Journal of Endocrinology and Reproduction

Open Access Open Access  Restricted Access Subscription Access
Open Access Open Access Open Access  Restricted Access Restricted Access Subscription Access

Gestational Exposure to Di(2-Ethylhexyl)Phthalate Modifies the Expression Pattern of Genes Controlling Thyroid Hormone Biosynthesis in Puberal Rat Progeny


Affiliations
1 Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600113, Tamil Nadu, India
     

   Subscribe/Renew Journal


Di(2-ethylhexyl) phthalate (DEHP), a plasticiser, is known to disrupt thyroid functions but the underlying molecular mechanism remains obscure. The present study was conducted testing the hypothesis that gestational exposure to DEHP may modify the expression of specific genes controlling biosynthesis and action of thyroid hormones in the male progeny at puberal age. Pregnant rats were administered with DEHP [1, 10 and 100 mg (in olive oil)/Kgb.wt./day] from embryonic day 9 to 21 through oral route. The pups were sacrificed on post-natal day 60. Enzyme Immuno Assay (EIA) revealed a dose-dependent decrease in serum 3,5,3’ triiodothyronine (T3) and L-thyroxine (T4) titres in DEHP-treated rats. Real-time RT-PCR and western blot analyses of thyroidal genes revealed decreased expression level of sodium/iodide symporter (Nis) and thyroid hormone receptor α (Trα), whereas the expression of thyroid stimulating hormone receptor (Tshr), thyroid hormone receptor β (Trβ) and pendrin (Pds) increased. While western blot detection showed decreased expression level of thyroperoxidase (Tpo), RTPCR data pointed out augmented expression. Western blot detection of transcriptional factors showed decreased expression levels of fork-headbox e1 (Foxe1) and haematopoietically expressed homeobox (Hhex), whereas thyroid transcription factor-1 (Ttf-1) and paired-box domain 8 (Pax8) increased. Our study demonstrates, for the first time, that gestational exposure to DEHPaffects the expression of genes controlling thyroid hormone synthesis in puberal rat progeny, and the hypothyroid state in these rats may be linked to decreased expression of Nis, Tpo, Foxe1 and Hhex.

Keywords

Pendrin, Sodium/Iodide Symporter, Thyroperoxidase, Thyrotrophin Receptor, Haematopoietically Expressed Homeobox.
Subscription Login to verify subscription
User
Notifications
Font Size


  • Chou K, Wright RO. Phthalates in food and medical devices. Journal Medical Toxicology. 2006; 2:126–35.https://doi.org/10.1007/BF03161027 PMCid:PMC3550149

  • Cho SC, Bhang SY, Hong YC, Shin MS, Kim BN, Kim JW.Relationship between environmental phthalate exposure and the intelligence of school-age children. Environ Health Perspect. 2010; 118:1027–32. https://doi.org/10.1289/ ehp.0901376 PMid:20194078 PMCid:PMC2920903

  • Shea KM. Pediatric exposure and potential toxicity of phthalate plasticizers. Pediatrics. 2003; 111(6 Pt 1):1467–74.https://doi.org/10.1542/peds.111.6.1467 PMid:12777573

  • Latini G. Monitoring phthalate exposure in humans. Clin Chim Acta. 2005; 361:20–9. https://doi.org/10.1016/j.cccn.2005.05.003 PMid:16004980

  • Silva MJ, Reidy JA, Herbert AR, Preau Jr JL, Needham LL, Calafat AM. Detection of phthalate metabolites in human amniotic fluid. Bull Environ Contam Toxicol. 2004; 72:1226–31. https://doi.org/10.1007/s00128-004-0374-4 PMid:15362453

  • Silva MJ, Samandar E, Preau Jr JL, Reidy JA, Needham LL, Calafat A. Automated solid-phase extraction and quantitative analysis of 14 phthalate metabolites in human serum using isotope dilution-high-performance liquid chromatographytandem mass spectrometry. J Anal Toxicol.2005; 29:819–24. https://doi.org/10.1093/jat/29.8.819 PMid:16374941

  • Zoeller RT. Environmental chemicals as thyroid hormone analogues: new studies indicate that thyroid hormone receptors are targets of industrial chemicals? Mol Cell Endocrinol. 2005; 242:10–5. https://doi.org/10.1016/j.mce.2005.07.006 PMid:16150534

  • Boas M, Feldt-Rasmussen U, Main KM. Thyroid effects of endocrine disrupting chemicals. Mol Cell Endocrinol.2012; 355:240–8. https://doi.org/10.1016/j.mce.2011.09.005 PMid:21939731

  • Sekaran S, Jagadeesan A. In utero exposure to phthalate down regulates critical genes in Leydig cells of F1 male progeny. J Cell Biochem. 2015; 116:1466–77. https://doi.org/10.1002/jcb.25108 PMid:25649163

  • Rajesh P, Balasubramanian K. Gestational exposure to di(2-ethylhexyl) phthalate (DEHP) impairs pancreatic beta-cell function in F1 rat offspring. Toxicol Lett. 2015; 232:46–57. https://doi.org/10.1016/j.toxlet.2014.09.025 PMid:25280772

  • Poon R, Lecavalier P, Mueller R, Valli VE, Procter BG, Chu I. Subchronicoral toxicity of di-n-octyl phthalate and di(2-ethylhexyl) phthalate in the rat. Food ChemToxicol.1997; 35:225–39. https://doi.org/10.1016/S02786915(96)00064-6

  • Hinton RH, Mitchell FE, Mann A. Effects of phthalic acid esters on the liver and thyroid. Environ Health Perspect.1986; 70:195–210. https://doi.org/10.1289/ehp.8670195 PMid:3830106 PMCid:PMC1474287

  • Price SC, Chescoe D, Grasso P, Wright M, Hinton RH. Alterations in the thyroids of rats treated for long periods with di-(2-ethylhexyl) phthalate or with hypolipidaemic agents. Toxicol Lett. 1988; 40:37–46. https://doi.org/10.1016/0378-4274(88)90181-6

  • ATSDR. Toxicological profile for di(2-Ethylhexyl) Phthalate. Agency for Toxic Substances and Disease; 2002.

  • Howarth JA, Price SC, Dobrota M, Kentish PA, Hinton RH.Effects on male rats of di-(2-ethylhexyl) phthalate and dinhexylphthalate administered alone or in combination.Toxicol Lett. 2001; 121:35–43. https://doi.org/10.1016/ S0378-4274(01)00313-7

  • Wenzel A, Franz C, BreousE, Loos U. Modulation of iodide uptake by dialkylphthalate plasticizers in FRTL-5 rat thyroid follicular cells. Mol Cell Endocrinol. 2005; 244: 63–71.https://doi.org/10.1016/j.mce.2005.02.008 PMid:16289305

  • Breous E, Wenzel A, Loos U. The promoter of the human sodium/iodide symporter responds to certain phthalate plasticisers. Mol Cell Endocrinol. 2005; 244:75–8. https:// doi.org/10.1016/j.mce.2005.06.009 PMid:16257484

  • Meeker JD, Calafat AM, Hauser R. Di-(2-ethylhexyl) phthalate metabolites may alter thyroid hormone levels in men. Environ Health Perspect. 2007; 115:1029–34.https://doi.org/10.1289/ehp.9852 PMid:17637918 PMCid:PMC1913587

  • Meeker JD, Ferguson KK. Relationship between urinary phthalate and bisphenol A concentrations and serum thyroid measures in US adults and adolescents from the National Health and Nutrition Examination Survey (NHANES) 2007–2008. Environ Health Perspect. 2011; 119:1396–402. https://doi.org/10.1289/ehp.1103582 PMid:21749963 PMCid:PMC3230451

  • Van dartel DA, Pennings JL, Hendriksen PJ, Van schooten FJ, Piersma AH. Early gene expression changes during embryonic stem cell differentiation into cardiomyocytes and their modulation by monobutyl phthalate. Reprod Toxicol. 2009; 27:93–102. https://doi.org/10.1016/j.reprotox.2008.12.009 PMid:19162170

  • Damante G, Tell G, DiLauro R. A unique combination of transcription factors controls differentiation of thyroid cells. Prog Nucleic Acid Res Mol Biol. 2001; 66:307–56.https://doi.org/10.1016/S0079-6603(00)66033-6

  • Francis-Lang H, Zannini M, De Felice M, Berlingieri MT, Fusco A, DiLauro R. Multiple mechanisms of interference between transformation and differentiation in thyroid cells.Mol Cell Biol. 1992; 12:5793–800. https://doi.org/10.1128/ MCB.12.12.5793 PMid:1448106 PMCid:PMC360519

  • Koch HM, Drexler H, Angerer J. An estimation of the daily intake of Di(2-Ethylhexyl)Phthalate (DEHP) and other phthalates in the general population. Int J Hyg Environ Health. 2003; 206:77–83. https://doi.org/10.1078/14384639-00205 PMid:12708228

  • Frederiksen H, Aksglaede L, Sorensen K, Skakkebaek NE, Juul A, Andersson AM. Urinary excretion of phthalate metabolites in 129 healthy Danish children and adolescents: Estimation of daily phthalate intake. Environ Res. 2011; 111:656–63. https://doi.org/10.1016/j.envres.2011.03.005 PMid:21429484

  • Aruldhas MM, Ramalingam N, Jaganathan A, Sashi AMJ, Stanley JA, Nagappan AS, Vasavan J, Kannan A, Seshadri VN. Gestational and neonatal-onset hypothyroidism alters androgen receptor status in rat prostate glands at adulthood.Prostate. 2010; 70:689–700. PMid:20033886

  • Liu C, Zhao L, Wei L, Li L. DEHP reduces thyroid hormones via interacting with hormone synthesis-related proteins, deiodinases, transthyretin, receptors, and hepatic enzymes in rats. Environ Sci Pollut Res Int. 2015; 22:12711–9. https:// doi.org/10.1007/s11356-015-4567-7 PMid:25913319

  • Stuart A, Oates E, Hall C, Grumbles R, Fernandez L, Taylor N, Puett D, Jin S. Identification of a point mutation in the thyrotropin receptor of the hyt/hyt hypothyroid mouse.Mol Endocrinol. 1994; 8:129–38. https://doi.org/10.1210/ mend.8.2.8170469 https://doi.org/10.1210/me.8.2.129

  • Shupnik MA, Ridgway EC, Chin WW. Molecular biology of thyrotropin. Endocr Rev. 1989; 10:459–75. https://doi.org/10.1210/edrv-10-4-459 PMid:2693083

  • Roelfsema F, Veldhuis JD. Thyrotropin secretion patterns in health and disease. Endocr Revs. 2013; 34:619–57. https:// doi.org/10.1210/er.2012-1076 PMid:23575764

  • Ishihara A, Sawatsubashi S, Yamauchi K. Endocrine disrupting chemicals: Interference of thyroid hormone binding to transthyretins and to thyroid hormone receptors.Mol Cell Endocrinol. 2003; 199:105–17. https://doi.org/10.1016/S0303-7207(02)00302-7

  • Sugiyama S, Shimada N, Miyoshi H, Yamauchi K. Detection of thyroid system-disrupting chemicals using in vitro and in vivo screening assays in Xenopus laevis. Toxicol Sci.2005; 88:367–74. https://doi.org/10.1093/toxsci/kfi330 PMid:16179385

  • Bizhanova A, Kopp P. Minireview: The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid.Endocrinology. 2009; 150:1084-90. https://doi.org/10.1210/ en.2008-1437 PMid:19196800 PMCid:PMC2654752

  • Kohn LD, Suzuki K, Nakazato M, Royaux I, Green ED.Effects of thyroglobulin and pendrin on iodide flux through the thyrocyte. Trends Endocrinol Metab. 2001; 12:10-16.https://doi.org/10.1016/S1043-2760(00)00337-4

  • Lin JD. Thyroglobulin and human thyroid cancer. Clin Chim Acta. 2008; 388:15–21. https://doi.org/10.1016/j.cca.2007.11.002 PMid:18060877

  • Kohn LD, Shimura H, Shimura Y, Hidaka A, Giuliani C, Napolitano G, Ohmori M, Laglia G, Saji M. The Thyrotropin Receptor. Vitamins and Hormones. 1995; 50:287–384.https://doi.org/10.1016/S0083-6729(08)60658-5

  • Kambe F and Seo H. Thyroid-specific transcription factors.Journal of Endocrinolgy. 1997; 44:775–84. https://doi.org/10.1507/endocrj.44.775

  • Dohan O, De la Vieja A and Paroder V. Molecular analysis of the sodium/iodide symporter: Characterization, regulation, and medical significance. Endocrine Reviews.2003; 24:48–77. https://doi.org/10.1210/er.2001-0029 PMid:12588808

  • Taki K, Kogai T, Kanamoto Y, Hershman JM, Brent GA.A thyroid-specific far-upstream enhancer in the human sodium/ iodide symporter gene requires Pax-8 binding and cyclic adenosine 3’,5’-monophosphate response elementlike sequence binding proteins for full activity and is differentially regulated in normal and thyroid cancer cells.Molecular Endocrinology. 2002; 16:2266–82. https://doi.org/10.1210/me.2002-0109 PMid:12351692


Abstract Views: 268

PDF Views: 2




  • Gestational Exposure to Di(2-Ethylhexyl)Phthalate Modifies the Expression Pattern of Genes Controlling Thyroid Hormone Biosynthesis in Puberal Rat Progeny

Abstract Views: 268  |  PDF Views: 2

Authors

V. Sambavi
Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600113, Tamil Nadu, India
M. M. Aruldhas
Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600113, Tamil Nadu, India
S. Suganya
Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600113, Tamil Nadu, India
P. Rajesh
Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600113, Tamil Nadu, India
E. Suthagar
Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600113, Tamil Nadu, India
A. K. Navin
Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600113, Tamil Nadu, India
N. Shobana
Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600113, Tamil Nadu, India
B. Ravi Sankar
Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600113, Tamil Nadu, India
R. Ilangovan
Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600113, Tamil Nadu, India

Abstract


Di(2-ethylhexyl) phthalate (DEHP), a plasticiser, is known to disrupt thyroid functions but the underlying molecular mechanism remains obscure. The present study was conducted testing the hypothesis that gestational exposure to DEHP may modify the expression of specific genes controlling biosynthesis and action of thyroid hormones in the male progeny at puberal age. Pregnant rats were administered with DEHP [1, 10 and 100 mg (in olive oil)/Kgb.wt./day] from embryonic day 9 to 21 through oral route. The pups were sacrificed on post-natal day 60. Enzyme Immuno Assay (EIA) revealed a dose-dependent decrease in serum 3,5,3’ triiodothyronine (T3) and L-thyroxine (T4) titres in DEHP-treated rats. Real-time RT-PCR and western blot analyses of thyroidal genes revealed decreased expression level of sodium/iodide symporter (Nis) and thyroid hormone receptor α (Trα), whereas the expression of thyroid stimulating hormone receptor (Tshr), thyroid hormone receptor β (Trβ) and pendrin (Pds) increased. While western blot detection showed decreased expression level of thyroperoxidase (Tpo), RTPCR data pointed out augmented expression. Western blot detection of transcriptional factors showed decreased expression levels of fork-headbox e1 (Foxe1) and haematopoietically expressed homeobox (Hhex), whereas thyroid transcription factor-1 (Ttf-1) and paired-box domain 8 (Pax8) increased. Our study demonstrates, for the first time, that gestational exposure to DEHPaffects the expression of genes controlling thyroid hormone synthesis in puberal rat progeny, and the hypothyroid state in these rats may be linked to decreased expression of Nis, Tpo, Foxe1 and Hhex.

Keywords


Pendrin, Sodium/Iodide Symporter, Thyroperoxidase, Thyrotrophin Receptor, Haematopoietically Expressed Homeobox.

References





DOI: https://doi.org/10.18519/jer%2F2016%2Fv20%2F165442