有機(jī)磷阻燃劑的環(huán)境暴露與動(dòng)物毒性效應(yīng)

周啟星, 趙夢(mèng)陽(yáng), 來(lái)子陽(yáng), 李學(xué)彥

1. 南開(kāi)大學(xué)環(huán)境科學(xué)與工程學(xué)院, 環(huán)境污染過(guò)程與基準(zhǔn)教育部重點(diǎn)實(shí)驗(yàn)室, 天津 300071 2. 中國(guó)人民解放軍沈陽(yáng)軍區(qū)總醫(yī)院，沈陽(yáng)110016

近年來(lái)，有機(jī)磷阻燃劑(organophosphorus flame retardants, OPFRs)作為阻燃劑和增塑劑廣泛應(yīng)用于商業(yè)產(chǎn)品生產(chǎn)中，包括塑料、紡織品、繪畫顏料和家具等[1]，世界范圍內(nèi)對(duì)OPFRs的需求量和生產(chǎn)量也在逐年增加。有機(jī)磷阻燃劑對(duì)于人類生活來(lái)說(shuō)是必不可少的，但越來(lái)越多的OPFRs也隨之進(jìn)入到環(huán)境中，如大氣、土壤和水體[2-7]。一方面，空氣顆粒物、室內(nèi)灰塵、辦公設(shè)備、食物和飲用水中均含有微量的有機(jī)磷阻燃劑，這些有機(jī)磷阻燃劑可以通過(guò)不同的方式參與到人類的生產(chǎn)和生活過(guò)程當(dāng)中，從而對(duì)人體健康產(chǎn)生潛在危害；另一方面，OPFRs也會(huì)進(jìn)入到生態(tài)系統(tǒng)中，進(jìn)而對(duì)生態(tài)系統(tǒng)產(chǎn)生一定的不良影響。因此，這種廣泛使用的阻燃劑的環(huán)境影響開(kāi)始受到有關(guān)方面的關(guān)注，尤其是其毒性效應(yīng)及生態(tài)風(fēng)險(xiǎn)。諸多研究表明，不同種類的有機(jī)磷阻燃劑在不同濃度條件下對(duì)小鼠、雞、隼等生物有著不同程度的影響[8-10]。另外，也有綜述很好地總結(jié)了近年來(lái)有機(jī)磷阻燃劑在動(dòng)物體內(nèi)及人體內(nèi)的相關(guān)研究，包括吸收、生物積累、代謝以及體內(nèi)暴露研究等[11]。本文則主要針對(duì)有機(jī)磷阻燃劑的動(dòng)物毒性研究，綜述了近年來(lái)關(guān)于OPFRs的動(dòng)物毒性效應(yīng)，包括OPFRs對(duì)生物體分子、細(xì)胞、器官和個(gè)體水平的影響，并針對(duì)有機(jī)磷阻燃劑的毒性效應(yīng)對(duì)未來(lái)研究重點(diǎn)進(jìn)行了展望。

1 有機(jī)磷阻燃劑的環(huán)境暴露(Environmental exposure of OPFRs)

1.1 有機(jī)磷阻燃劑在環(huán)境中的存在濃度

各國(guó)研究人員對(duì)不同環(huán)境介質(zhì)中的OPFRs檢測(cè)結(jié)果表明，有機(jī)磷阻燃劑已廣泛存在于世界范圍內(nèi)，且存在于各種非生物介質(zhì)中。有研究表明各國(guó)已在室內(nèi)大氣中檢測(cè)到OPFRs。Dodson等[12]對(duì)加利福尼亞50戶家庭室內(nèi)灰塵的成分進(jìn)行了定性定量檢測(cè)，發(fā)現(xiàn)含有幾種有機(jī)磷阻燃劑且濃度在μg·g-1水平。Joyce等[13]檢測(cè)了西班牙巴塞羅那一些居住區(qū)、學(xué)校、劇院以及研究所的室內(nèi)OPFRs濃度，發(fā)現(xiàn)總濃度在2 053～72 090 ng·g-1，且磷酸三(二-氯)異丙酯(TCIPP, tris(2-chloroisopropyl) phosphate)的所占比例最高。由于人類生產(chǎn)生活的原因，有機(jī)磷阻燃劑也隨之進(jìn)入到自然環(huán)境中(如圖1所示)。Guo等[14]對(duì)北美五大湖中的湖紅點(diǎn)鮭(Salvelinusnamaycush)、玻璃梭鱸(Sandervitreus)體內(nèi)的有機(jī)磷阻燃劑進(jìn)行了檢測(cè)，總量為36.6 ng·g-1脂質(zhì)。Cao等[15]對(duì)五大湖區(qū)的蘇必利爾湖、密歇根湖以及安大略湖的底泥中有機(jī)磷阻燃劑進(jìn)行了檢測(cè)，發(fā)現(xiàn)總含量分別為2.2，4.7，16.6 ng·g-1dw(干重)。甚至在極地地區(qū)也發(fā)現(xiàn)了有機(jī)磷阻燃劑的蹤跡，Esteban等[16]在南極半島北部地區(qū)的大陸水中檢測(cè)出有機(jī)磷阻燃劑，濃度為19.60～9 209 ng·L-1。

圖1 有機(jī)磷阻燃劑在環(huán)境中的遷移Fig. 1 The migration of organophosphorus flame retardants (OPFRs) in the environment

在我國(guó)，科研人員對(duì)有機(jī)磷阻燃劑的環(huán)境水平也做了大量監(jiān)測(cè)工作。在華南地區(qū)的鄉(xiāng)村、城市居民區(qū)和大學(xué)宿舍內(nèi)都檢測(cè)到了OPFRs(7.48～11.0 μg·g-1)[17]。同時(shí)，在飲用水[18-20]和食物[21]中(均在ng·g-1水平)也檢測(cè)到了含量較低的有機(jī)磷阻燃劑。Cao等[22]對(duì)我國(guó)太湖沉積物中的有機(jī)磷阻燃劑進(jìn)行了檢測(cè)，結(jié)果顯示其濃度在3.38～14.25 mg·kg-1范圍內(nèi)。Wang等[23]2015年檢測(cè)了我國(guó)渤海入?？诘?1條河流中的有機(jī)磷阻燃劑，總濃度為9.6～1 549 ng·L-1。在我國(guó)南海區(qū)域的大氣中也檢測(cè)到了47.1～160.9 pg·m-3的有機(jī)磷阻燃劑[24]。Wan等[25]在塑料廢物處理區(qū)域內(nèi)土壤中檢測(cè)出有機(jī)磷酸酯，濃度為38～1 250 ng·g-1dw。Ren等[26]檢測(cè)了中國(guó)上海市懸浮顆粒物中的有機(jī)磷阻燃劑含量，郊區(qū)總含量均值為19.4 ng·m-3，市區(qū)為6.6 ng·m-3，且各種有機(jī)磷阻燃劑的比重為磷酸三氯丙酯(TCPP, tris(chloropropyl) phosphate)和磷酸三(2-氯)乙酯(TCEP, tris(2-chloroethyl) phosphate)>磷酸三(1,3-二氯)異丙酯(TDCIPP, tris(1,3-dichloroisopropyl) phosphate)>磷酸三丁酯(TBP, tributyl phosphate)>磷酸三(鄰甲苯酯)(TCP, tricresyl phosphate)。Ding等[27]對(duì)中國(guó)東部50個(gè)人體胎盤樣品進(jìn)行了12種有機(jī)磷阻燃劑的檢測(cè)，發(fā)現(xiàn)總量在34.4～862 ng·g-1lipid weight (lw)，中值為301 ng·g-1lw，TCEP含量最多，為142 ng·g-1lw，數(shù)據(jù)分析結(jié)果顯示：各種有機(jī)磷阻燃劑與胎盤的脂含量不相關(guān)，且與飲食習(xí)慣也無(wú)明顯的相關(guān)性。Ma等[28]在2011年和2015年對(duì)山東一些居民血清內(nèi)的有機(jī)磷阻燃劑進(jìn)行了檢測(cè)，發(fā)現(xiàn)這2年OPFRs總含量分別為680 ng·g-1脂質(zhì)和709 ng·g-1脂質(zhì)，含量最多的為TCEP,占總含量的82%，研究還發(fā)現(xiàn)含氯的有機(jī)磷阻燃劑比不含氯的更容易在人體內(nèi)積累。

1.2 有機(jī)磷阻燃劑的暴露水平

既然在環(huán)境中發(fā)現(xiàn)了不同水平的有機(jī)磷阻燃劑，那么該物質(zhì)對(duì)人類和其他生物的暴露水平也備受關(guān)注，且在不同生物體內(nèi)均可檢測(cè)到一定濃度的OPFRs。

表1 有機(jī)磷阻燃劑對(duì)動(dòng)物個(gè)體的毒性效應(yīng)Table 1 The toxic effect of OPFRs on animals

注： TPP為磷酸三苯酯, TCEP為磷酸三(2-氯)乙酯 , TDCIPP為磷酸三(1,3-二氯)異丙酯。

Note： TPP stands for triphenyl phosphate; TCEP stands for tris(2-chloroethyl) phosphate; TDCIPP stands for tris(1,3-dichloroisopropyl) phosphate.

Kate等[29]檢測(cè)了8位懷孕女性尿液中的OPFRs代謝產(chǎn)物水平，發(fā)現(xiàn)TDCIPP的代謝產(chǎn)物磷酸二(1,3-二氯)異丙酯(BDCPP, bis(1,3-dichloro-2-propyl) phosphate)和磷酸三苯酯(TPP, triphenyl phosphate)的代謝產(chǎn)物磷酸二苯酯(DPP, diphenyl phosphate)的濃度分別為1.3 ng·mL-1和1.9 ng·mL-1。Nele等[30]對(duì)溫莎和普林斯頓地區(qū)的女性及其孕育兒童尿液中的OPFRs進(jìn)行了檢測(cè)，發(fā)現(xiàn)幾種有機(jī)磷酸酯的濃度在0.1～100 ng·mL-1水平，且兒童的暴露量高于母親。Ali等[31]對(duì)巴基斯坦幾處清真寺及居民區(qū)進(jìn)行了暴露評(píng)估，發(fā)現(xiàn)有機(jī)磷阻燃劑在成人體內(nèi)的暴露量為0.65 ng·kg-1bw·d-1，兒童體內(nèi)的暴露量為15.2 ng·kg-1bw·d-1。Mohamed等[32]進(jìn)行了人體表皮體外實(shí)驗(yàn)，發(fā)現(xiàn)對(duì)TCEP、 TCIPP和TDCIPP的吸收率分別為28%、25%和13%，滲透率分別為16%、11%和9%，并用模型計(jì)算得出英國(guó)兒童的暴露量為36 ng·kg-1·d-1，成人為4 ng·kg-1·d-1。Courtney等[33]采集了29名辦公室工作人員的尿液進(jìn)行了代謝組分析，發(fā)現(xiàn)尿液中存在408 pg·mL-1的BDCPP，即TDCIPP的代謝產(chǎn)物。Fromme等[34]對(duì)德國(guó)63個(gè)托兒所的兒童尿液進(jìn)行了檢測(cè)，發(fā)現(xiàn)尿液中磷酸三(2-丁氧基)乙酯(TBEP, tris(2-butoxyethyl) phosphate)、磷酸三(2-氯)丙酯(TCPP, tri(2-chloropropyl) phosphate)和磷酸三正丁酯(TnBP, tri-n-butyl phosphate)的代謝產(chǎn)物濃度在0.8～2.0 μg·L-1范圍內(nèi)。人們不僅暴露在室內(nèi)的OPFRs中，甚至在徒步旅行中也會(huì)有所暴露[35]。近期的研究表明在野生動(dòng)物體內(nèi)也檢測(cè)到了有機(jī)磷阻燃劑，例如北美雌性銀鷗的脂肪內(nèi)含量最高(32.3 ± 9.8 ng·g-1濕重(ww))，蛋黃 (14.8 ± 2.4 ng·g-1ww) ≈ 蛋清 (14.8 ± 5.9 ng·g-1ww) > 肌肉 (10.9 ± 5.1 ng·g-1ww) ≥血紅細(xì)胞(1.00 ±0.62 ng·g-1ww)，然而在肝臟、血清以及大腦中并未檢測(cè)到有機(jī)磷阻燃劑[36]。

綜上所述，現(xiàn)階段有機(jī)磷阻燃劑在環(huán)境中的暴露的特點(diǎn)為：全球性范圍廣泛分布；人類活動(dòng)區(qū)域的濃度水平高于自然界；暴露水平較低。

2 有機(jī)磷阻燃劑的動(dòng)物毒性效應(yīng)(Toxic effects of OPFRs on animals)

2.1 對(duì)動(dòng)物個(gè)體的毒性效應(yīng)

為了更加深入地研究有機(jī)磷阻燃劑的毒性效應(yīng)，對(duì)各種模式生物進(jìn)行了研究，且大部分集中于魚類、禽類和鼠類等(表1)。

2.1.1 對(duì)魚類的毒性效應(yīng)

由于斑馬魚是一種很好的模式生物，且基因與人類十分相似，因此對(duì)魚類的研究以斑馬魚為主。成魚暴露于高濃度的有機(jī)磷阻燃劑會(huì)通過(guò)調(diào)節(jié)體內(nèi)的激素水平從而改變其行為。Liu等[37]將4個(gè)月大的斑馬魚成魚暴露于不同濃度的TDCIPP (0, 0.04, 0.2, 1 mg·L-1), TPP (0, 0.04, 0.2, 1 mg·L-1), TCP (0, 0.008, 0.04, 0.2 mg·L-1)，14 d后檢測(cè)發(fā)現(xiàn)在雄魚體內(nèi)，睪丸素和11-氧化睪丸素降低，而17β-雌二醇升高；在雌魚體內(nèi)，CYP17和 CYP19a基因在2種性激素中顯著上調(diào)，而卵黃蛋白原基因下調(diào)，這些結(jié)果表明有機(jī)磷阻燃劑可以通過(guò)類固醇生成或雌激素代謝而改變性激素的平衡。Liu等[38]發(fā)現(xiàn)長(zhǎng)期(120 d)暴露于高濃度(500 mg·L-1)的TPP會(huì)導(dǎo)致斑馬魚成魚通過(guò)改變激素平衡來(lái)提高求偶性。將TPP(0.050 mg·L-1和0.300 mg·L-1)暴露于斑馬魚7 d后，檢測(cè)發(fā)現(xiàn)葡萄糖、UDP-葡萄糖、乳酸、琥珀酸、延胡索酸酯、膽堿、乙?；鈮A和一些脂肪酸的水平均有顯著改變。轉(zhuǎn)錄組結(jié)果顯示：對(duì)相關(guān)通路均有顯著影響，包括鞘糖脂生物合成、PPAR信號(hào)通路和脂肪酸伸長(zhǎng)。這些結(jié)果表明TPP暴露會(huì)明顯擾亂斑馬魚肝臟糖類和脂類代謝。此外，DNA復(fù)制、細(xì)胞周期、非同源性末端接合、堿基切除修復(fù)也會(huì)受到嚴(yán)重影響，因此認(rèn)為這種有機(jī)磷阻燃劑阻礙了斑馬魚肝臟細(xì)胞的DNA損傷修復(fù)系統(tǒng)[39]。

斑馬魚的胚胎和仔魚因?yàn)闆](méi)有完善的器官和系統(tǒng)，其抵抗力不如成魚，大量研究也表明低濃度的有機(jī)磷阻燃劑就會(huì)對(duì)胚胎或仔魚造成一定程度的損傷。對(duì)于1～5 dpf 的斑馬魚仔魚，在磷酸三(2,3-二溴)丙酯(TDBPP, tris(2,3-dibromopropyl) phosphate)>1 μmol·L-1時(shí)有顯著毒性，TDCIPP>10 μmol·L-1時(shí)有顯著毒性效應(yīng)，TCEP和TCPP在100 μmol·L-1濃度時(shí)也沒(méi)有明顯的毒性，均沒(méi)有顯著改變仔魚的游泳能力[40]。斑馬魚仔魚暴露于200 μg·L-1的磷酸三(2-丁氧基)乙酯(TBOEP, tris(2-butoxyethyl) phosphate)會(huì)引起激素的合成、阿黑皮素原和促卵泡激素相關(guān)基因的下調(diào)，從而導(dǎo)致一些受體基因(thr,tshr,gr,mr,er,ar)的上調(diào)，這些分子水平上的改變會(huì)導(dǎo)致斑馬魚的水腫、畸形以及最后的死亡[41]。Ma等[42]研究發(fā)現(xiàn)暴露于0.5 μmol·L-1的TBOEP可以顯著上調(diào)雌激素受體基因(ERs,er1,er2a,er2b)表達(dá)以及相關(guān)基因(vtg4,vtg5,pgr,ncor,ncoa3)的表達(dá)，表明TBOEP可以影響雌激素受體的通路。

不同的有機(jī)磷阻燃劑對(duì)斑馬魚胚胎的毒性不同，毒性由高到低可排序?yàn)榱姿崛锦?TPHP, triphenyl phosphate)，四溴雙酚A(TBBPA, tetrabromobisphenol A)，異苯丙基磷酸酯(IPP, isopropylated phenyl phosphate)，TDCIPP，叔丁基苯基磷酸酯(BPDP, tert-butylphenyl diphenyl phosphate)，(2-乙基己基)聯(lián)苯磷酸酯(EHDP, 2-ethylhexyl diphenyl phosphate)，甲基苯基磷酸酯(TMPP, trimethyl phenyl phosphate)，TCEP[43]。有機(jī)磷阻燃劑可以在斑馬魚胚胎形成期，通過(guò)干擾調(diào)節(jié)基因的轉(zhuǎn)錄和表達(dá)引起心臟毒性，Du等[44]發(fā)現(xiàn)暴露于0.10 mg·L-1TPHP 或者三磷酸甲苯酯(CDP, cresyl diphenyl phosphate)會(huì)阻礙心臟循環(huán)過(guò)程。在0.50，1.0 mg·L-1TPHP 暴露組以及 0.10, 0.50, 1.0 mg·L-1CDP暴露組均出現(xiàn)了心動(dòng)過(guò)緩及心肌減少的現(xiàn)象。0～48 hpf是斑馬魚胚胎最為脆弱的時(shí)期，TPHP 和 CDP會(huì)對(duì)其成長(zhǎng)造成較大影響。同時(shí)有研究表明有機(jī)磷阻燃劑可以通過(guò)調(diào)節(jié)基因造成激素的合成紊亂[45]。有機(jī)磷阻燃劑對(duì)胚胎的發(fā)育毒性也受到很多科研工作者的重視。Fu等[46]采用微列陣及同位素標(biāo)記相對(duì)和絕對(duì)定量(iTRAQ, isobaric tags for relative and absolute quantification)標(biāo)記定量蛋白質(zhì)組測(cè)定分析，結(jié)果顯示3 μmol·L-1的TDCIPP從0.75 hpf到4 hpf會(huì)抑制細(xì)胞的重新排列，使得延期至5.7和8.5 hpf，并且在14～45 hpf導(dǎo)致了反常發(fā)育(例如短尾、身長(zhǎng)縮短)和致死，可能與胚胎形成相關(guān)基因表達(dá)的改變有關(guān)。此外，暴露于1或3 μmol·L-1的 TDCIPP后，在96 hpf時(shí)觀測(cè)到軀干彎曲的表型。Noyes等[47]也發(fā)現(xiàn)斑馬魚胚胎的神經(jīng)發(fā)育對(duì)有機(jī)磷阻燃劑具有高度敏感性。雖然有機(jī)磷阻燃劑會(huì)對(duì)斑馬魚胚胎和仔魚造成一定的損傷，但是這種生物體內(nèi)的視黃酸受體可能會(huì)參與調(diào)節(jié)TPP引起的胚胎發(fā)育毒性，起到一定的抵抗作用[48]。

針對(duì)斑馬魚的毒性實(shí)驗(yàn)，不論是成魚、胚胎還是仔魚，大都是短期暴露，而長(zhǎng)期暴露的研究較少。Wang等[49]將斑馬魚胚胎(2 hpf)暴露于TDCIPP (0～100 μg·L-1) 6個(gè)月，急性暴露結(jié)果顯示在受精后5 d的斑馬魚仔魚組織中檢測(cè)到TDCIPP和它的代謝產(chǎn)物BDCPP，長(zhǎng)期暴露實(shí)驗(yàn)結(jié)果表明任何暴露組對(duì)斑馬魚的運(yùn)動(dòng)、乙酰膽堿酯酶的活性、神經(jīng)遞質(zhì)多巴胺和5-羥色胺的水平、信使RNA和蛋白質(zhì)的表達(dá)與中樞神經(jīng)系統(tǒng)的發(fā)展均沒(méi)有產(chǎn)生影響。然而，在成年魚中，雌魚大腦中檢測(cè)出多巴胺及血清素水平的降低。在雄魚和雌魚大腦中均發(fā)現(xiàn)神經(jīng)系統(tǒng)發(fā)育基因的下調(diào)。在成魚組織中檢測(cè)出TDCIPP，并且在大腦組織中含量最高。雌魚對(duì)TDCIPP的刺激比雄魚更敏感，而且長(zhǎng)期暴露會(huì)導(dǎo)致神經(jīng)毒性。

有機(jī)磷阻燃劑對(duì)其他魚類也有一定程度的損傷。Yuan等[50]將中國(guó)稀有鮈鯽暴露于TCEP (1.25, 2.5, 5 mg·L-1), TDCIPP (0.75, 1.5, 3 mg·L-1), TPP(0.5, 1, 2 mg·L-1)中共21 d。結(jié)果顯示高濃度的TPP對(duì)乙酰膽堿酯酶和丁酰膽堿酯酶的活性均有顯著抑制作用，但另外2種有機(jī)磷阻燃劑并無(wú)發(fā)現(xiàn)此現(xiàn)象。此外，實(shí)驗(yàn)證明TDCIPP對(duì)于膽堿酯酶的活性以及神經(jīng)遞質(zhì)的水平無(wú)顯著影響。但是，這種有機(jī)磷阻燃劑對(duì)于神經(jīng)營(yíng)養(yǎng)因子及其受體(例如ntf3,ntrk1,ntrk2,ngfr,fgf2,fgf11,fgf22,fgfr4)表現(xiàn)出普遍的毒性效應(yīng)，表明TDCIPP和其他的有機(jī)磷阻燃劑可能會(huì)通過(guò)影響神經(jīng)營(yíng)養(yǎng)因子及其受體而引起神經(jīng)毒性[50]。Arukwe等[51-52]研究了TBOEP和TCEP對(duì)幼年鮭魚的影響，發(fā)現(xiàn)這2種有機(jī)磷阻燃劑在高濃度下(1 mg·L-1)暴露7 d會(huì)導(dǎo)致脂質(zhì)過(guò)氧化的升高，而且對(duì)神經(jīng)的及原始的類固醇生成均有一定影響。

2.1.2 對(duì)禽類的毒性效應(yīng)

Bradley等[8]研究了2種有機(jī)磷阻燃劑(TMPP和TDCIPP)對(duì)來(lái)亨雞的毒性效應(yīng)，對(duì)其注射不同濃度的TMPP (0, 10, 100, 1 000 ng·g-1)和TDCIPP (0, 10, 100, 1 000, 50 000 ng·g-1)，實(shí)驗(yàn)周期為從出生截至第21天，結(jié)果表明TMPP對(duì)孵化沒(méi)有影響，而100 和50 000 ng·g-1TDCIPP處理組的雞有較高的早期致死率；通過(guò)翻正反射、平衡、步態(tài)模式、翼皮瓣反射以及開(kāi)放區(qū)域的移動(dòng)對(duì)第7～9 天的雞進(jìn)行行為評(píng)估，結(jié)果發(fā)現(xiàn)暴露于100 ng·g-1TDCIPP的雞比正常雞的最大速度低40%，然而暴露于1 000 ng·g-1TDCIPP比正常雞最快速度高20%。暴露于50 000 ng·g-1TDCIPP處理組的雞翻正反射成功率明顯降低，對(duì)其他幾項(xiàng)測(cè)試無(wú)影響。解剖10 d的雞大腦半球來(lái)測(cè)試神經(jīng)化學(xué)(乙酰膽堿酯酶活性、煙堿)，解剖小腦測(cè)試組織病理學(xué)，發(fā)現(xiàn)并無(wú)明顯損傷。

Farhat等[53]對(duì)不同有機(jī)磷阻燃劑對(duì)雞胚的毒性效應(yīng)做了一系列研究，發(fā)現(xiàn)TCPP和TDCIPP(最大劑量分別為51 600和45 000 ng·g-1)這2種有機(jī)磷阻燃劑都不會(huì)降低破殼成功率，然而TCPP在劑量為9 240和51 600 ng·g-1時(shí)顯著延遲了破殼時(shí)間，并且在51 600 ng·g-1時(shí)降低了臉板長(zhǎng)度。TDCIPP(45 000 ng·g-1)的暴露顯著降低頭和喙的長(zhǎng)度、胚胎質(zhì)量、膽囊尺寸，并且在7 640 ng·g-1下降低了游離 T4的水平。TCPP顯著引起Ⅰ型脫碘酶、肝脂肪酸結(jié)合蛋白和細(xì)胞色素P450(CYP)3A37 mRNA水平的改變，然而TDCIPP引起了 CYP3A37 和 CYP2H1的改變。在出生后0, 5, 11, 18, 19 d時(shí)檢測(cè)出的體內(nèi)有機(jī)磷阻燃劑濃度，均大于注射劑量的92%，且第5 天時(shí)檢測(cè)值最高。他們[54]還發(fā)現(xiàn)TDCIPP可以擾亂雞胚免疫反應(yīng)相關(guān)基因的表達(dá)和類固醇代謝，TDCIPP在低劑量(7.6 μg·g-1)時(shí)可以引起5個(gè)基因的顯著改變，在高劑量(45 μg·g-1)時(shí)可以引起47個(gè)基因的顯著改變，但肝臟膽汁酸和膽固醇水平?jīng)]有發(fā)生變化，這些結(jié)果表明TDCIPP針對(duì)脂質(zhì)代謝過(guò)程具有靶向性毒性效應(yīng)。TDCIPP在雞胚內(nèi)還可以引起其轉(zhuǎn)錄和表型的改變，然而它的主要代謝物BDCPP生物活性且毒性較低[55]。Crump等[56]發(fā)現(xiàn)高濃度(261 400 ng·g-1)的TMPP可導(dǎo)致胚胎畸形，增加肝體指數(shù)和血漿膽汁酸濃度，并且改變了異性生物質(zhì)、脂類代謝和甲狀腺激素通路的基因表達(dá)水平。Caroline等[57]也發(fā)現(xiàn)TBOEP和磷酸三乙酯(TEP, triethyl phosphate)均可影響雞胚的正常發(fā)育，包括肝臟mRNA的表達(dá)和甲狀腺激素的水平，以及循環(huán)膽汁酸濃度的改變。

2.1.3 對(duì)鼠類的毒性效應(yīng)

Chen等[9]將5周大的雄性小鼠經(jīng)口攝入100, 300 mg·kg-1的TPP和TCEP共35 d，結(jié)果發(fā)現(xiàn)濃度為300 mg·kg-1時(shí)，2種有機(jī)磷阻燃劑均可導(dǎo)致體重和睪丸重量的下降；TPP處理組中肝臟內(nèi)的丙二醛含量顯著上升，而谷胱甘肽在300 mg·kg-1的TPP和TCEP處理組中均顯著下降。另外，抗氧化酶(谷胱甘肽過(guò)氧化物酶、過(guò)氧化氫酶和谷胱甘肽巰基轉(zhuǎn)移酶)活性的相關(guān)基因均受到一定影響。同時(shí)，300 mg·kg-1的TPP和TCEP處理組導(dǎo)致了組織病理學(xué)損傷并且降低了睪丸睪酮水平。此外，睪丸素合成的主要相關(guān)基因(steroidogenicacute regulatory protein (StAR), low-density lipoprotein receptor (LDL-R), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) and cytochrome P450 17α-hydroxysteroid dehydrogenase (P450-17α))的表達(dá)量在300 mg·kg-1的TPP和TCEP處理組中有所降低。綜上所述，雄性小鼠暴露于2種有機(jī)磷阻燃劑會(huì)導(dǎo)致氧化應(yīng)激以及內(nèi)分泌紊亂。

Zhao等[58]也發(fā)現(xiàn)TDCIPP可以影響雌性大鼠的甲狀腺功能，暴露于250 mg·kg-1共21 d會(huì)明顯升高血清三碘甲狀腺氨酸，一些相關(guān)基因的表達(dá)和蛋白的水平也有明顯的劑量依賴效應(yīng)。Moser等[59]將懷孕的Long-Evans大鼠經(jīng)口攝入TDCIPP (15, 50, 150 mg·kg-1)或者TCEP (12, 40, 90 mg·kg-1)，實(shí)驗(yàn)周期為受孕后10 d至幼鼠斷奶，結(jié)果表明母親體重或血清甲狀腺激素都無(wú)明顯變化，但在高濃度TDCIPP和TCEP暴露下肝臟相對(duì)重量會(huì)有所升高。在子代鼠中，2種有機(jī)磷酸酯對(duì)其活性、同胎生子數(shù)、出生體重都無(wú)影響。對(duì)于TDCIPP暴露組的大鼠，絕對(duì)肝臟重量在斷奶期較低，且高劑量暴露組的子代鼠體重增加較慢，直到2個(gè)月大后才恢復(fù)正常。子代鼠的甲狀腺激素和大腦重量都無(wú)變化，大腦和血漿中的乙酰膽堿酯酶也沒(méi)有受到有機(jī)磷酸酯的抑制作用。2種有機(jī)磷阻燃劑對(duì)子代鼠行為表現(xiàn)出的影響都是微小的?？傊?，研究表明這2種有機(jī)磷阻燃劑不會(huì)引起明顯的毒性。

2.1.4 對(duì)其他動(dòng)物的毒性效應(yīng)

有研究人員發(fā)現(xiàn)有機(jī)磷阻燃劑對(duì)大型溞或者四膜蟲都有一定程度的毒性效應(yīng)。Li等[60]發(fā)現(xiàn)出生時(shí)長(zhǎng)小于12 h的大型溞，在暴露于濃度為0, (65 ± 7.1), (550 ± 33), (6 500 ± 1 400) ng·L-1的TDCIPP后，會(huì)導(dǎo)致57個(gè)基因的明顯改變，而且蛋白合成、代謝、內(nèi)吞的相關(guān)通路也會(huì)受到較大影響。但是腐殖酸可以通過(guò)吸附有機(jī)磷阻燃劑而降低其對(duì)大型溞的毒性[61]。不同的OPFRs對(duì)大型溞產(chǎn)生毒性效應(yīng)的有效濃度是不同的，Cristale等[62]發(fā)現(xiàn)他們所測(cè)試的9種有機(jī)磷阻燃劑(TCEP，TCPP， TBEP，TBP，磷酸三(2-氯-1-氯甲基)甲酯(TDCP, tris[2-chloro-1-(chloromethyl)ethyl] phosphate)，TPHP，磷酸三(2-乙基)己酯(TEHP, tris(2-ethylhexyl) phosphate)，TCP，EHDP)對(duì)大型溞的半數(shù)效應(yīng)濃度相差超過(guò)3個(gè)數(shù)量級(jí)(0.31～381 mg·L-1)。

有機(jī)磷阻燃劑還可以對(duì)纖毛原生動(dòng)物四膜蟲造成一定的損傷。Li等[63]將四膜蟲暴露于0.01，0.1，1 μmol·L-1的TDCIPP 共5 d，發(fā)現(xiàn)相對(duì)生物量顯著降低(細(xì)胞數(shù)目減少)，且細(xì)胞尺寸和纖毛質(zhì)量都呈現(xiàn)劑量依賴效應(yīng)。另外，RNA序列分析表明21個(gè)核糖體蛋白質(zhì)基因下調(diào)，這些基因被濃縮在“核糖體”KEGG通路中，結(jié)果表明暴露于TDCIPP會(huì)通過(guò)干擾核糖體影響四膜蟲的生長(zhǎng)和繁殖。有研究表明，有機(jī)磷阻燃劑對(duì)四膜蟲的長(zhǎng)期暴露也會(huì)有多代效應(yīng)[64]，Li等[64]將四膜蟲暴露于TDCIPP (0，300，3 000 ng·L-1) 共60 d(～372代)，隨后進(jìn)行了60 d的恢復(fù)實(shí)驗(yàn)(期間不再進(jìn)行暴露)。結(jié)果表明300和3 000 ng·L-1實(shí)驗(yàn)組暴露60 d后顯著降低了個(gè)體數(shù)目、個(gè)體尺寸、纖毛數(shù)量、基體纖毛體的深度和半徑，并使得與纖毛裝配和維護(hù)的相關(guān)基因表達(dá)上調(diào)。后期恢復(fù)實(shí)驗(yàn)表明，四膜蟲的整體或局部均有恢復(fù)現(xiàn)象，包括個(gè)體尺寸和基因表達(dá)，但是有機(jī)磷阻燃劑對(duì)四膜蟲的纖毛數(shù)量、基體纖毛體的深度和半徑的影響是不可逆的。

2.2 對(duì)動(dòng)物細(xì)胞的毒性效應(yīng)

為了模擬有機(jī)磷阻燃劑對(duì)人類健康的影響，科研人員進(jìn)行了大量的體外實(shí)驗(yàn)，運(yùn)用各種細(xì)胞(包括人體細(xì)胞、鼠類細(xì)胞等)來(lái)測(cè)試不同水平有機(jī)磷阻燃劑的毒性效應(yīng)。

Zhang等[65]將HepG2/C3A細(xì)胞和A549細(xì)胞于1，10，100 μmol·L-1的TDCIPP中暴露24 h和72 h，而后對(duì)比轉(zhuǎn)錄組和代謝組的改變。結(jié)果表明于10 μmol·L-1暴露24 h后，轉(zhuǎn)錄組發(fā)現(xiàn)應(yīng)激反應(yīng)(異型生物質(zhì)新陳代謝和ABC轉(zhuǎn)運(yùn)通路)。能量代謝相關(guān)的轉(zhuǎn)錄通路(氧化磷酸化)在100 μmol·L-1的TDCIPP暴露下下調(diào)較多，同時(shí)伴隨著細(xì)胞增殖的相關(guān)通路(細(xì)胞周期和DNA復(fù)制)受到抑制，然而毒性效應(yīng)的顯著性并不高。Liu等[37]將H295R細(xì)胞暴露于TDCIPP、TPP、TCP (0.001, 0.01, 0.1, 1, 10, 100 mg·L-1)中48 h后，發(fā)現(xiàn)在高濃度暴露下，細(xì)胞內(nèi)雌二醇和睪酮的濃度會(huì)升高；同時(shí)將MVLN細(xì)胞暴露于TDCIPP、TPP、TCP(0.001, 0.01, 0.1, 1, 10 mg·L-1) 中72 h后，發(fā)現(xiàn)沒(méi)有OPFRs作為雌激素受體興奮劑，然而TDCIPP、TPP、TCP可以作為拮抗劑來(lái)抑制E2與雌激素受體的結(jié)合。An等[66]發(fā)現(xiàn)細(xì)胞于高濃度(200 μmol·L-1)的TPP、TBP、TBEP、TCPP暴露24 h均可以抑制細(xì)胞活性，產(chǎn)生過(guò)量ROS，導(dǎo)致DNA損傷，提高乳酸脫氫酶釋放。

Jin等[67]將小鼠Tm3睪丸間質(zhì)細(xì)胞于TBEP(30，100 μg·mL-1)中暴露6, 12, 24 h，發(fā)現(xiàn)在100 μg·mL-1濃度下暴露24 h后，谷胱甘肽的含量顯著降低，氧化型谷胱甘肽的含量顯著升高，抗氧化酶(例如超氧化物歧化酶、過(guò)氧化氫酶、谷胱甘肽過(guò)氧化物酶、谷胱甘肽巰基轉(zhuǎn)移酶)的活性也顯著升高，由此證明TBEP會(huì)引起Tm3睪丸間質(zhì)細(xì)胞的氧化應(yīng)激反應(yīng)。另外，于100 μg·mL-1暴露24 h后，與睪丸素合成的相關(guān)基因，包括細(xì)胞色素P450膽固醇側(cè)鏈裂解酶(P450scc)、細(xì)胞色素P450 17α-羥化類固醇脫氫酶(P450-17α)、17β-羥化類固醇脫氫酶(17β-HSD)以及睪丸素的水平均顯著下降。Ren等[68]發(fā)現(xiàn)依賴于甲狀腺激素的大鼠垂體腫瘤細(xì)胞的生長(zhǎng)，在暴露于100 μmol·L-1的TDCIPP下會(huì)受到抑制，然而暴露于磷酸三甲酯(TMP, trimethyl phosphate)、TEP、TCEP則不會(huì)抑制生長(zhǎng)。Schang等[69]發(fā)現(xiàn)除了TPP外，有機(jī)磷阻燃劑均可作為內(nèi)分泌干擾物質(zhì)影響鼠睪丸間質(zhì)腫瘤細(xì)胞的激素水平。

除了腫瘤細(xì)胞，人們還研究了有機(jī)磷阻燃劑對(duì)神經(jīng)細(xì)胞的毒性效應(yīng)。Crump等[70]發(fā)現(xiàn)高濃度(300 μmol·L-1)的TCPP對(duì)雞胚神經(jīng)細(xì)胞的存活率沒(méi)有明顯的影響，TDCIPP對(duì)這種細(xì)胞的LC50為(28.7 ± 19.1) μmol·L-1，這2種有機(jī)磷阻燃劑對(duì)神經(jīng)細(xì)胞的基因表達(dá)均無(wú)明顯影響。Na等[71]研究了TDCIPP和TCEP對(duì)神經(jīng)細(xì)胞PC12的形態(tài)、存活率、凋亡的影響，以及CAMKII、GAP43、tubulin 和 NF-H基因及蛋白的表達(dá)情況。結(jié)果表明2種有機(jī)磷阻燃劑在高濃度(200 μmol·L-1)下可以抑制細(xì)胞生長(zhǎng)，促進(jìn)凋亡，改變基本形態(tài)，顯著影響基因和蛋白的表達(dá)。Wang等[72]發(fā)現(xiàn)在非毒性濃度條件下，含有芳香基和氯代烷基的有機(jī)磷阻燃劑都對(duì)PC12細(xì)胞賴氨酸脫羧酶的活性表現(xiàn)出一定的抑制效應(yīng)，并導(dǎo)致了尸胺含量的顯著下降。Laura等[73]也發(fā)現(xiàn)TDCIPP對(duì)PC12細(xì)胞的毒性效應(yīng)呈現(xiàn)濃度依賴性，可抑制DNA合成，減少細(xì)胞數(shù)目以及改變神經(jīng)分化。Li等[74 -75]對(duì)TDCIPP于SH-SY5Y神經(jīng)母細(xì)胞瘤細(xì)胞的影響做了較深入的研究，通過(guò)一系列基本細(xì)胞實(shí)驗(yàn)及基因蛋白測(cè)試(包括Bax和Bc 1-2基因以及細(xì)胞凋亡蛋白酶等)，發(fā)現(xiàn)TDCIPP可以引起SH-SY5Y細(xì)胞的神經(jīng)毒性以及細(xì)胞自噬，并且證明了其機(jī)理，即TDCIPP通過(guò)影響細(xì)胞的ROS(包括內(nèi)質(zhì)網(wǎng)壓力以及線粒體凋亡通路，AlVIPK/mTOR/ULK1 pathways(細(xì)胞自噬通路))引起細(xì)胞的神經(jīng)毒性。此外，人們也通過(guò)分子對(duì)接和分子動(dòng)力學(xué)模擬，研究了OPFRs對(duì)中國(guó)倉(cāng)鼠卵巢細(xì)胞(CHO-K1)和人乳腺腺癌細(xì)胞(MCF-7)的毒性效應(yīng)。Zhang等[76]通過(guò)3種體外模型(熒光素酶報(bào)告基因檢測(cè)、酵母雙雜交檢測(cè)和E-screen檢測(cè))，檢測(cè)9種OPFRs的激動(dòng)/拮抗活性，并運(yùn)用分子對(duì)接進(jìn)一步解釋雌激素受體α(ER α)和OPFRs之間的關(guān)系。熒光素酶報(bào)告基因分析顯示，3種有機(jī)磷阻燃劑可以誘導(dǎo)雌激素效應(yīng)，由高到低分別為TPP > TCP > TDCIPP，而TCEP和TEHP有顯著的抗雌激素性能。除了TBP在E-screen檢測(cè)中表現(xiàn)出促進(jìn)雌激素的活性外，熒光素酶報(bào)告基因檢測(cè)與其他模型的檢測(cè)結(jié)果呈現(xiàn)高度一致。

3 研究展望(Prospect on future researches)

綜上所述，全球范圍內(nèi)的環(huán)境中均可檢測(cè)到有機(jī)磷阻燃劑，從人類工業(yè)區(qū)到人跡罕至的南極半島，且在各種生物體內(nèi)均可檢測(cè)到，不過(guò)暴露水平很低，影響很小。所有研究表明：高濃度的有機(jī)磷阻燃劑可以對(duì)動(dòng)物造成一定的損傷效應(yīng)，而低濃度暴露則無(wú)顯著影響，OPFRs主要通過(guò)對(duì)基因的調(diào)節(jié)改變激素水平，從而使動(dòng)物出現(xiàn)不良效應(yīng)。隨著這種有機(jī)物越來(lái)越多地應(yīng)用于人類生活的各個(gè)方面，由此越來(lái)越多的OPFRs也進(jìn)入到生態(tài)環(huán)境中，威脅動(dòng)物的健康以及生態(tài)平衡。對(duì)于新興的阻燃劑，今后針對(duì)其環(huán)境暴露及毒性的探索需對(duì)以下幾個(gè)方面進(jìn)行重點(diǎn)研究：

(1)加強(qiáng)人類生活環(huán)境中有機(jī)磷阻燃劑的監(jiān)測(cè)。例如，生活生產(chǎn)區(qū)域內(nèi)大氣、土壤、水體，以及工廠排放三廢中有機(jī)磷阻燃劑的含量。

(2)加強(qiáng)對(duì)暴露量大的動(dòng)物及人類體內(nèi)有機(jī)磷阻燃劑的監(jiān)測(cè)。例如，汗液、尿液等排泄物，以及人體血液中有機(jī)磷阻燃劑的含量檢測(cè)，探索疾病與OPFRs的相關(guān)性。

(3)開(kāi)展更多的有機(jī)磷阻燃劑毒性實(shí)驗(yàn)研究。一方面測(cè)試其他生物暴露于有機(jī)磷阻燃劑中的毒性效應(yīng)，例如，其他哺乳動(dòng)物貓、狗和靈長(zhǎng)類動(dòng)物等，以及對(duì)同種動(dòng)物不同性別及年齡的毒性效應(yīng)；另一方面深入研究有機(jī)磷阻燃劑的在不同生物層面的致毒機(jī)理，以分子水平為主，重點(diǎn)研究OPFRs對(duì)基因蛋白的表達(dá)影響以及其他生物激素分泌的影響，進(jìn)而構(gòu)建分子層面與細(xì)胞水平、器官水平以及個(gè)體水平之間的影響機(jī)理。

(4)加強(qiáng)有機(jī)磷阻燃劑對(duì)動(dòng)物的間接毒性研究。動(dòng)物攝入OPFRs后，會(huì)對(duì)所接觸到的細(xì)胞及組織造成一定的損傷，受損部位分泌的蛋白或激素是否對(duì)其他器官或組織有毒性效應(yīng)也需要深入研究；另一方面，要加強(qiáng)不同動(dòng)物個(gè)體間的間接影響研究。例如，產(chǎn)子后親代暴露對(duì)子代的影響，同一群落中暴露的動(dòng)物是否影響未暴露的動(dòng)物以及影響如何。

(5)研究動(dòng)物對(duì)攝入體內(nèi)的有機(jī)磷阻燃劑的清除及機(jī)制，探索動(dòng)物的主要代謝器官對(duì)OPFRs的代謝途徑及代謝效率，探尋代謝器官對(duì)OPFRs的最大無(wú)損傷劑量(即OPFRs攝入與代謝的平衡)。

(6)加強(qiáng)研究不同有機(jī)磷阻燃劑的動(dòng)物體內(nèi)復(fù)合毒性研究，探索不同的有機(jī)磷阻燃劑化合物在生物體內(nèi)的復(fù)合毒性，有無(wú)相互促進(jìn)或抑制毒性的作用。

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