环境中有机磷酸酯阻燃剂(TDCP、TECP和TCPP)对人胚肾细胞(HEK 293)的影响（英文）
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摘要
水环境中的微污染物有机磷酸酯如三(2-氯乙基)磷酸酯(TCEP)、三(2-氯-异丙基)磷酸酯(TCPP)和三(1,3-二氯丙基)磷酸酯(TDCP)主要用作聚氨酯泡沫塑料的阻燃剂。物理、化学和生物处理很难完全消除这些污染物。研究阻燃剂在环境水平和较高浓度下对人细胞系的细胞毒性和细胞周期效应。结果表明,在浓度为0. 001 mg/L和0. 01 mg/L时,只有TDCP具有轻微的细胞毒性,而当这三种化学物质浓度100 mg/L以上时对细胞毒性有显著的诱导作用。TCEP和TCPP的EC50分别为276. 8 mg/L和58. 4 mg/L。三种药物均能抑制CDK 4的表达,TDCP能增加CDK 2和cyclin E的表达,而TCEP和TCPP在CDK 2和cyclin E的表达上表现出自差现象。TDCP和TCEP使细胞数量减少,细胞形态发生改变。可见三种化学物质对HEK 293细胞的杀伤作用可能是通过抑制CDK 4调节蛋白而产生的。
The organophosphate such as tris( 2-chloroethyl) phosphate( TCEP),tris( 2-chloro-isopropyl)phosphate( TCPP),and tris( 1-trichloropropyl) phosphate( TDCP) are mostly used as fire retardants in polyurethane foams. They are remained as micropollutants in water environment because complete elimination is difficult by physical,chemical and biological treatment. The aim was to investigate cytotoxic and cell cyclic effect of the flame retardants on human cell line at environmental level and upper concentrations. The results showed that only TDCP had slight cytotoxicity at 0. 001 mg/L and 0. 01 mg/L,but the three chemicals significantly induced cytotoxicity upper 100 mg/L. The EC50 values for TCEP and TCPP were 276. 8 mg/L and 58. 4 mg/L,respectively. The three tested chemicals inhibited the expression of CDK4,but TDCP increased the expression of CDK2 and cyclin E,whereas TCEP and TCPP showed self-discrepancy results at the expression of CDK2 and cyclin E. TDCP and TCEP decrease cell number,and TCPP induce both decrease of cell number and change of morphology. In conclusion,the three chemicals induced cytotoxic effects on HEK293 cells,and the cytotoxicity might be induced through inhibition of CDK4 regulatory protein.
The organophosphate such as tris( 2-chloroethyl) phosphate( TCEP),tris( 2-chloro-isopropyl)phosphate( TCPP),and tris( 1-trichloropropyl) phosphate( TDCP) are mostly used as fire retardants in polyurethane foams. They are remained as micropollutants in water environment because complete elimination is difficult by physical,chemical and biological treatment. The aim was to investigate cytotoxic and cell cyclic effect of the flame retardants on human cell line at environmental level and upper concentrations. The results showed that only TDCP had slight cytotoxicity at 0. 001 mg/L and 0. 01 mg/L,but the three chemicals significantly induced cytotoxicity upper 100 mg/L. The EC50 values for TCEP and TCPP were 276. 8 mg/L and 58. 4 mg/L,respectively. The three tested chemicals inhibited the expression of CDK4,but TDCP increased the expression of CDK2 and cyclin E,whereas TCEP and TCPP showed self-discrepancy results at the expression of CDK2 and cyclin E. TDCP and TCEP decrease cell number,and TCPP induce both decrease of cell number and change of morphology. In conclusion,the three chemicals induced cytotoxic effects on HEK293 cells,and the cytotoxicity might be induced through inhibition of CDK4 regulatory protein.
引文
1 Kim U,Kannan K. Occurrence and distribution of organophosphate flame retardants/plasticizers in surface waters,tap water,and rainwater:Implications for human exposure[J]. Environmental Science&Technology,2018,52(10):5625-5633
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12 Dishaw L,Poers C,Ryde I,et al. Is the Penta BDE replacement,tris(1,3-dichloropropyl)phosphate(TDCPP),a developmental neurotoxicant? Studies in PC12 cells[J]. Toxicology and Applied Pharmacology,2011,256(3):281-289
13 Ren X,Lee Y,Han H,et al. Effect of tris-(2-chloroethyl)-phosphate(TCEP)at environmental concentration on the levels of cell cycle regulatory protein expression in primary cultured rabbit renal proximal tubule cells[J]. Chemosphere,2008,74(1):84-88
14 Lee Y,Han H. Role of ATP in DNA synthesis of renal proximal tubule cells:Involvement of calcium,MAPKs,and CDKs. American Journal of Physiology[J]. Renal Physiology,2006,291(1):98-106
15 Reddy A,Reddy Y,Krishna D,et al. Multi wall carbon nanotubes induce oxidative stress and cytotoxicity in human embryonic kidney(HEK293)cells[J]. Toxicology,2010,272(1-3):11-16
16 Pomati F,Castiglioni S,Zuccato E,et al. Effects of a complex mixture of therapeutic drugs at environmental levels on human embryonic cells[J]. Environmental Science and Technology,2006,40(7):2442-2447
17 Nurse P. Ordering S phase and M phase in the cell cycle[J]. Cell,1994,79(4):547-550
18 Liu X,Ji K,Choi K. Endocrine disruption potentials of organophosphate flame retardants and related mechanisms in H295R and MVLN cell lines and in zebrafish[J]. Aquatic Toxicology,2012,114-115:173-181
19 Ta N,Li C,Fang Y,et al. Toxicity of TDCPP and TCEP on PC12cell:Changes in CAMKII,GAP43,tubulin and NF-H gene and protein levels[J]. Toxicology Letters,2014,227(3):164-171
20 Morgan O. Cyclin-dependent kinases:Engines,clocks,and microprocessors[J]. Annual Review of Cell Developmental Biology,1997,13:261-291
21 Bartek J,Lukas J. Pathways governing G1/S transition and their response to DNA damage[J]. FEBS Letters,2001,490(3):117-122
22 Bouchard C,Staller P,Eilers M. Control of cell proliferation by Myc[J]. Trends in Cell Biology,1998,8(5):202-206
2 Wei G,Li D,Zhuo M,et al. Organophosphorus flame retardants and plasticizers:Sources,occurrence,toxicity and human exposure[J].Environmental Pollution,2015,196:29-46
3 Meyer J,Bester K. Organophosphate flame retardants and plasticisers in wastewater treatment plants[J]. Journal of Environmental Monitoring,2004,6(7):599-605
4 Andresen J,Bester K. Elimination of organophosphate ester flame retardants and plasticizers in drinking water purification[J]. Water Research,2006,40(3):621-629
5 Bernhard M,Muller J. Knepper T. Biodegradation of persistent polar pollutants in wastewater:Comparison of an optimized lab-scale membrane bioreactor and activated sludge treatment[J]. Water Research,2006,40(18):3419-3428
6 Kim S,Cho J,Kim I,et al. Occurrence and removal of pharmaceuticals and endocrine disruptors in South Korean surface,drinking,and waste waters[J]. Water Research,2007,41(5):1013-1021
7 Stackelberg P,Gibs J,Furlong E,et al. Efficiency of conventional drinking-water-treatment processes in removal of pharmaceuticals and other organic compounds[J]. Science of Total Environment,2007,377(2-3):255-272
8 Lee S,Quyet N,Lee E,et al. Efficient removals of tris(2-chloroethyl)phosphate(TCEP)and perchlorate using NF membrane filtrations[J]. Desalination,2008,221(1-3):234-237
9 Guo J,Marta V,Amina S,et al. Bioaccumulation of Dechloranes,organophosphate esters,and other flame retardants in Great Lakes fish[J]. Science of the Total Environment,2017,583:1-9
10 Veen I,Boer J. Phosphorus flame retardants:Properties,production,environmental occurrence,toxicity and analysis[J]. Chemosphere,2012,88(10):1119-1153
11 F9llmann W,Wober J. Investigation of cytotoxic,genotoxic,mutagenic,and estrogenic effects of the flame retardants tris-(2-chloroethyl)-phosphate(TCEP)and tris-(2-chloropropyl)-phosphate(TCPP)in vitro[J]. Toxicology Letters,2006,161(2):124-134
12 Dishaw L,Poers C,Ryde I,et al. Is the Penta BDE replacement,tris(1,3-dichloropropyl)phosphate(TDCPP),a developmental neurotoxicant? Studies in PC12 cells[J]. Toxicology and Applied Pharmacology,2011,256(3):281-289
13 Ren X,Lee Y,Han H,et al. Effect of tris-(2-chloroethyl)-phosphate(TCEP)at environmental concentration on the levels of cell cycle regulatory protein expression in primary cultured rabbit renal proximal tubule cells[J]. Chemosphere,2008,74(1):84-88
14 Lee Y,Han H. Role of ATP in DNA synthesis of renal proximal tubule cells:Involvement of calcium,MAPKs,and CDKs. American Journal of Physiology[J]. Renal Physiology,2006,291(1):98-106
15 Reddy A,Reddy Y,Krishna D,et al. Multi wall carbon nanotubes induce oxidative stress and cytotoxicity in human embryonic kidney(HEK293)cells[J]. Toxicology,2010,272(1-3):11-16
16 Pomati F,Castiglioni S,Zuccato E,et al. Effects of a complex mixture of therapeutic drugs at environmental levels on human embryonic cells[J]. Environmental Science and Technology,2006,40(7):2442-2447
17 Nurse P. Ordering S phase and M phase in the cell cycle[J]. Cell,1994,79(4):547-550
18 Liu X,Ji K,Choi K. Endocrine disruption potentials of organophosphate flame retardants and related mechanisms in H295R and MVLN cell lines and in zebrafish[J]. Aquatic Toxicology,2012,114-115:173-181
19 Ta N,Li C,Fang Y,et al. Toxicity of TDCPP and TCEP on PC12cell:Changes in CAMKII,GAP43,tubulin and NF-H gene and protein levels[J]. Toxicology Letters,2014,227(3):164-171
20 Morgan O. Cyclin-dependent kinases:Engines,clocks,and microprocessors[J]. Annual Review of Cell Developmental Biology,1997,13:261-291
21 Bartek J,Lukas J. Pathways governing G1/S transition and their response to DNA damage[J]. FEBS Letters,2001,490(3):117-122
22 Bouchard C,Staller P,Eilers M. Control of cell proliferation by Myc[J]. Trends in Cell Biology,1998,8(5):202-206