Influence of phthalates on glucose homeostasis and atherosclerosis in hyperlipidemic mice

BMC Endocrine Disorders

Weibin SHI¹  Mei-Hua Chen¹  Wei Zhou² 

[1] Departments of Radiology & Medical Imaging and of Biochemistry & Molecular Genetics, University of Virginia, 266 Snyder Bldg, 480 Ray C Hunt Drive, Charlottesville 22908, VA, USA;Department of Endocrinology of Jianghuai Hospital, Huaian 223001, Jiangsu Province, China

关键词: Mice;    Dyslipidemia;    Atherosclerosis;    Type 2 diabetes;    Phthalates;   

Others  :  1145761
DOI  :  10.1186/s12902-015-0015-4

 received in 2014-12-03, accepted in 2015-03-27,  发布年份 2015

【 摘 要 】

Background

Phthalates are widely used as plasticizer and are considered as a typical endocrine-disrupting chemical. Epidemiological studies have associated serum or urinary phthalate metabolites with the prevalence of type 2 diabetes or related phenotypes. However, direct evidence supporting a causal role for exposure to phthalates in type 2 diabetes is lacking.

Methods

To determine the potential influence of phthalates on glucose homeostasis and atherosclerosis, female apolipoprotein E-deficient (Apoe^−/−) mice were started at 6 weeks of age on a Western diet together with or without Bis-(2-ethylhexyl) phthalate. Phthalate was administered in drinking water at a daily dosage of 100 mg/kg. We examined glucose and insulin tolerance, plasma glucose and triglyceride levels, body weight, and atherosclerotic lesions in the aortic root.

Results

Two weeks after treatment, phthalate-exposed mice had significantly higher fasting blood glucose level (97.9 ± 2.1 vs. 84.3 ± 5.3 mg/dl, P = 0.034) and exhibited a trend of increased glucose intolerance compared to control mice. Insulin tolerance test on non-fasted mice 3 weeks after treatment revealed that phthalate had little influence on insulin sensitivity though phthalate-treated mice had a higher glucose concentration (159.2 ± 6.0 vs. 145.2 ± 3.6 mg/dl; P = 0.086). On the Western diet, Apoe^−/− mice showed a time-dependent rise in fasting plasma glucose and triglyceride levels. However, no significant differences were observed between phthalate-treated and control mice in either phenotype after 4, 8, and 12 weeks of phthalate exposure. Neither body weight nor atherosclerotic lesions of Apoe^−/− mice was affected.

Conclusion

This study indicates that exposure to phthalates gives rise to a brief interference of glucose homeostasis but has little impact on the development of type 2 diabetes and atherosclerosis in Apoe^−/− mice.

【 授权许可】

   
2015 Zhou et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Wittassek M, Koch HM, Angerer J, Bruning T: Assessing exposure to phthalates - the human biomonitoring approach. Mol Nutr Food Res 2011, 55(1):7-31.
• [2]Silva MJ, Barr DB, Reidy JA, Malek NA, Hodge CC, Caudill SP, et al.: Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999–2000. Environ Health Perspect 2004, 112(3):331-8.
• [3]Meeker JD, Calafat AM, Hauser R: Urinary phthalate metabolites and their biotransformation products: predictors and temporal variability among men and women. J Expo Sci Environ Epidemiol 2012, 22(4):376-85.
• [4]Stahlhut RW, van Wijngaarden E, Dye TD, Cook S, Swan SH: Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. Environ Health Perspect 2007, 115(6):876-82.
• [5]Hatch EE, Nelson JW, Qureshi MM, Weinberg J, Moore LL, Singer M, et al.: Association of urinary phthalate metabolite concentrations with body mass index and waist circumference: a cross-sectional study of NHANES data, 1999–2002. Environ Health 2008, 7:27. BioMed Central Full Text
• [6]Svensson K, Hernandez-Ramirez RU, Burguete-Garcia A, Cebrian ME, Calafat AM, Needham LL, et al.: Phthalate exposure associated with self-reported diabetes among Mexican women. Environ Res 2011, 111(6):792-6.
• [7]James-Todd T, Stahlhut R, Meeker JD, Powell SG, Hauser R, Huang T, et al. Urinary Phthalate Metabolite Concentrations and Diabetes among Women in the National Health and Nutrition Examination Survey (NHANES) 2001–2008. Environ Health Perspect 2012; 120(9):1307-13.
• [8]Kim JH, Park HY, Bae S, Lim YH, Hong YC: Diethylhexyl phthalates is associated with insulin resistance via oxidative stress in the elderly: a panel study. PLoS ONE 2013, 8(8):e71392.
• [9]Lind PM, Zethelius B, Lind L: Circulating levels of phthalate metabolites are associated with prevalent diabetes in the elderly. Diabetes Care 2012, 35(7):1519-24.
• [10]Sun Q, Cornelis MC, Townsend MK, Tobias DK, Eliassen AH, Franke AA, et al. Association of Urinary Concentrations of Bisphenol A and Phthalate Metabolites with Risk of Type 2 Diabetes: A Prospective Investigation in the Nurses' Health Study (NHS) and NHSII Cohorts. Environ Health Perspect. 2014;122(6):616-23.
• [11]Martinelli MI, Mocchiutti NO, Bernal CA: Dietary di(2-ethylhexyl)phthalate-impaired glucose metabolism in experimental animals. Hum Exp Toxicol 2006, 25(9):531-8.
• [12]Lin Y, Wei J, Li Y, Chen J, Zhou Z, Song L, et al.: Developmental exposure to di(2-ethylhexyl) phthalate impairs endocrine pancreas and leads to long-term adverse effects on glucose homeostasis in the rat. Am J Physiol Endocrinol Metab 2011, 301(3):E527-38.
• [13]Rajesh P, Sathish S, Srinivasan C, Selvaraj J, Balasubramanian K: Phthalate is associated with insulin resistance in adipose tissue of male rat: role of antioxidant vitamins. J Cell Biochem 2013, 114(3):558-69.
• [14]Sun W, Ban JB, Zhang N, Zu YK, Sun WX: Perinatal exposure to di-(2-ethylhexyl)-phthalate leads to cognitive dysfunction and phospho-tau level increase in aged rats. Environ Toxicol 2014, 29(5):596-603.
• [15]Nakane F, Kunieda M, Shimizu S, Kobayashi Y, Akane H, Akie Y, et al.: Twenty-six-week oral toxicity of diheptyl phthalate with special emphasis on its induction of liver proliferative lesions in male F344 rats. J Toxicol Sci 2012, 37(3):527-37.
• [16]Feige JN, Gerber A, Casals-Casas C, Yang Q, Winkler C, Bedu E, et al.: The pollutant diethylhexyl phthalate regulates hepatic energy metabolism via species-specific PPARalpha-dependent mechanisms. Environ Health Perspect 2010, 118(2):234-41.
• [17]Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R: ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb 1994, 14(1):133-40.
• [18]Shi W, Wang NJ, Shih DM, Sun VZ, Wang X, Lusis AJ: Determinants of atherosclerosis susceptibility in the C3H and C57BL/6 mouse model: evidence for involvement of endothelial cells but not blood cells or cholesterol metabolism. Circ Res 2000, 86(10):1078-84.
• [19]Zhang SH, Reddick RL, Piedrahita JA, Maeda N: Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 1992, 258(5081):468-71.
• [20]Su Z, Li Y, James JC, Matsumoto AH, Helm GA, Lusis AJ, et al.: Genetic linkage of hyperglycemia, body weight and serum amyloid-P in an intercross between C57BL/6 and C3H apolipoprotein E-deficient mice. Hum Mol Genet 2006, 15(10):1650-8.
• [21]Paigen B, Holmes PA, Mitchell D, Albee D: Comparison of atherosclerotic lesions and HDL-lipid levels in male, female, and testosterone-treated female mice from strains C57BL/6, BALB/c, and C3H. Atherosclerosis 1987, 64(2–3):215-21.
• [22]Li J, Wang Q, Chai W, Chen MH, Liu Z, Shi W: Hyperglycemia in apolipoprotein E-deficient mouse strains with different atherosclerosis susceptibility. Cardiovasc Diabetol 2011, 10(1):117. BioMed Central Full Text
• [23]Li J, Lu Z, Wang Q, Su Z, Bao Y, Shi W: Characterization of Bglu3, a mouse fasting glucose locus, and identification of Apcs as an underlying candidate gene. Physiol Genomics 2012, 44(6):345-51.
• [24]Manichaikul A, Wang Q, Shi YL, Zhang Z, Leitinger N, Shi W: Characterization of Ath29, a major mouse atherosclerosis susceptibility locus, and identification of Rcn2 as a novel regulator of cytokine expression. Am J Physiol Heart Circ Physiol 2011, 301(3):H1056-61.
• [25]Lu Z, Yuan Z, Miyoshi T, Wang Q, Su Z, Chang CC, et al.: Identification of Soat1 as a quantitative trait locus gene on mouse chromosome 1 contributing to hyperlipidemia. PLoS ONE 2011, 6(10):e25344.
• [26]Ter Veld MG, Zawadzka E, Rietjens IM, Murk AJ: Estrogenicity of food-associated estrogenic compounds in the fetuses of female transgenic mice upon oral and IP maternal exposure. Reprod Toxicol 2009, 27(2):133-9.
• [27]Zhang Z, Rowlan JS, Wang Q, Shi W: Genetic analysis of atherosclerosis and glucose homeostasis in an intercross between C57BL/6 and BALB/cJ apolipoprotein E-deficient mice. Circ Cardiovasc Genet 2012, 5(2):190-201.
• [28]Tian J, Pei H, James JC, Li Y, Matsumoto AH, Helm GA, et al.: Circulating adhesion molecules in apoE-deficient mouse strains with different atherosclerosis susceptibility. Biochem Biophys Res Commun 2005, 329(3):1102-7.
• [29]Rowlan JS, Zhang Z, Wang Q, Fang Y, Shi W: New quantitative trait loci for carotid atherosclerosis identified in an intercross derived from apolipoprotein E-deficient mouse strains. Physiol Genomics 2013, 45(8):332-42.
• [30]Su Z, Li Y, James JC, McDuffie M, Matsumoto AH, Helm GA, et al.: Quantitative trait locus analysis of atherosclerosis in an intercross between C57BL/6 and C3H mice carrying the mutant apolipoprotein E gene. Genetics 2006, 172(3):1799-807.
• [31]Zhang Y, Kundu B, Zhong M, Huang T, Li J, Chordia MD, et al.: PET imaging detection of macrophages with a formyl peptide receptor antagonist. Nucl Med Biol 2015, 42(4):381-6.
• [32]Clee SM, Attie AD: The genetic landscape of type 2 diabetes in mice. Endocr Rev 2007, 28(1):48-83.
• [33]Gayathri NS, Dhanya CR, Indu AR, Kurup PA: Changes in some hormones by low doses of di (2-ethyl hexyl) phthalate (DEHP), a commonly used plasticizer in PVC blood storage bags & medical tubing. Indian J Med Res 2004, 119(4):139-44.
• [34]Lake BG, Rijcken WR, Gray TJ, Foster JR, Gangolli SD: Comparative studies of the hepatic effects of di- and mono-n-octyl phthalates, di-(2-ethylhexyl) phthalate and clofibrate in the rat. Acta Pharmacol Toxicol (Copenh) 1984, 54(3):167-76.
• [35]Song Y, Hauser R, Hu FB, Franke A, Liu S, Sun Q. Urinary concentrations of bisphenol a and phthalate metabolites and weight change: a prospective investigation in US women. Int J Obes (Lond). 2014; 38(12):1532-7.
• [36]Trasande L, Attina TM, Sathyanarayana S, Spanier AJ, Blustein J: Race/ethnicity-specific associations of urinary phthalates with childhood body mass in a nationally representative sample. Environ Health Perspect 2013, 121(4):501-6.
• [37]Lind PM, Roos V, Ronn M, Johansson L, Ahlstrom H, Kullberg J, et al.: Serum concentrations of phthalate metabolites are related to abdominal fat distribution two years later in elderly women. Environ Health 2012, 11:21. BioMed Central Full Text
• [38]Wang H, Zhou Y, Tang C, He Y, Wu J, Chen Y, et al.: Urinary phthalate metabolites are associated with body mass index and waist circumference in Chinese school children. PLoS ONE 2013, 8(2):e56800.
• [39]Teupser D, Pavlides S, Tan M, Gutierrez-Ramos JC, Kolbeck R, Breslow JL: Major reduction of atherosclerosis in fractalkine (CX3CL1)-deficient mice is at the brachiocephalic artery, not the aortic root. Proc Natl Acad Sci U S A 2004, 101(51):17795-800.