长期砷暴露的大鼠尿液代谢组学研究
|
摘要
慢性无机砷暴露可引发多种疾病和损害,但其所涉及的生物学过程尚未完全阐明。全球约有超过2亿人面临饮用水砷污染的威胁。本研究以自由饮水的方式对健康大鼠进行无机砷的长期暴露,并对大鼠尿液的代谢组变化进行系统分析。结果表明,长期砷暴露大鼠的尿液代谢组与对照组具有显著区别,且高剂量砷暴露对大鼠尿液代谢组产生的影响更显著。本研究共鉴定出36种差异代谢物,其中14种与氨基酸代谢相关的代谢物发生了显著变化,涉及到色氨酸代谢、精氨酸和脯氨酸代谢、赖氨酸降解、β-丙氨酸代谢、半胱氨酸和蛋氨酸代谢、甘氨酸、丝氨酸和苏氨酸代谢; 11种与脂类代谢相关的代谢物,涉及到的代谢通路有鞘脂代谢、脂肪酸代谢;同时发现蛋白质的表达与翻译后修饰也受到干扰。这些生物学过程的改变均可作为砷毒性机理的关键分子事件。
Long term inorganic arsenic exposure can cause many diseases and health damage, and the biological mechanism underneath remains unclear. Globally, over 200 million people are under the threat of arsenic pollution of drinking water. In this study, we performed metabolomics analysis of rat urine samples which were exposed to inorganic arsenic through drinking water for a long term. The results indicated that long-term arsenic exposure could cause significant urinary metabolome change, especially for the high-dose exposure groups. Totally 36 kinds of differential metabolites were identified, in which 14 were related with amino acid metabolism, including tryptophan, arginine, proline, lysine, β-alanine, cysteine, methionine, glycine, serine and threonine, and 11 were related with lipid metabolism, including sphingolipids and fatty acids. The expression and post-translational modifications of proteins were also influenced. Such biological process mutations are the key molecular indicators of arsenic toxicological mechanisms.
Long term inorganic arsenic exposure can cause many diseases and health damage, and the biological mechanism underneath remains unclear. Globally, over 200 million people are under the threat of arsenic pollution of drinking water. In this study, we performed metabolomics analysis of rat urine samples which were exposed to inorganic arsenic through drinking water for a long term. The results indicated that long-term arsenic exposure could cause significant urinary metabolome change, especially for the high-dose exposure groups. Totally 36 kinds of differential metabolites were identified, in which 14 were related with amino acid metabolism, including tryptophan, arginine, proline, lysine, β-alanine, cysteine, methionine, glycine, serine and threonine, and 11 were related with lipid metabolism, including sphingolipids and fatty acids. The expression and post-translational modifications of proteins were also influenced. Such biological process mutations are the key molecular indicators of arsenic toxicological mechanisms.
引文
1 Rodríguez-Lado L,Sun G,Berg M,Zhang Q,Xue H,Zheng Q,Johnson C A.Science,2013,341(6148):866-868
2 Karn S K.Environ.Pollut.,2015,207:434-435
3 Pham L H,Nguyen H T,Tran C V,Nguyen H M,Nguyen T H,Tu M B.Environ.Geochem.Hlth.,2017,39(3):517-529
4 Naujokas M F,Anderson B,Ahsan H,Aposhian H V,Graziano J H,Thompson C,Suk W A.Environ.Health Perspect.,2013,121(3):295-302
5 Jomova K,Jenisova Z,Feszterova M,Baros S,Liska J,Hudecova D,Rhodes C J,Valko M.J.App.Toxicol.,2011,31(2):95-107
6 Shen H,Xu W,Zhang J,Chen M,Martin F L,Xia Y,Liu L,Dong S,Zhu Y G.Environ.Sci.Technol.,2013,47(15):8843-8851
7 Xu W,Bao H,Liu F,Liu L,Zhu Y G,She J,Dong S,Cai M,Li L,Li C,Shen H.Environ.Health,2012,11(1):46
8 Huang Q,Xi G,Alamdar A,Zhang J,Shen H.Environ.Pollut.,2017,229:210-218
9 Weng R,Shen S,Tian Y,Burton C,Xu X,Liu Y,Chang C,Bai Y,Liu H.Sci.Rep.,2015,5:11864
10 YANG Xiu-Juan,YANG Zhi-Jun,LI Shuo,DENG Yi,YANG Yan-Ze,MAN Qiong,LI Peng-Jie.Chinese Journal of Chromatography,2019,37(1):71-79杨秀娟,杨志军,李硕,邓毅,杨延泽,曼琼,李鹏杰.色谱,2019,37(1):71-79
11 Vlaanderen J J,Janssen N A,Hoe K,G,Keski-Rahkonen P,Barupal D K,Cassee F R,Gosens I,Strak M,Steenhof M,Lan Q,Brunekreef B,Scalbert A,Vermeulen R C H.Environ.Res.,2017,156:341-348
12 Wang Z,Xu X,He B,Guo J,Zhao B,Zhang Y,Zhou Z,Zhou X,Zhang R,Abliz Z.Ecotoxicol.Environ.Safe.,2019,169:232-239
13 Chen C H S,Yuan T H,Shie R H,Wu K Y,Chan C C.Environ.Inter.,2017,102:87-96
14 Karu N,Deng L,Slae M,Guo A C,Sajed T,Huynh H,Win E,Wishart D S.Anal.Chim.Acta,2018,1030:1-24
15 Wishart D S,Mandal R,Stanislaus A,Ramirez-Gaona M.Metabolites,2016,6(1):10-26
16 Aretz I,Meierhofer D.Int.J.Mol.Sci.,2016,17(5):632-64
17 Wishart D S.Bioanalysis,2009,1(9):1579-1596
18 Zhang J,Liu L,Wang X,Huang Q,Tian M,Shen H.Environ.Sci.Technol.,2016,50(11):5953-5960
19 Wang X,Liu L,Zhang W,Zhang J,Du X,Huang Q,Tian M,Shen H.Environ.Pollut.,2017,229:168-176
20 Nagato E G,Jessica C,Lankadurai B P,Poirier D G,Reiner E J,Simpson A J,Simpson M J.Chemosphere,2013,93(2):331-337
21 Lu K,Ryan P A,Schlieper K A,Graffam M E,Levine S,Wishnok J S,Swenberg J A,Tannenbaum S R,Fox J G.Environ.Health Perspect.,2014,122(3):284-291
22 Shi X,Wei X,Koo I,Schmidt R H,Yin X,Kim S H,Vaughn A,McClain C J,Arteel G E,Zhang X,Watson W H.J.Proteome Res.,2013,13(2):547-554
23 Wu H,Zhang X,Wang Q,Li L,Ji C,Liu X,Zhao J,Yin X.Ecotoxicol.Environ.Saf.,2013,90:1-6
24 Sefaur R,Sinha A C,Pati R,Mukhopadhyay D.Environ.Geochem.Hlth.,2013,35(1):119-132
25 Mandal B K,Chowdhury T R,Samanta G,Basu G K,Chowdhury P P,Chanda C,Lodh D,Karan N K,Dhar R K,Tamili D K,Das D,Saha K C,Chakraborti D.Curr.Sci.,1996,70(11):976-986
26 Nordstrom D K.Science,2002,296(5576):2143-2145
27 Herreweghe S V,Swennen R,Vandecasteele C,Cappuyns V.Environ.Pollut.,2003,122(3):323-342
28 Reaganshaw S,Nihal M,Ahmad N.FASEB J.,2008,22(3):659-661
29 Zhang W,Feng H,Gao Y,Sun L,Wang J,Li Y,Wang C,Zhao L,Hu X,Sun H,Wei Y,Sun D.Biol.Trace Elem.Res.,2013,151(2):269-276
30 Veenstra T D.Genome Med.,2012,4:40
31 Dunn W B,Wilson I D,Nicholls A W,Broadhurs D.Bioanalysis,2012,4(18):2249-2264
32 Luan H,Ji F,Chen Y,Cai Z.Anal.Chim.Acta,2018,1036:66-72
33 Max Bylesj9,Rantalainen M,Cloarec O,Nicholson J K,Holmes E,Trygg J.J.Chemometr.,2010,20(8-10):341-351
34 BAI Cai-Jun,LIU Dan,LI Bing.Practical Preventive Medicine,2012,19(2):314-316白彩军,刘丹,李冰.实用预防医学,2012,19(2):314-316
35 Shi H,Shi X,Liu K J.Mol.Cell.Biochem.,2004,255(1-2):67-78
36 Zhong F,Zhang S,Shao C,Yang J,Wu X.Pathol.Oncol.Res.,2010,16(3):413-420
37 ZHANG Ai-Hua,LI Jian,PAN Xue-Li,JIANG Xian-Yao,CEN Du-Cai,HUANG Xiao-Xin.Chinese Journal of Endemiology,2005,24(2):121-123张爱华,李健,潘雪莉,蒋宪瑶,岑笃才,黄晓欣.中华地方病学杂志,2005,24(2):121-123
38 Chanda S.Toxicol.Sci.,2006,89(2):431-437
39 Ali S,Ali S.BMC Med.Genomics,2010,3(1):35
40 Wang L,Kou M C,Weng C Y,Hu L W,Wang Y J,Wu M J.Arch.Toxicol.,2012,86(6):879-896
41 Davey J C,Nomikos A P,Wungjiranirun M,Sherman J R,Ingram L,Batki C,Lariviere J P,Hamilton J W.Environ.Health Perspect.,2008,116(2):165-172
42 Peng Q,Harlow S D,Park S K.Int.J.Hyg.Environ Heal.,2015,218(4):407-413
43 Sung T C,Huang J W,Guo H R.Biomed.Res.Int.,2015:368087
44 Pan W C,Seow W J,Kile M L,Hoffman E B,Quamruzzaman Q,Rahman M,Mahiuddin G,Mostofa G,Lu Q,Christiani D C.Am.J.Epidemiol.,2013,178(10):1563-1570
45 Li X,Li B,Xi S,Zheng Q,Wang D,Sun G.Environ.Health,2013,12(1):37
46 Manoochehr M,Dariush S,Sonia O,Shabnam J.J.Res.Med.Sci.,2013,18(5):408-412
47 Tsuji J S,Perez V,Garry M R,Alexander D D.Toxicology,2014,323:78-94
48 Zhang J,Shen H,Xu W,Xia Y,Barr D B,Mu X,Wang X,Liu L,Huang Q,Tian M.Environ.Sci.Technol.,2014,48(20):12265-12274
49 Lee S H,Woo H M,Jung B H,Lee J,Kwon O S,Pyo H S,Choi M H,Chung B C.Anal.Chem.,2007,79(16):6102-6110
50 SONG Xuan-Bo,ZHAO Li-Jun,WEI Yu-Dan.Chinese Journal of Endemiology,2018,37(2):165-168宋选波,赵丽军,魏玉丹.中华地方病学杂志,2018,37(2):165-168
51 HAN Xiao-Fei,HUANG Yu-Hong,WANG Long-Xing,YANG Qian-Xu,XIAO Hong-Bin,ZHANG De-Qin.Chinese J.Anal.Chem.,2010,38(5):697-701韩晓菲,黄宇虹,王龙星,杨乾栩,肖红斌,张德芹.分析化学,2010,38(5):697-701
52 Hughes M F,Beck B D,Chen Y,Lewis A S,Thomas D J.Toxicol.Sci.,2011,123(2):305-332
53 Leeuwenburgh C,Heinecke J W.Curr.Med.Chem.,2001,8(7):829-838
54 Xiong Y,Xiong Y,Zhou S,Sun Y,Zhao Y,Ren X,Zhang Y,Zhang N.Rejuv.Res.,2017,20(2):85-92
2 Karn S K.Environ.Pollut.,2015,207:434-435
3 Pham L H,Nguyen H T,Tran C V,Nguyen H M,Nguyen T H,Tu M B.Environ.Geochem.Hlth.,2017,39(3):517-529
4 Naujokas M F,Anderson B,Ahsan H,Aposhian H V,Graziano J H,Thompson C,Suk W A.Environ.Health Perspect.,2013,121(3):295-302
5 Jomova K,Jenisova Z,Feszterova M,Baros S,Liska J,Hudecova D,Rhodes C J,Valko M.J.App.Toxicol.,2011,31(2):95-107
6 Shen H,Xu W,Zhang J,Chen M,Martin F L,Xia Y,Liu L,Dong S,Zhu Y G.Environ.Sci.Technol.,2013,47(15):8843-8851
7 Xu W,Bao H,Liu F,Liu L,Zhu Y G,She J,Dong S,Cai M,Li L,Li C,Shen H.Environ.Health,2012,11(1):46
8 Huang Q,Xi G,Alamdar A,Zhang J,Shen H.Environ.Pollut.,2017,229:210-218
9 Weng R,Shen S,Tian Y,Burton C,Xu X,Liu Y,Chang C,Bai Y,Liu H.Sci.Rep.,2015,5:11864
10 YANG Xiu-Juan,YANG Zhi-Jun,LI Shuo,DENG Yi,YANG Yan-Ze,MAN Qiong,LI Peng-Jie.Chinese Journal of Chromatography,2019,37(1):71-79杨秀娟,杨志军,李硕,邓毅,杨延泽,曼琼,李鹏杰.色谱,2019,37(1):71-79
11 Vlaanderen J J,Janssen N A,Hoe K,G,Keski-Rahkonen P,Barupal D K,Cassee F R,Gosens I,Strak M,Steenhof M,Lan Q,Brunekreef B,Scalbert A,Vermeulen R C H.Environ.Res.,2017,156:341-348
12 Wang Z,Xu X,He B,Guo J,Zhao B,Zhang Y,Zhou Z,Zhou X,Zhang R,Abliz Z.Ecotoxicol.Environ.Safe.,2019,169:232-239
13 Chen C H S,Yuan T H,Shie R H,Wu K Y,Chan C C.Environ.Inter.,2017,102:87-96
14 Karu N,Deng L,Slae M,Guo A C,Sajed T,Huynh H,Win E,Wishart D S.Anal.Chim.Acta,2018,1030:1-24
15 Wishart D S,Mandal R,Stanislaus A,Ramirez-Gaona M.Metabolites,2016,6(1):10-26
16 Aretz I,Meierhofer D.Int.J.Mol.Sci.,2016,17(5):632-64
17 Wishart D S.Bioanalysis,2009,1(9):1579-1596
18 Zhang J,Liu L,Wang X,Huang Q,Tian M,Shen H.Environ.Sci.Technol.,2016,50(11):5953-5960
19 Wang X,Liu L,Zhang W,Zhang J,Du X,Huang Q,Tian M,Shen H.Environ.Pollut.,2017,229:168-176
20 Nagato E G,Jessica C,Lankadurai B P,Poirier D G,Reiner E J,Simpson A J,Simpson M J.Chemosphere,2013,93(2):331-337
21 Lu K,Ryan P A,Schlieper K A,Graffam M E,Levine S,Wishnok J S,Swenberg J A,Tannenbaum S R,Fox J G.Environ.Health Perspect.,2014,122(3):284-291
22 Shi X,Wei X,Koo I,Schmidt R H,Yin X,Kim S H,Vaughn A,McClain C J,Arteel G E,Zhang X,Watson W H.J.Proteome Res.,2013,13(2):547-554
23 Wu H,Zhang X,Wang Q,Li L,Ji C,Liu X,Zhao J,Yin X.Ecotoxicol.Environ.Saf.,2013,90:1-6
24 Sefaur R,Sinha A C,Pati R,Mukhopadhyay D.Environ.Geochem.Hlth.,2013,35(1):119-132
25 Mandal B K,Chowdhury T R,Samanta G,Basu G K,Chowdhury P P,Chanda C,Lodh D,Karan N K,Dhar R K,Tamili D K,Das D,Saha K C,Chakraborti D.Curr.Sci.,1996,70(11):976-986
26 Nordstrom D K.Science,2002,296(5576):2143-2145
27 Herreweghe S V,Swennen R,Vandecasteele C,Cappuyns V.Environ.Pollut.,2003,122(3):323-342
28 Reaganshaw S,Nihal M,Ahmad N.FASEB J.,2008,22(3):659-661
29 Zhang W,Feng H,Gao Y,Sun L,Wang J,Li Y,Wang C,Zhao L,Hu X,Sun H,Wei Y,Sun D.Biol.Trace Elem.Res.,2013,151(2):269-276
30 Veenstra T D.Genome Med.,2012,4:40
31 Dunn W B,Wilson I D,Nicholls A W,Broadhurs D.Bioanalysis,2012,4(18):2249-2264
32 Luan H,Ji F,Chen Y,Cai Z.Anal.Chim.Acta,2018,1036:66-72
33 Max Bylesj9,Rantalainen M,Cloarec O,Nicholson J K,Holmes E,Trygg J.J.Chemometr.,2010,20(8-10):341-351
34 BAI Cai-Jun,LIU Dan,LI Bing.Practical Preventive Medicine,2012,19(2):314-316白彩军,刘丹,李冰.实用预防医学,2012,19(2):314-316
35 Shi H,Shi X,Liu K J.Mol.Cell.Biochem.,2004,255(1-2):67-78
36 Zhong F,Zhang S,Shao C,Yang J,Wu X.Pathol.Oncol.Res.,2010,16(3):413-420
37 ZHANG Ai-Hua,LI Jian,PAN Xue-Li,JIANG Xian-Yao,CEN Du-Cai,HUANG Xiao-Xin.Chinese Journal of Endemiology,2005,24(2):121-123张爱华,李健,潘雪莉,蒋宪瑶,岑笃才,黄晓欣.中华地方病学杂志,2005,24(2):121-123
38 Chanda S.Toxicol.Sci.,2006,89(2):431-437
39 Ali S,Ali S.BMC Med.Genomics,2010,3(1):35
40 Wang L,Kou M C,Weng C Y,Hu L W,Wang Y J,Wu M J.Arch.Toxicol.,2012,86(6):879-896
41 Davey J C,Nomikos A P,Wungjiranirun M,Sherman J R,Ingram L,Batki C,Lariviere J P,Hamilton J W.Environ.Health Perspect.,2008,116(2):165-172
42 Peng Q,Harlow S D,Park S K.Int.J.Hyg.Environ Heal.,2015,218(4):407-413
43 Sung T C,Huang J W,Guo H R.Biomed.Res.Int.,2015:368087
44 Pan W C,Seow W J,Kile M L,Hoffman E B,Quamruzzaman Q,Rahman M,Mahiuddin G,Mostofa G,Lu Q,Christiani D C.Am.J.Epidemiol.,2013,178(10):1563-1570
45 Li X,Li B,Xi S,Zheng Q,Wang D,Sun G.Environ.Health,2013,12(1):37
46 Manoochehr M,Dariush S,Sonia O,Shabnam J.J.Res.Med.Sci.,2013,18(5):408-412
47 Tsuji J S,Perez V,Garry M R,Alexander D D.Toxicology,2014,323:78-94
48 Zhang J,Shen H,Xu W,Xia Y,Barr D B,Mu X,Wang X,Liu L,Huang Q,Tian M.Environ.Sci.Technol.,2014,48(20):12265-12274
49 Lee S H,Woo H M,Jung B H,Lee J,Kwon O S,Pyo H S,Choi M H,Chung B C.Anal.Chem.,2007,79(16):6102-6110
50 SONG Xuan-Bo,ZHAO Li-Jun,WEI Yu-Dan.Chinese Journal of Endemiology,2018,37(2):165-168宋选波,赵丽军,魏玉丹.中华地方病学杂志,2018,37(2):165-168
51 HAN Xiao-Fei,HUANG Yu-Hong,WANG Long-Xing,YANG Qian-Xu,XIAO Hong-Bin,ZHANG De-Qin.Chinese J.Anal.Chem.,2010,38(5):697-701韩晓菲,黄宇虹,王龙星,杨乾栩,肖红斌,张德芹.分析化学,2010,38(5):697-701
52 Hughes M F,Beck B D,Chen Y,Lewis A S,Thomas D J.Toxicol.Sci.,2011,123(2):305-332
53 Leeuwenburgh C,Heinecke J W.Curr.Med.Chem.,2001,8(7):829-838
54 Xiong Y,Xiong Y,Zhou S,Sun Y,Zhao Y,Ren X,Zhang Y,Zhang N.Rejuv.Res.,2017,20(2):85-92