基于Wnt信号通路探讨氟砷混合暴露的生物暴露限值
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摘要
慢性氟砷联合中毒是全世界的一个重大公共卫生问题,影响着数千万人.目前该病病因清楚,但发病机制未明,且无特效治疗方法,因此,早期预防尤为重要.生物暴露限值旨在探讨外源化学物引起机体有害效应的最高容许浓度.为了探讨氟砷混合暴露的生物暴露限值(BEL),本研究通过比较对照及氟砷联合暴露地区环境介质中的氟、砷含量,分析氟、砷与Wnt信号通路关键蛋白的剂量-效应及剂量-反应关系,利用基准剂量法估算氟砷混合暴露的生物暴露限值.结果表明:氟砷联合暴露地区煤、黏土、室内空气、室外空气、辣椒、大米中的氟含量以及煤、黏土、室外空气、辣椒、大米中的砷含量均高于对照;随着氟、砷暴露水平的增加,糖原合酶激酶3β(GSK3β)、β-连环蛋白(β-catenin)含量以及Wnt/β连环蛋白信号通路拮抗蛋白(DKK1)、GSK3β、β-catenin的异常检出率逐渐增加,但DKK1含量显著降低;基于Wnt信号通路,氟砷混合暴露的生物暴露限值UF为0.52 mg·g-1Cr,UAs为6.59μg·g-1Cr.本研究对于早期预防氟砷联合中毒引起的机体损伤具有重要的指导意义.
Chronic fluoride-arsenic combined poisoning is a global public health problem. While the cause of the disease is clear,the pathogenesis is unknown. Given that there is no specific treatment,early prevention is particularly important. Biological exposure limits are designed to investigate the maximum allowable concentration of harmful effects from exogenous chemicals. To explore the biological exposure limits for mixed exposures of fluoride and arsenic,we compared the contents of fluorine and arsenic in the environmental media of the control and fluoride-arsenic combined exposure areas and analyzed the dose-effect and dose-response relationship between fluoride,arsenic and the key proteins of Wnt signaling pathways. The benchmark dose method was used to estimate the biological exposure limit for fluoride-arsenic combined exposure. The results showed that the content of fluoride in coal,clay,indoor air,outdoor air,chili and rice,as well as arsenic content in coal,clay,outdoor air,chili and rice was higher than that of the control. With the increase of fluoride and arsenic exposure levels,the glycogen synthase kinase 3β( GSK3β),β-catenincontents and the prevalence of Wnt/β-catenin signaling pathway antagonistic protein Dickkopf-1( DKK1),GSK3β,Beta-catenin( β-catenin) gradually increased,but the content of DKK1 significantly decreased.Based on the Wnt signaling pathway,the biological exposure limit for fluoride-arsenic combined exposure was urinary fluoride of 0.52 mg·g-1creatinine and urinary arsenic of 6.59 mg·g-1creatinine. Our results had important guiding significance for early prevention of body damage caused by fluoride-arsenic combined poisoning.
Chronic fluoride-arsenic combined poisoning is a global public health problem. While the cause of the disease is clear,the pathogenesis is unknown. Given that there is no specific treatment,early prevention is particularly important. Biological exposure limits are designed to investigate the maximum allowable concentration of harmful effects from exogenous chemicals. To explore the biological exposure limits for mixed exposures of fluoride and arsenic,we compared the contents of fluorine and arsenic in the environmental media of the control and fluoride-arsenic combined exposure areas and analyzed the dose-effect and dose-response relationship between fluoride,arsenic and the key proteins of Wnt signaling pathways. The benchmark dose method was used to estimate the biological exposure limit for fluoride-arsenic combined exposure. The results showed that the content of fluoride in coal,clay,indoor air,outdoor air,chili and rice,as well as arsenic content in coal,clay,outdoor air,chili and rice was higher than that of the control. With the increase of fluoride and arsenic exposure levels,the glycogen synthase kinase 3β( GSK3β),β-catenincontents and the prevalence of Wnt/β-catenin signaling pathway antagonistic protein Dickkopf-1( DKK1),GSK3β,Beta-catenin( β-catenin) gradually increased,but the content of DKK1 significantly decreased.Based on the Wnt signaling pathway,the biological exposure limit for fluoride-arsenic combined exposure was urinary fluoride of 0.52 mg·g-1creatinine and urinary arsenic of 6.59 mg·g-1creatinine. Our results had important guiding significance for early prevention of body damage caused by fluoride-arsenic combined poisoning.
引文
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[13]Liu XL,Li CC,Liu KJ,et al.The influence of fluoride on the expression of inhibitors of Wnt/beta-catenin signaling pathway in rat skin fibroblast cells.Biological Trace Element Research,2012,148:117-121
[14]Pan L,Shi X,Liu S,et al.Fluoride promotes osteoblastic differentiation through canonical Wnt/betacatenin signaling pathway.Toxicology Letters,2014,225:34-42
[15]Wang X,Mandal AK,Saito H,et al.Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/beta-catenin signaling pathway.Toxicology and Applied Pharmacology,2012,262:11-21
[16]Zhang Z,Wang X,Cheng S,et al.Reactive oxygen species mediate arsenic induced cell transformation and tumorigenesis through Wnt/beta-catenin pathway in human colorectal adenocarcinoma DLD1 cells.Toxicology and Applied Pharmacology,2011,256:114-121
[17]Huang YZ,Qian XC,Wang GQ,et al.Syndrome of endemic arsenism and fluorosis:A clinical study.Chinese Medical Journal,1992,105:586-590
[18]Cadigan KM,Peifer M.Wnt signaling from development to disease:Insights from model systems.Cold Spring Harbor Perspectives in Biology,2009,1:a002881,doi:10.1101/cshperspect.a002881
[19]Jenny A.Planar cell polarity signaling in the Drosophila eye.Current Topics in Developmental Biology,2010,93:189-227
[20]Kohn AD,Moon RT.Wnt and calcium signaling:β-catenin-independent pathways.Cell Calcium,2005,38:439-446
[21]Crump KS.A new method for determining allowable daily intake.Fundamental and Applied Toxicology,1984,4:854-871
[22]Shao B(邵波),Jin T-Y(金泰廙),Qian H-L(钱海雷),et al.Application of benchmark dose(BMD)in estimating biological exposure limit(BEL).Chinese Journal of Industrial Hygiene and Occupational Diseases(中华劳动卫生职业病杂志),2006,24(1):20-22(in Chinese)
[23]Filipsson AF,Sand S,Nilsson J,et al.The benchmark dose method:Review of available models,and recommendations for application in health risk assessment.Critical Reviews in Toxicology,2003,33:505-542
[2]Chouhan S,Flora SJ.Arsenic and fluoride:Two major ground water pollutants.Indian Journal of Experimental Biology,2010,48:666-678
[3]Zhang A-H(张爱华),Sun Z-W(孙志伟).Basis of Toxicology.Beijing:Science Press,2008:126(in Chinese)
[4]Zeng QB,Xu YY,Yu X,et al.The combined effects of fluorine and arsenic on renal function in a Chinese population.Toxicology Research,2014,3:359-366
[5]Zeng Q-B(曾奇兵),Yu X(喻仙),Yang J(杨鋆),et al.Biological exposure limit in bone metabolism damage induced by co-exposure to fluorine and arsenic from coal burning.Chinese Journal of Endemiology(中华地方病学杂志),2012,31(5):523-525(in Chinese)
[6]Zeng Q-B(曾奇兵),Liu Y(刘云),Hong F(洪峰),et al.Determination of damage in bone metabolism caused by co-exposure to fluoride and arsenic using benchmark dose method in Chinese population.Chinese Journal of Public Health(中国公共卫生),2012,28(5):631-632(in Chinese)
[7]Lerner UH,Ohlsson C.The WNT system:Background and its role in bone.Internal Medicine Journal,2015,277:630-649
[8]Padhi D,Jang G,Stouch B,et al.Single-dose,placebocontrolled,randomized study of AMG 785,a sclerostin monoclonal antibody.Journal of Bone and Mineral Research,2011,26:19-26
[9]Wang FS,Ko JY,Lin CL,et al.Knocking down dickkopf-1 alleviates estrogen deficiency induction of bone loss.A histomorphological study in ovariectomized rats.Bone,2007,40:485-492
[10]Bodine PV,Stauffer B,Ponce-De-Leon H,et al.Asmall molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation.Bone,2009,44:1063-1068
[11]Gopalsamy A,Shi M,Stauffer B,et al.Identification of diarylsulfone sulfonamides as secreted frizzled related protein-1(s FRP-1)inhibitors.Journal of Medicinal Chemistry,2008,51:7670-7672
[12]Wang W,Xu J,Liu K,et al.Suppression of sclerostin and dickkopf-1 levels in patients with fluorine bone injury.Environmental Toxicology and Pharmacology,2013,35:402-407
[13]Liu XL,Li CC,Liu KJ,et al.The influence of fluoride on the expression of inhibitors of Wnt/beta-catenin signaling pathway in rat skin fibroblast cells.Biological Trace Element Research,2012,148:117-121
[14]Pan L,Shi X,Liu S,et al.Fluoride promotes osteoblastic differentiation through canonical Wnt/betacatenin signaling pathway.Toxicology Letters,2014,225:34-42
[15]Wang X,Mandal AK,Saito H,et al.Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/beta-catenin signaling pathway.Toxicology and Applied Pharmacology,2012,262:11-21
[16]Zhang Z,Wang X,Cheng S,et al.Reactive oxygen species mediate arsenic induced cell transformation and tumorigenesis through Wnt/beta-catenin pathway in human colorectal adenocarcinoma DLD1 cells.Toxicology and Applied Pharmacology,2011,256:114-121
[17]Huang YZ,Qian XC,Wang GQ,et al.Syndrome of endemic arsenism and fluorosis:A clinical study.Chinese Medical Journal,1992,105:586-590
[18]Cadigan KM,Peifer M.Wnt signaling from development to disease:Insights from model systems.Cold Spring Harbor Perspectives in Biology,2009,1:a002881,doi:10.1101/cshperspect.a002881
[19]Jenny A.Planar cell polarity signaling in the Drosophila eye.Current Topics in Developmental Biology,2010,93:189-227
[20]Kohn AD,Moon RT.Wnt and calcium signaling:β-catenin-independent pathways.Cell Calcium,2005,38:439-446
[21]Crump KS.A new method for determining allowable daily intake.Fundamental and Applied Toxicology,1984,4:854-871
[22]Shao B(邵波),Jin T-Y(金泰廙),Qian H-L(钱海雷),et al.Application of benchmark dose(BMD)in estimating biological exposure limit(BEL).Chinese Journal of Industrial Hygiene and Occupational Diseases(中华劳动卫生职业病杂志),2006,24(1):20-22(in Chinese)
[23]Filipsson AF,Sand S,Nilsson J,et al.The benchmark dose method:Review of available models,and recommendations for application in health risk assessment.Critical Reviews in Toxicology,2003,33:505-542