睾丸变性相关基因 (adc, cdc6, acp6, oat, gatm, cycE1, orc3, flad1等) 表达的显著变化,表明莠去津可能通过干扰雄性非洲爪蟾发育过程中相关基因的表达而影响生殖系统和免疫系统[70]。此外Sai等的研究结果表明,西玛津对雄性非洲爪蟾繁殖具有潜在的损害,导致其性腺质量减少、精原细胞肥大和睾丸形状不规则等。当蝌蚪暴露于西玛津时,观察到睾丸组织的显著退化,且参与细胞周期控制和氨基酸代谢途径的基因显著下调[71]。利谷隆是农业生产中常用的除草剂,研究表明,利谷隆可能是一种内分泌干扰物[72]。非洲爪蟾蝌蚪在NF 40期暴露于利谷隆,直至变态完成,可观察到其雌性化的性别比例和第二性征的去雄性化及雄性生育力降低,体现出其抗雄激素作用[73]

    • p,p'-二氯二苯基二氯乙烯 (p,p'-DDE) 是杀虫剂二氯二苯基三氯乙烷 (DDT) 的代谢产物。由于DDT和DDE的半衰期极长,虽然DDT从20世纪70年代开始已被各国逐步禁用,但到目前为止,在环境中DDT和DDE仍有检出[65]。在两栖动物试验中,DDE被发现是一种抗雄激素内分泌干扰化学物质[74]。将雄性非洲爪蟾暴露于DDE 96 h后性唤起降低,显示出DDE的雌激素和抗雄激素的作用方式,其中任何一种都可能对非洲爪蟾的生殖生理和行为产生不利影响[75]。交配行为对于无尾两栖动物成功繁殖至关重要, 因此,DDE暴露可能会导致非洲爪蟾繁殖成功率降低[75]。毒死蜱是世界上使用广泛的有机磷农药,也被怀疑其是一种内分泌干扰物。Ilaria等的研究发现,长期暴露于毒死蜱降低了具有正常睾丸的林蛙的雄性百分比,损害林蛙的性腺发育,通过诱导睾丸间质状况和睾丸形态的改变而影响性腺分化。因此,毒死蜱可能通过内分泌干扰机制干扰蛙的性别分化和生殖发育[76]。将成年雌性非洲爪蟾暴露于杀虫剂甲氧滴滴涕 (MXC),结果发现雌性产卵被延迟,且产卵数量减少,不可受精卵数量增加[77]。这些数据表明,将成年雌性非洲爪蟾暴露于具有内分泌干扰活性的MXC中可导致其发生生殖和内分泌功能障碍[77]

    • 农药可有效保障农业生产,防治农业生产的病虫害,达到农产品产量提高的目的。它不仅仅是保障现代农业发展的重要因素之一,同时对现代经济的贡献也是不可磨灭的。然而农药是一把双刃剑,它的滥用和过度使用是农业生态环境恶化的源头之一。研究发现,某些农药为内分泌干扰物,能够干扰生物体的激素分泌甚至干扰生殖功能。

      1996年,经合组织成立了内分泌干扰物测试和评估咨询小组,并制定了内分泌干扰物测试和评估的概念框架[78]。框架分为5个等级,涉及哺乳动物和非哺乳动物,两栖动物也包含在内,根据毒理学试验数据及相关信息对内分泌干扰物进行了评级[78]。美国环保局和欧盟也正在系统地进行EDCs筛选与测评方法研究[79]。2015年中国出台了《农药内分泌干扰物评价方法》,以大鼠为实验动物,分2个阶段采用7项试验以系统评价农药是否存在内分泌干扰作用,完善了农药毒理学评价技术[80]

      无尾两栖动物对环境的变化较为敏感,其皮肤具有高渗透性,且它们具有水生和陆地生命阶段的双相生命周期,这些特征使得无尾两栖动物成为环境质量的良好指示生物。此外,无尾两栖动物在食物链中也具有重要地位,各种内分泌干扰物易在两栖动物体内富集并达到较高浓度,这不仅对两栖动物自身的生长发育产生影响,更有可能影响到整个生态系统。因此在进行化学品安全性评价时把化学品对无尾两栖类的影响考虑在内是有必要的。此前,中国已禁止了六六六、DDT、除草醚等一些农药类EDCs的使用,以减轻对环境及人体的危害[81]。通过研究农药是否对无尾两栖动物具有内分泌干扰效应可进一步评价农药的生态风险,为农药类EDCs的深入研究提供依据,有助于全面地认识农药类EDCs,同时推动毒理学、生态学、农药学等学科的相互渗透与交叉,扩展对农药毒性评价试验的范围。在农药注册登记方面,对引入更加全面、科学的试验方法和和评价标准具有深远意义。

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