上海市300名中老年2型糖尿病患者邻苯二甲酸酯暴露的肝脏受损风险评估
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摘要
[目的]多种邻苯二甲酸酯(PAEs)被报道具有肝脏毒性。因暴露于PAEs而导致肝脏损伤的健康风险评估曾在一般人群中被报道,但在2型糖尿病(T2DM)患者中鲜见报道,而肝脏受损可加剧T2DM的发生发展。本研究旨在了解上海市社区中老年T2DM患者的PAEs暴露情况,并评估其肝脏受损的健康风险。[方法]采用横断面的研究设计,收集2016年上海市黄浦区某社区医院的300名中老年T2DM患者的一次随机尿样,采用液相色谱串联质谱法对其尿中6种常见PAEs的10种代谢物进行检测,并根据肌酐校正后的代谢物浓度推算其接触PAEs的每日估计暴露量(EDI);采用危害指数(HI)法对患者接触PAEs的累积暴露水平进行肝脏受损的健康风险评估,并采用线性回归分析一般人口学特征与PAEs的危害商(HQ)和HI的相关性。[结果] T2DM患者尿中10种PAEs代谢物的检出率除邻苯二甲酸单甲酯(MMP)、邻苯二甲酸单苄基酯(MBzP)和单(2-羧基己基)邻苯二甲酸酯(MCMHP)外,均为100%。肌酐校正后的浓度较高的为邻苯二甲酸单乙酯(MEP)、邻苯二甲酸单正丁酯(MnBP)和邻苯二甲酸单异丁酯(MiBP),其中位数分别为137.13、265.73、381.53μg/g。MBzP的检出率(88.3%)和浓度(中位数3.70μg/g)均为最低。6种PAEs中,邻苯二甲酸二异丁酯(DiBP)的EDI中位数[12.95μg/(kg·d)]远高于其他5种PAEs。邻苯二甲酸二(2-乙基己基)酯(DEHP)、DiBP和邻苯二甲酸二正丁酯(DnBP)的HQ中位数远高于邻苯二甲酸二乙酯(DEP)和邻苯二甲酸丁基苄酯(BBP),分别为0.169 4、0.129 5和0.081 8。HI≥1的患者有55名(18.33%)。糖尿病家族史与DEP、DiBP和BBP的HQ呈正相关(P<0.05)。[结论]上海市社区中老年T2DM患者因接触PAEs而可能存在一定的肝脏受损风险,主要来源于DEHP。
[Objective] Phthalates(PAEs) have been reported to have hepatotoxicity. Several studies have assessed the health risks of exposure to PAEs in general population, but not in patients diagnosed with type 2 diabetes mellitus(T2DM) which would be aggravated by liver damage. In this study,we aim to evaluate the levels of cumulative exposure to PAEs in elder T2DM patients and assess the health risk of liver damage related to the exposure.[Methods] A cross-sectional study was conducted. A total of 300 spot urine samples were collected from elder T2DM patients from a community health service center of Huangpu District, Shanghai in 2016. Liquid chromatography-tandem mass spectrometry was used to determine 10 metabolites of 6 kinds of PAEs in urine. Estimated daily intake(EDI) was calculated based on the creatinine-adjusted concentrations of the 10 metabolites. Hazard index(HI) as a measure of health risk assessment was used to assess the liver damage induced by cumulative exposure to PAEs. The associations of demographic characteristic with hazard quotient(HQ) and HI of PAEs were analyzed using linear regression.[Results] Except mono-methyl phthalate(MMP), mono-benzyl phthalate(MBzP), and mono-2-carboxymethyl-hexyl phthalate(MCMHP), the detection rates of the other 7 metabolites were 100% positive in urine samples of T2DM patients. Mono-ethyl phthalate(MEP), mono-n-butyl phthalate(MnBP), and monoisobutyl phthalate(MiBP) showed highest levels, with the medians of creatinine-adjusted concentrations being 137.13, 265.73, and 381.53 μg/g, respectively. Comparatively, the positive detection rate(88.3%) and the concentration(median: 3.70 μg/g) of MBzP were the lowest. The EDI of di-isobutyl phthalate(DiBP) was much higher than those of the others, with a median of 12.95 μg/(kg·d). The HQs of di-2-ethylhexyl phthalate(DEHP), DiBP, and di-n-butyl phthalate(DnBP) were much higher than those of di-ethyl phthalate(DEP) and butyl-benzyl phthalate(BBP), with medians of 0.169 4, 0.129 5, and 0.081 8, respectively. The participants(n=55) with HI ≥ 1 accounted for 18.33% of total study participants. Having a family history of diabetes was positively associated with the HQs of DEP, DiBP, and BBP(P< 0.05).[Conclusion] The exposure to PAEs may be a risk factor of liver damage among elder T2DM patients from Shanghai, and DEHP plays a dominant role.
[Objective] Phthalates(PAEs) have been reported to have hepatotoxicity. Several studies have assessed the health risks of exposure to PAEs in general population, but not in patients diagnosed with type 2 diabetes mellitus(T2DM) which would be aggravated by liver damage. In this study,we aim to evaluate the levels of cumulative exposure to PAEs in elder T2DM patients and assess the health risk of liver damage related to the exposure.[Methods] A cross-sectional study was conducted. A total of 300 spot urine samples were collected from elder T2DM patients from a community health service center of Huangpu District, Shanghai in 2016. Liquid chromatography-tandem mass spectrometry was used to determine 10 metabolites of 6 kinds of PAEs in urine. Estimated daily intake(EDI) was calculated based on the creatinine-adjusted concentrations of the 10 metabolites. Hazard index(HI) as a measure of health risk assessment was used to assess the liver damage induced by cumulative exposure to PAEs. The associations of demographic characteristic with hazard quotient(HQ) and HI of PAEs were analyzed using linear regression.[Results] Except mono-methyl phthalate(MMP), mono-benzyl phthalate(MBzP), and mono-2-carboxymethyl-hexyl phthalate(MCMHP), the detection rates of the other 7 metabolites were 100% positive in urine samples of T2DM patients. Mono-ethyl phthalate(MEP), mono-n-butyl phthalate(MnBP), and monoisobutyl phthalate(MiBP) showed highest levels, with the medians of creatinine-adjusted concentrations being 137.13, 265.73, and 381.53 μg/g, respectively. Comparatively, the positive detection rate(88.3%) and the concentration(median: 3.70 μg/g) of MBzP were the lowest. The EDI of di-isobutyl phthalate(DiBP) was much higher than those of the others, with a median of 12.95 μg/(kg·d). The HQs of di-2-ethylhexyl phthalate(DEHP), DiBP, and di-n-butyl phthalate(DnBP) were much higher than those of di-ethyl phthalate(DEP) and butyl-benzyl phthalate(BBP), with medians of 0.169 4, 0.129 5, and 0.081 8, respectively. The participants(n=55) with HI ≥ 1 accounted for 18.33% of total study participants. Having a family history of diabetes was positively associated with the HQs of DEP, DiBP, and BBP(P< 0.05).[Conclusion] The exposure to PAEs may be a risk factor of liver damage among elder T2DM patients from Shanghai, and DEHP plays a dominant role.
引文
[1]KOO H J,LEE B M.Human monitoring of phthalates and risk assessment[J].J Toxicol Environ Health,Part A,2005,68(16):1379-1392.
[2]LEHMANN K P,PHILLIPS S,SAR M,et al.Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di(n-butyl)phthalate[J].Toxicol Sci,2004,81(1):60-68.
[3]MA R C,LIN X,JIA W.Causes of type 2 diabetes in China[J].Lancet Diabetes Endocrinol,2014,2(12):980-991.
[4]VALENTI L,BUGIANESI E,PAJVANI U,et al.Nonalcoholic fatty liver disease:cause or consequence of type 2diabetes?[J].Liver Int,2016,36(11):1563-1579.
[5]陈婧司,高曦,郭佳林,等.上海市237名新生儿胎粪中邻苯二甲酸酯累积暴露的健康风险评估[J].环境与职业医学,2017,34(5):379-384.
[6]STARLING A P,ENGEL L S,CALAFAT A M,et al.Predictors and long-term reproducibility of urinary phthalate metabolites in middle-aged men and women living in urban Shanghai[J].Environ Int,2015,84:94-106.
[7]TRANFO G,PAPALEO B,CAPOROSSI L,et al.Urinary metabolite concentrations of phthalate metabolites in Central Italy healthy volunteers determined by a validated HPLC/MS/MS analytical method[J].Int J Hyg Environ Health,2013,216(4):481-485.
[8]张晗.上海社区居民邻苯二甲酸酯累积暴露风险评估[D].上海:复旦大学,2016.
[9]KOHN M C,PARHAM F,MASTEN S A,et al.Human exposure estimates for phthalates[J].Environ Health Perspect,2000,108(10):A440-A442.
[10]REMER T,NEUBERT A,MASER-GLUTH C.Anthropometrybased reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research[J].Am J Clin Nutr,2002,75(3):561-569.
[11]ANDERSON W A,CASTLE L,HIRD S,et al.A twenty-volunteer study using deuterium labelling to determine the kinetics and fractional excretion of primary and secondary urinary metabolites of di-2-ethylhexylphthalate and di-iso-nonylphthalate[J].Food Chem Toxicol,2011,49(9):2022-2029.
[12]GUO Y,WU Q,KANNAN K.Phthalate metabolites in urine from China,and implications for human exposures[J].Environ Int,2011,37(5):893-898.
[13]DONG R,ZHENG J,ZHANG M,et al.The concentrations and cumulative risk assessment of phthalates in general population from Shanghai:The comparison between groups with different ages[J].Sci Total Environ,2018,637-638:871-880.
[14]陈浩,张晓鹏,贾旭东,等.内分泌干扰物联合作用与累积风险评估研究进展[J].卫生研究,2014,43(1):157-161.
[15]U.S.EPA.Dibutyl phthalate;CASRN 84-74-2[EB/OL].[2019-03-06].https://cfpub.epa.gov/ncea/iris/iris_documents/documents/subst/0038_summary.pdf.
[16]U.S.EPA.Di(2-ethylhexyl)phthalate(DEHP);CASRN 117-81-7[EB/OL].[2019-03-06].https://cfpub.epa.gov/ncea/iris/iris_documents/documents/subst/0014_summary.pdf.
[17]U.S.EPA.Butyl benzyl phthalate(BBP);CASRN 85-68-7[EB/OL].[2019-03-06].https://cfpub.epa.gov/ncea/iris2/chemicalLanding.cfm?substance_nmbr=293.
[18]U.S.EPA.Diethyl phthalate;CASRN 84-66-2[EB/OL].[2019-03-09].https://cfpub.epa.gov/ncea/iris/iris_documents/documents/subst/0226_summary.pdf#nameddest=rfd.
[19]SVENSSON K,HERNáNDEZ-RAMíREZ R U,BURGUETE-GARCíA A,et al.Phthalate exposure associated with selfreported diabetes among Mexican women[J].Environ Res,2011,111(6):792-796.
[20]KIM J H,PARK H Y,BAE S,et al.Diethylhexyl phthalates is associated with insulin resistance via oxidative stress in the elderly:a panel study[J].PLoS One,2013,8(8):e71392.
[21]CHRISTENSEN K L,MAKRIS S L,LORBER M.Generation of hazard indices for cumulative exposure to phthalates for use in cumulative risk assessment[J].Regul Toxicol Pharmacol,2014,69(3):380-389.
[22]HARTMANN C,UHL M,WEISS S,et al.Human biomonitoring of phthalate exposure in Austrian children and adults and cumulative risk assessment[J].Int J Hyg Environ Health,2015,218(5):489-499.
[23]BENSON R.Hazard to the developing male reproductive system from cumulative exposure to phthalate estersdibutyl phthalate,diisobutyl phthalate,butylbenzyl phthalate,diethylhexyl phthalate,dipentyl phthalate,and diisononyl phthalate[J].Regul Toxicol Pharmacol,2009,53(2):90-101.
[24]AYDEMIR D,KARABULUT G,?IM?EK G,et al.Impact of the Di(2-Ethylhexyl)phthalate administration on trace element and mineral levels in relation of kidney and liver damage in rats[J].Biol Trace Elem Res,2018,186(2):474-488.
[25]PRAVEENA S M,TEH S W,RAJENDRAN R K,et al.Recent updates on phthalate exposure and human health:a special focus on liver toxicity and stem cell regeneration[J].Environ Sci Pollut Res,2018,25(12):11333-11342.
[26]ZHANG W,SHEN X Y,ZHANG W W,et al.Di-(2-ethylhexyl)phthalate could disrupt the insulin signaling pathway in liver of SD rats and L02 cells via PPARγ[J].Toxicol Appl Pharmacol,2017,316:17-26.
[27]WANG W,XU X,FAN C Q.Health hazard assessment of occupationally di-(2-ethylhexyl)-phthalate-exposed workers in China[J].Chemosphere,2015,120:37-44.
[28]CHEN J,ZHOU X,ZHANG H,et al.Association between urinary concentration of phthalate metabolites and impaired renal function in Shanghai adults[J].Environ Pollut,2019,245:149-162.
[2]LEHMANN K P,PHILLIPS S,SAR M,et al.Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di(n-butyl)phthalate[J].Toxicol Sci,2004,81(1):60-68.
[3]MA R C,LIN X,JIA W.Causes of type 2 diabetes in China[J].Lancet Diabetes Endocrinol,2014,2(12):980-991.
[4]VALENTI L,BUGIANESI E,PAJVANI U,et al.Nonalcoholic fatty liver disease:cause or consequence of type 2diabetes?[J].Liver Int,2016,36(11):1563-1579.
[5]陈婧司,高曦,郭佳林,等.上海市237名新生儿胎粪中邻苯二甲酸酯累积暴露的健康风险评估[J].环境与职业医学,2017,34(5):379-384.
[6]STARLING A P,ENGEL L S,CALAFAT A M,et al.Predictors and long-term reproducibility of urinary phthalate metabolites in middle-aged men and women living in urban Shanghai[J].Environ Int,2015,84:94-106.
[7]TRANFO G,PAPALEO B,CAPOROSSI L,et al.Urinary metabolite concentrations of phthalate metabolites in Central Italy healthy volunteers determined by a validated HPLC/MS/MS analytical method[J].Int J Hyg Environ Health,2013,216(4):481-485.
[8]张晗.上海社区居民邻苯二甲酸酯累积暴露风险评估[D].上海:复旦大学,2016.
[9]KOHN M C,PARHAM F,MASTEN S A,et al.Human exposure estimates for phthalates[J].Environ Health Perspect,2000,108(10):A440-A442.
[10]REMER T,NEUBERT A,MASER-GLUTH C.Anthropometrybased reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research[J].Am J Clin Nutr,2002,75(3):561-569.
[11]ANDERSON W A,CASTLE L,HIRD S,et al.A twenty-volunteer study using deuterium labelling to determine the kinetics and fractional excretion of primary and secondary urinary metabolites of di-2-ethylhexylphthalate and di-iso-nonylphthalate[J].Food Chem Toxicol,2011,49(9):2022-2029.
[12]GUO Y,WU Q,KANNAN K.Phthalate metabolites in urine from China,and implications for human exposures[J].Environ Int,2011,37(5):893-898.
[13]DONG R,ZHENG J,ZHANG M,et al.The concentrations and cumulative risk assessment of phthalates in general population from Shanghai:The comparison between groups with different ages[J].Sci Total Environ,2018,637-638:871-880.
[14]陈浩,张晓鹏,贾旭东,等.内分泌干扰物联合作用与累积风险评估研究进展[J].卫生研究,2014,43(1):157-161.
[15]U.S.EPA.Dibutyl phthalate;CASRN 84-74-2[EB/OL].[2019-03-06].https://cfpub.epa.gov/ncea/iris/iris_documents/documents/subst/0038_summary.pdf.
[16]U.S.EPA.Di(2-ethylhexyl)phthalate(DEHP);CASRN 117-81-7[EB/OL].[2019-03-06].https://cfpub.epa.gov/ncea/iris/iris_documents/documents/subst/0014_summary.pdf.
[17]U.S.EPA.Butyl benzyl phthalate(BBP);CASRN 85-68-7[EB/OL].[2019-03-06].https://cfpub.epa.gov/ncea/iris2/chemicalLanding.cfm?substance_nmbr=293.
[18]U.S.EPA.Diethyl phthalate;CASRN 84-66-2[EB/OL].[2019-03-09].https://cfpub.epa.gov/ncea/iris/iris_documents/documents/subst/0226_summary.pdf#nameddest=rfd.
[19]SVENSSON K,HERNáNDEZ-RAMíREZ R U,BURGUETE-GARCíA A,et al.Phthalate exposure associated with selfreported diabetes among Mexican women[J].Environ Res,2011,111(6):792-796.
[20]KIM J H,PARK H Y,BAE S,et al.Diethylhexyl phthalates is associated with insulin resistance via oxidative stress in the elderly:a panel study[J].PLoS One,2013,8(8):e71392.
[21]CHRISTENSEN K L,MAKRIS S L,LORBER M.Generation of hazard indices for cumulative exposure to phthalates for use in cumulative risk assessment[J].Regul Toxicol Pharmacol,2014,69(3):380-389.
[22]HARTMANN C,UHL M,WEISS S,et al.Human biomonitoring of phthalate exposure in Austrian children and adults and cumulative risk assessment[J].Int J Hyg Environ Health,2015,218(5):489-499.
[23]BENSON R.Hazard to the developing male reproductive system from cumulative exposure to phthalate estersdibutyl phthalate,diisobutyl phthalate,butylbenzyl phthalate,diethylhexyl phthalate,dipentyl phthalate,and diisononyl phthalate[J].Regul Toxicol Pharmacol,2009,53(2):90-101.
[24]AYDEMIR D,KARABULUT G,?IM?EK G,et al.Impact of the Di(2-Ethylhexyl)phthalate administration on trace element and mineral levels in relation of kidney and liver damage in rats[J].Biol Trace Elem Res,2018,186(2):474-488.
[25]PRAVEENA S M,TEH S W,RAJENDRAN R K,et al.Recent updates on phthalate exposure and human health:a special focus on liver toxicity and stem cell regeneration[J].Environ Sci Pollut Res,2018,25(12):11333-11342.
[26]ZHANG W,SHEN X Y,ZHANG W W,et al.Di-(2-ethylhexyl)phthalate could disrupt the insulin signaling pathway in liver of SD rats and L02 cells via PPARγ[J].Toxicol Appl Pharmacol,2017,316:17-26.
[27]WANG W,XU X,FAN C Q.Health hazard assessment of occupationally di-(2-ethylhexyl)-phthalate-exposed workers in China[J].Chemosphere,2015,120:37-44.
[28]CHEN J,ZHOU X,ZHANG H,et al.Association between urinary concentration of phthalate metabolites and impaired renal function in Shanghai adults[J].Environ Pollut,2019,245:149-162.