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Archives of Toxicology

, Volume 90, Issue 5, pp 1211–1224 | Cite as

Maternal exposure to di-(2-ethylhexyl) phthalate exposure deregulates blood pressure, adiposity, cholesterol metabolism and social interaction in mouse offspring

  • Kuan-I Lee
  • Chin-Wei Chiang
  • Hui-Ching Lin
  • Jin-Feng Zhao
  • Cheng-Ta Li
  • Song-Kun Shyue
  • Tzong-Shyuan Lee
Reproductive Toxicology

Abstract

Long-term exposure to di-(2-ethylhexyl) phthalate (DEHP) is highly associated with carcinogenicity, fetotoxicity, psychological disorders and metabolic diseases, but the detrimental effects and mechanisms are not fully understood. We investigated the effect of exposing mouse mothers to DEHP, and the underlying mechanism, on blood pressure, obesity and cholesterol metabolism as well as psychological and learning behaviors in offspring. Tail-cuff plethysmography was used for blood pressure measurement; Western blot used was for phosphorylation and expression of protein; hematoxylin and eosin staining, Nissl staining and Golgi staining were used for histological examination. The serum levels of cholesterol, triglycerides and glucose were measured by blood biochemical analysis. Hepatic cholesterol and triglyceride levels were assessed by colorimetric assay kits. Offspring behaviors were evaluated by open-field activity, elevated plus maze, social preference test and Morris water maze. Maternal DEHP exposure deregulated the phosphorylation of endothelial nitric oxide synthase and upregulated angiotensin type 1 receptor in offspring, which led to increased blood pressure. It led to obesity in offspring by increasing the size of adipocytes in white adipose tissue and number of adipocytes in brown adipose tissue. It increased the serum level of cholesterol in offspring by decreasing the hepatic capacity for cholesterol clearance. The impaired social interaction ability induced by maternal DEHP exposure might be due to abnormal neuronal development. Collectively, our findings provide new evidence that maternal exposure to DEHP has a lasting effect on the physiological functions of the vascular system, adipose tissue and nerve system in offspring.

Keywords

Di-(2-ethylhexyl) phthalate Blood pressure Adiposity Cholesterol metabolism Social interaction Offspring 

Notes

Acknowledgments

The authors thank Laura Smales for help in language editing. This study was supported by grants from the National Science Council (101-2628-B-010-001-MY2, 101-2811-B-010-039, 102-2628-B-010-001-MY3 and 103-2628-B-010-040-MY3), Yen Tjing Ling Medical Foundation (CI-104-13) and Ministry of Education, Aim for the Top University Plan, Taiwan.

Conflict of interest

The authors declare no conflict of interest.

References

  1. Andrade AJ, Grande SW, Talsness CE, Grote K, Chahoud I (2006) A dose-response study following in utero and lactational exposure to di-(2-ethylhexyl)-phthalate (DEHP): non-monotonic dose-response and low dose effects on rat brain aromatase activity. Toxicology 227:185–192CrossRefPubMedGoogle Scholar
  2. Arnal JF, Dinh-Xuan AT, Pueyo M, Darblade B, Rami J (1999) Endothelium-derived nitric oxide and vascular physiology and pathology. Cell Mol Life Sci 55:1078–1087CrossRefPubMedGoogle Scholar
  3. Beutler LR, Eldred KC, Quintana A, Keene CD, Rose SE, Postupna N, Montine TJ, Palmiter RD (2011) Severely impaired learning and altered neuronal morphology in mice lacking NMDA receptors in medium spiny neurons. PLoS One 6:e28168CrossRefPubMedPubMedCentralGoogle Scholar
  4. Brewer HB Jr (2000) The lipid-laden foam cell: an elusive target for therapeutic intervention. J Clin Invest 105:703–705CrossRefPubMedPubMedCentralGoogle Scholar
  5. Carbone S, Samaniego YA, Cutrera R, Reynoso R, Cardoso N, Scacchi P, Moguilevsky JA, Ponzo OJ (2012) Different effects by sex on hypothalamic-pituitary axis of prepubertal offspring rats produced by in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP). Neurotoxicology 33:78–84CrossRefPubMedGoogle Scholar
  6. Carbone S, Ponzo OJ, Gobetto N, Samaniego YA, Reynoso R, Scacchi P, Moguilevsky JA, Cutrera R (2013) Antiandrogenic effect of perinatal exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate increases anxiety-like behavior in male rats during sexual maturation. Horm Behav 63:692–699CrossRefPubMedGoogle Scholar
  7. Chen ML, Chen JS, Tang CL, Mao IF (2008) The internal exposure of Taiwanese to phthalate—an evidence of intensive use of plastic materials. Environ Int 34:79–85CrossRefPubMedGoogle Scholar
  8. Chen T, Yang W, Li Y, Chen X, Xu S (2011) Mono-(2-ethylhexyl) phthalate impairs neurodevelopment: inhibition of proliferation and promotion of differentiation in PC12 cells. Toxicol Lett 201:34–41CrossRefPubMedGoogle Scholar
  9. Chiang HC, Kuo YT, Shen CC, Lin YH, Wang SL, Tsou TC (2015) Mono(2-ethylhexyl)phthalate accumulation disturbs energy metabolism of fat cells. Arch Toxicol. 28 Dec 2014. [Epub ahead of print]Google Scholar
  10. Ching LC, Kou YR, Shyue SK, Su KH, Wei J, Cheng LC, Yu YB, Pan CC, Lee TS (2011) Molecular mechanisms of activation of endothelial nitric oxide synthase mediated by transient receptor potential vanilloid type 1. Cardiovasc Res 91:492–501CrossRefPubMedGoogle Scholar
  11. Ching LC, Chen CY, Su KH, Hou HH, Shyue SK, Kou YR, Lee TS (2012) Implication of AMP-activated protein kinase in transient receptor potential vanilloid type 1-mediated activation of endothelial nitric oxide synthase. Mol Med 18:805–815CrossRefPubMedGoogle Scholar
  12. Ching LC, Zhao JF, Su KH, Shyue SK, Hsu CP, Lu TM, Lin SJ, Lee TS (2013) Activation of transient receptor potential vanilloid 1 decreases endothelial nitric oxide synthase phosphorylation at Thr497 by protein phosphatase 2B-dependent dephosphorylation of protein kinase C. Acta Physiol (Oxf) 209:124–135CrossRefGoogle Scholar
  13. Davignon J, Ganz P (2004) Role of endothelial dysfunction in atherosclerosis. Circulation 109:III27–32CrossRefPubMedGoogle Scholar
  14. Desvergne B, Feige JN, Casals-Casas C (2009) PPAR-mediated activity of phthalates: a link to the obesity epidemic? Mol Cell Endocrinol 304:43–48CrossRefPubMedGoogle Scholar
  15. Engel SM, Zhu C, Berkowitz GS, Calafat AM, Silva MJ, Miodovnik A, Wolff MS (2009) Prenatal phthalate exposure and performance on the Neonatal Behavioral Assessment Scale in a multiethnic birth cohort. Neurotoxicology 30:522–528CrossRefPubMedPubMedCentralGoogle Scholar
  16. Feige JN, Gelman L, Rossi D, Zoete V, Métivier R, Tudor C, Anghel SI, Grosdidier A, Lathion C, Engelborghs Y, Michielin O, Wahli W, Desvergne B (2007) The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis. J Biol Chem 282:19152–19166CrossRefPubMedGoogle Scholar
  17. Glass MJ, Robinson DC, Waters E, Pickel VM (2013) Deletion of the NMDA-NR1 receptor subunit gene in the mouse nucleus accumbens attenuates apomorphine-induced dopamine D1 receptor trafficking and acoustic startle behavior. Synapse 67:265–279CrossRefPubMedPubMedCentralGoogle Scholar
  18. Goldfarb DA (1994) The renin-angiotensin system. New concepts in regulation of blood pressure and renal function. Urol Clin North Am 21:187–194PubMedGoogle Scholar
  19. Grande SW, Andrade AJ, Talsness CE, Grote K, Golombiewski A, Sterner-Kock A, Chahoud I (2007) A dose-response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): reproductive effects on adult female offspring rats. Toxicology 229:114–122CrossRefPubMedGoogle Scholar
  20. Griffiths WC, Camara P, Lerner KS (1985) Bis-(2-ethylhexyl) phthalate, an ubiquitous environmental contaminant. Ann Clin Lab Sci 15:140–151PubMedGoogle Scholar
  21. Griffiths WC, Camara PD, Saritelli A, Gentile J (1988) The in vitro serum protein-binding characteristics of bis-(2-ethylhexyl) phthalate and its principal metabolite, mono-(2-ethylhexyl) phthalate. Environ Health Perspect 77:151–156CrossRefPubMedPubMedCentralGoogle Scholar
  22. Gulati K, Lall SB (1996) Angiotensin II–receptor subtypes characterization and pathophysiological implications. Indian J Exp Biol 34:91–97PubMedGoogle Scholar
  23. Halden RU (2010) Plastics and health risks. Annu Rev Public Health 31:179–194CrossRefPubMedGoogle Scholar
  24. Hao C, Cheng X, Xia H, Ma X (2012) The endocrine disruptor mono-(2-ethylhexyl) phthalate promotes adipocyte differentiation and induces obesity in mice. Biosci Rep 32:619–629CrossRefPubMedPubMedCentralGoogle Scholar
  25. Huber WW, Grasl-Kraupp B, Schulte-Hermann R (1996) Hepatocarcinogenic potential of di(2-ethylhexyl) phthalate in rodents and its implications on human risk. Crit Rev Toxicol 26:365–481CrossRefPubMedGoogle Scholar
  26. Hussain A, Nookaew I, Khoomrung S, Andersson L, Larsson I, Hulthén L, Jansson N, Jakubowicz R, Nilsson S, Sandberg AS, Nielsen J, Holmäng A (2013) A maternal diet of fatty fish reduces body fat of offspring compared with a maternal diet of beef and a post-weaning diet of fish improves insulin sensitivity and lipid profile in adult C57BL/6 male mice. Acta Physiol (Oxf) 209:220–234Google Scholar
  27. Ito Y, Yokota H, Wang R, Yamanoshita O, Ichihara G, Wang H, Kurata Y, Takagi K, Nakajima T (2005) Species differences in the metabolism of di(2-ethylhexyl) phthalate (DEHP) in several organs of mice, rats, and marmosets. Arch Toxicol 79:147–154CrossRefPubMedGoogle Scholar
  28. Jaeger RJ, Rubin RJ (1972) Migration of a phthalate ester plasticizer from polyvinyl chloride blood bags into stored human blood and its localization in human tissues. N Engl J Med 287:1114–1118CrossRefPubMedGoogle Scholar
  29. Jia L, Betters JL, Yu L (2011) Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annu Rev Physiol 73:239–259CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kawai M, Rosen CJ (2010) PPARγ: a circadian transcription factor in adipogenesis and osteogenesis. Nat Rev Endocrinol 6:629–636CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kepez A, Oto A, Dagdelen S (2006) Peroxisome proliferator-activated receptor-gamma: novel therapeutic target linking adiposity, insulin resistance, and atherosclerosis. BioDrugs 20:121–135CrossRefPubMedGoogle Scholar
  32. Kim SH, Park MJ (2014) Phthalate exposure and childhood obesity. Ann Pediatr Endocrinol Metab 19:69–75CrossRefPubMedPubMedCentralGoogle Scholar
  33. Kim BN, Cho SC, Kim Y, Shin MS, Yoo HJ, Kim JW, Yang YH, Kim HW, Bhang SY, Hong YC (2009) Phthalates exposure and attention-deficit/hyperactivity disorder in school-age children. Biol Psychiatry 66:958–963CrossRefPubMedGoogle Scholar
  34. Kjaergaard M, Nilsson C, Rosendal A, Nielsen MO, Raun K (2014) Maternal chocolate and sucrose soft drink intake induces hepatic steatosis in rat offspring associated with altered lipid gene expression profile. Acta Physiol (Oxf) 210:142–153CrossRefGoogle Scholar
  35. Koch HM, Bolt HM, Angerer J (2004) Di(2-ethylhexyl)phthalate (DEHP) metabolites in human urine and serum after a single oral dose of deuterium-labelled DEHP. Arch Toxicol 78:123–130CrossRefPubMedGoogle Scholar
  36. Koch HM, Bolt HM, Preuss R, Angerer J (2005) New metabolites of di(2-ethylhexyl)phthalate (DEHP) in human urine and serum after single oral doses of deuterium-labelled DEHP. Arch Toxicol 79:367–376CrossRefPubMedGoogle Scholar
  37. Latini G, Del Vecchio A, Massaro M, Verrotti A, De Felice C (2006) In utero exposure to phthalates and fetal development. Curr Med Chem 13:2527–2534CrossRefPubMedGoogle Scholar
  38. Leret ML, Rua C, Garcia-Montojo M, Lecumberri M, González JC (2009) Influence of metyrapone treatment during pregnancy on the development and maturation of brain monoaminergic systems in the rat. Acta Physiol (Oxf) 197:333–340CrossRefGoogle Scholar
  39. Lien YJ, Ku HY, Su PH, Chen SJ, Chen HY, Liao PC, Chen WJ, Wang SL (2015) Prenatal exposure to phthalate esters and behavioral syndromes in children at eight years of age: Taiwan maternal and infant cohort study. Environ Health Perspect 123:95–100CrossRefPubMedPubMedCentralGoogle Scholar
  40. Lim CK, Kim SK, Ko DS, Cho JW, Jun JH, An SY, Han JH, Kim JH, Yoon YD (2009) Differential cytotoxic effects of mono-(2-ethylhexyl) phthalate on blastomere-derived embryonic stem cells and differentiating neurons. Toxicology 264:145–154CrossRefPubMedGoogle Scholar
  41. Lin S, Ku HY, Su PH, Chen JW, Huang PC, Angerer J, Wang SL (2011a) Phthalate exposure in pregnant women and their children in central Taiwan. Chemosphere 82:947–955CrossRefPubMedGoogle Scholar
  42. Lin Y, Wei J, Li Y, Chen J, Zhou Z, Song L, Wei Z, Lv Z, Chen X, Xia W, Xu S (2011b) 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 301:E527–538CrossRefPubMedGoogle Scholar
  43. Ljungvall K, Tienpont B, David F, Magnusson U, Törneke K (2004) Kinetics of orally administered di(2-ethylhexyl) phthalate and its metabolite, mono(2-ethylhexyl) phthalate, in male pigs. Arch Toxicol 78:384–389CrossRefPubMedGoogle Scholar
  44. Mangala Priya V, Mayilvanan C, Akilavalli N, Rajesh P, Balasubramanian K (2014) Lactational exposure of phthalate impairs insulin signaling in the cardiac muscle of F1 female albino rats. Cardiovasc Toxicol 14:10–20CrossRefPubMedGoogle Scholar
  45. Martino-Andrade AJ, Chahoud I (2010) Reproductive toxicity of phthalate esters. Mol Nutr Food Res 54:148–157CrossRefPubMedGoogle Scholar
  46. Masuo Y, Morita M, Oka S, Ishido M (2004) Motor hyperactivity caused by a deficit in dopaminergic neurons and the effects of endocrine disruptors: a study inspired by the physiological roles of PACAP in the brain. Regul Pept 123:225–234CrossRefPubMedGoogle Scholar
  47. Mettang T, Thomas S, Kiefer T, Fischer FP, Kuhlmann U, Wodarz R, Rettenmeier AW (1996) Uraemic pruritus and exposure to di(2-ethylhexyl) phthalate (DEHP) in haemodialysis patients. Nephrol Dial Transplant 11:2439–2443CrossRefPubMedGoogle Scholar
  48. Miodovnik A, Engel SM, Zhu C, Ye X, Soorya LV, Silva MJ, Calafat AM, Wolff MS (2011) Endocrine disruptors and childhood social impairment. Neurotoxicology 32:261–267CrossRefPubMedPubMedCentralGoogle Scholar
  49. Mount PF, Kemp BE, Power DA (2007) Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Mol Cell Cardiol 42:271–279CrossRefPubMedGoogle Scholar
  50. Paus T, Zijdenbos A, Worsley K, Collins DL, Blumenthal J, Giedd JN, Rapoport JL, Evans AC (1999) Structural maturation of neural pathways in children and adolescents: in vivo study. Science 283:1908–1911CrossRefPubMedGoogle Scholar
  51. Pruis MG, Lendvai A, Bloks VW, Zwier MV, Baller JF, de Bruin A, Groen AK, Plösch T (2014a) Maternal western diet primes non-alcoholic fatty liver disease in adult mouse offspring. Acta Physiol (Oxf) 210:215–227CrossRefGoogle Scholar
  52. Pruis MG, van Ewijk PA, Schrauwen-Hinderling VB, Plösch T (2014b) Lipotoxicity and the role of maternal nutrition. Acta Physiol (Oxf) 210:296–306CrossRefGoogle Scholar
  53. Rajesh P, Balasubramanian K (2014a) Gestational exposure to di (2-ethylhexyl) phthalate (DEHP) impairs pancreatic β-cell function in F1 rat offspring. Toxicol Lett 232:46–57CrossRefPubMedGoogle Scholar
  54. Rajesh P, Balasubramanian K (2014b) Phthalate exposure in utero causes epigenetic changes and impairs insulin signalling. J Endocrinol 223:47–66CrossRefPubMedGoogle Scholar
  55. Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661CrossRefPubMedGoogle Scholar
  56. Reddy JK, Lalwai ND (1983) Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. Crit Rev Toxicol 12:1–58CrossRefPubMedGoogle Scholar
  57. Sjöberg P, Lindquist NG, Montin G, Plöen L (1985) Effects of repeated intravenous infusions of the plasticizer di-(2-ethylhexyl) phthalate in young male rats. Arch Toxicol 58:78–83CrossRefPubMedGoogle Scholar
  58. Smith CA, Macdonald A, Holahan MR (2011) Acute postnatal exposure to di (2-ethylhexyl) phthalate adversely impacts hippocampal development in the male rat. Neuroscience 193:100–108CrossRefPubMedGoogle Scholar
  59. Specht IO, Bonde JP, Toft G, Lindh CH, Jönsson BA, Jørgensen KT (2015) Serum phthalate levels and time to pregnancy in couples from greenland, poland and ukraine. PLoS One 10:e0120070CrossRefPubMedPubMedCentralGoogle Scholar
  60. Stahlhut RW, van Wijngaarden E, Dye TD, Cook S, Swan SH (2007) Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. Environ Health Perspect 115:876–882CrossRefPubMedPubMedCentralGoogle Scholar
  61. Su KH, Yu YB, Hou HH, Zhao JF, Kou YR, Cheng LC, Shyue SK, Lee TS (2012) AMP-activated protein kinase mediates erythropoietin-induced activation of endothelial nitric oxide synthase. J Cell Physiol 227:3053–3062CrossRefPubMedGoogle Scholar
  62. Su KH, Lin SJ, Wei J, Lee KI, Zhao JF, Shyue SK, Lee TS (2014) The essential role of transient receptor potential vanilloid 1 in simvastatin-induced activation of endothelial nitric oxide synthase and angiogenesis. Acta Physiol (Oxf) 212:191–204CrossRefGoogle Scholar
  63. Sun X, Lin Y, Huang Q, Shi J, Qiu L, Kang M, Chen Y, Fang C, Ye T, Dong S (2014) Di (2-ethylhexyl) phthalate-induced apoptosis in rat INS-1 cells is dependent on activation of endoplasmic reticulum stress and suppression of antioxidant protection. J Cell Mol Med. doi: 10.1111/jcmm.12409 Google Scholar
  64. Taylor PD, Samuelsson AM, Poston L (2014) Maternal obesity and the developmental programming of hypertension: a role for leptin. Acta Physiol (Oxf) 210:508–523CrossRefGoogle Scholar
  65. Ter Veld MG, Zawadzka E, van den Berg JH, van der Saag PT, Rietjens IM, Murk AJ (2008) Food-associated estrogenic compounds induce estrogen receptor-mediated luciferase gene expression in transgenic male mice. Chem Biol Interact 174:126–133CrossRefPubMedGoogle Scholar
  66. Tickner JA, Schettler T, Guidotti T, McCally M, Rossi M (2001) Health risks posed by use of Di-2-ethylhexyl phthalate (DEHP) in PVC medical devices: acritical review. Am J Ind Med 39:100–111CrossRefPubMedGoogle Scholar
  67. Tomita I, Nakamura Y, Yagi Y, Tutikawa K (1982) Teratogenicity/fetotoxicity of DEHP in mice. Environ Health Perspect 45:71–75CrossRefPubMedPubMedCentralGoogle Scholar
  68. Trasande L, Sathyanarayana S, Spanier AJ, Trachtman H, Attina TM, Urbina EM (2013) Urinary phthalates are associated with higher blood pressure in childhood. J Pediatr 163:747–753CrossRefPubMedPubMedCentralGoogle Scholar
  69. Tsuchida A, Yamauchi T, Kadowaki T (2005) Nuclear receptors as targets for drug development: molecular mechanisms for regulation of obesity and insulin resistance by peroxisome proliferator-activated receptor gamma, CREB-binding protein, and adiponectin. J Pharmacol Sci 97:164–170CrossRefPubMedGoogle Scholar
  70. Vanhoutte PM, Shimokawa H, Tang EH, Feletou M (2009) Endothelial dysfunction and vascular disease. Acta Physiol (Oxf) 196:193–222CrossRefGoogle Scholar
  71. Venema RC (2002) Post-translational mechanisms of endothelial nitric oxide synthase regulation by bradykinin. Int Immunopharmacol 2:1755–1762CrossRefPubMedGoogle Scholar
  72. Viana Abranches M, Esteves de Oliveira FC, Bressan J (2011) Peroxisome proliferator-activated receptor: effects on nutritional homeostasis, obesity and diabetes mellitus. Nutr Hosp 26:271–279PubMedGoogle Scholar
  73. Wang CC, Held RG, Chang SC, Yang L, Delpire E, Ghosh A, Hall BJ (2011) A critical role for GluN2B-containing NMDA receptors in cortical development and function. Neuron 72:789–805CrossRefPubMedGoogle Scholar
  74. Wang DC, Chen TJ, Lin ML, Jhong YC, Chen SC (2014) Exercise prevents the increased anxiety-like behavior in lactational di-(2-ethylhexyl) phthalate-exposed female rats in late adolescence by improving the regulation of hypothalamus-pituitary-adrenal axis. Horm Behav 66:674–684CrossRefPubMedGoogle Scholar
  75. Wei Z, Song L, Wei J, Chen T, Chen J, Lin Y, Xia W, Xu B, Li X, Chen X, Li Y, Xu S (2012) Maternal exposure to di-(2-ethylhexyl) phthalate alters kidney development through the renin-angiotensin system in offspring. Toxicol Lett 212:212–221CrossRefPubMedGoogle Scholar
  76. Wei J, Ching LC, Zhao JF, Shyue SK, Lee HF, Kou YR, Lee TS (2013) Essential role of transient receptor potential vanilloid type 1 in evodiamine-mediated protection against atherosclerosis. Acta Physiol (Oxf) 207:299–307CrossRefGoogle Scholar
  77. Wittassek M, Angerer J (2008) Phthalates: metabolism and exposure. Int J Androl 31:131–138CrossRefPubMedGoogle Scholar
  78. Won H, Lee HR, Gee HY, Mah W, Kim JI, Lee J, Ha S, Chung C, Jung ES, Cho YS, Park SG, Lee JS, Lee K, Kim D, Bae YC, Kaang BK, Lee MG, Kim E (2012) Autistic-like social behavior in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486:261–265CrossRefPubMedGoogle Scholar
  79. Xu Z, Chen RQ, Gu QH, Yan JZ, Wang SH, Liu SY, Lu W (2009) Metaplastic regulation of long-term potentiation/long-term depression threshold by activity-dependent changes of NR2A/NR2B ratio. J Neurosci 29:8764–8773CrossRefPubMedGoogle Scholar
  80. Yen TH, Lin-Tan DT, Lin JL (2011) Food safety involving ingestion of foods and beverages prepared with phthalate-plasticizer-containing clouding agents. J Formos Med Assoc 110:671–684CrossRefPubMedGoogle Scholar
  81. Zhang LD, Deng Q, Wang ZM, Gao M, Wang L, Chong T, Li HC (2013) Disruption of reproductive development in male rat offspring following gestational and lactational exposure to di-(2-ethylhexyl) phthalate and genistein. Biol Res 46:139–146CrossRefPubMedGoogle Scholar
  82. Zhang Y, Meng X, Chen L, Li D, Zhao L, Zhao Y, Li L, Shi H (2014) Age and sex-specific relationships between phthalate exposures and obesity in Chinese children at puberty. PLoS One 9:e104852CrossRefPubMedPubMedCentralGoogle Scholar
  83. Zhao JF, Hsiao SH, Hsu MH, Pao KC, Kou YR, Shyue SK, Lee TS (2014) Di-(2-ethylhexyl) phthalate accelerates atherosclerosis in apolipoprotein E-deficient mice. Arch Toxicol. doi: 10.1007/s00204-014-1377-5 Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Kuan-I Lee
    • 1
  • Chin-Wei Chiang
    • 1
  • Hui-Ching Lin
    • 1
    • 2
  • Jin-Feng Zhao
    • 1
  • Cheng-Ta Li
    • 3
  • Song-Kun Shyue
    • 4
  • Tzong-Shyuan Lee
    • 1
    • 2
    • 5
  1. 1.Department of Physiology, School of MedicineNational Yang-Ming UniversityTaipeiTaiwan
  2. 2.Brain Research CenterNational Yang-Ming UniversityTaipeiTaiwan
  3. 3.Department of PsychiatryTaipei Veterans General HospitalTaipeiTaiwan
  4. 4.Cardiovascular Division, Institute of Biomedical SciencesAcademia SinicaTaipeiTaiwan
  5. 5.Genome Research CenterNational Yang-Ming UniversityTaipeiTaiwan

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