Skip to main content

DEHP reduces thyroid hormones via interacting with hormone synthesis-related proteins, deiodinases, transthyretin, receptors, and hepatic enzymes in rats


Di-(2-ethylhexyl) phthalate (DEHP) is used extensively in many personal care and consumer products, resulting in widespread nonoccupational human exposure through multiple routes and media. Limited studies suggest that exposure to DEHP may be associated with altered thyroid function, but detailed mechanisms are unclear. In order to elucidate potential mechanisms by which DEHP disturbs thyroid hormone homeostasis, Sprague-Dawley (SD) rats were dosed with DEHP by gavage at 0, 250, 500, and 750 mg/kg/day for 30 days and sacrificed within 24 h after the last dose. Gene expressions of thyroid hormone receptors, deiodinases, transthyretin, and hepatic enzymes were measured by RT-PCR; protein levels of transthyretin were also analyzed by Western blot. Results showed that DEHP caused histological changes in the thyroid and follicular epithelial cell hypertrophy and hyperplasia were observed. DEHP significantly reduced thyroid hormones (T3, T4) and thyrotropin releasing hormone (TRH) levels, whereas thyroid stimulating hormone (TSH) was not affected. After exposure to DEHP, biosynthesis of thyroid hormones was suppressed, and sodium iodide symporter (NIS) and thyroid peroxidase (TPO) levels were significantly reduced. Additionally, levels of deiodinases and transthyretin were also affected. TSH receptor (TSHr) level was downregulated, while TRH receptor (TRHr) level was upregulated. Metabolism of thyroid hormones was accelerated due to elevated gene expression of hepatic enzymes (UDPGTs and CYP2B1) by DEHP. Taken together, observed findings indicate that DEHP could reduce thyroid hormones through influencing biosynthesis, biotransformation, biotransport, receptor levels, and metabolism of thyroid hormones.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5


  • Barlow NJ, Phillips SL, Wallace DG, Sar M, Gaido KW, Foster PM (2003) Quantitative changes in gene expression in fetal Rat testes following exposure to Di(n-butyl) phthalate. Toxicol Sci 73:431–441

    Article  CAS  Google Scholar 

  • Bizhanova A, Kopp P (2009) Minireview: the sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid. Endocrinology 150:1084–1090

    Article  CAS  Google Scholar 

  • Breous E, Wenzel A, Loos U (2005) The promoter of the human sodium/iodide symporter responds to certain phthalate plasticisers. Mol Cell Endocrinol 244:75–78

    Article  CAS  Google Scholar 

  • Cheek AO, Kow K, Chen J, McLachlan JA (1999) Potential mechanisms of thyroid disruption in humans: interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid-binding globulin. Environ Health Perspect 107:273–278

    Article  CAS  Google Scholar 

  • Chopra IJ (1997) Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab 82:329–334

    Article  CAS  Google Scholar 

  • Coppola A, Hughes J, Esposito E, Schiavo L, Meli R, Diano S (2005) Suppression of hypothalamic deiodinase type II activity blunts TRH mRNA decline during fasting. FEBS Lett 579:4654–4658

    Article  CAS  Google Scholar 

  • DeGroot LJ (2006) Nonthyroidal illness syndrome. In: DeGroot LJ, Jameson JL (eds) Endocrinology, 5th edn. Elsevier, Philadelphia, pp 2101–2112

    Google Scholar 

  • Fekete C, Sarkar S, Christoffolete MA, Emerson C, Bianco AC, Lechan RM (2005) Bacterial lipopolysaccharide (LPS)-induced type 2 iodothyronine deiodinase (D2) activation in the mediobasal hypothalamus (MBH) is independent of the LPS-induced fall in serum thyroid hormone levels. Brain Res 1056:97–99

    Article  CAS  Google Scholar 

  • Ge RS, Chen GR, Dong Q, Akingbemi B, Sottas CM, Santos M, Sealfon SC, Bernard DJ, Hardy MP (2007) Biphasic effects of postnatal exposure to diethylhexylphthalate on the timing of puberty in male rats. J Androl 28:513–520

    Article  CAS  Google Scholar 

  • Howarth JA, Price SC, Dobrota M, Kentish PA, Hinton RH (2001) Effects on male rats of di-(2-ethylhexyl) phthalate and di-n-hexylphthalate administered alone or in combination. Toxicol Lett 121:35–43

    Article  CAS  Google Scholar 

  • Huang PC, Kuo PL, Guo YL, Liao PC, Lee CC (2007) Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. Hum Reprod 22:2715–2722

    Article  CAS  Google Scholar 

  • Ishihara A, Nishiyama N, Sugiyama S, Yamauchi K (2003) The effect of endocrine disrupting chemicals on thyroid hormone binding to Japanese quail transthyretin and thyroid hormone receptor. Gen Comp Endocrinol 134:36–43

    Article  CAS  Google Scholar 

  • Kester MH, Toussaint MJ, Punt CA, Matondo R, Aarnio AM, Darras VM, Everts ME, de Bruin A, Visser TJ (2009) Large induction of type III deiodinase expression after partial hepatectomy in the regenerating mouse and rat liver. Endocrinology 150:540–545

    Article  CAS  Google Scholar 

  • Kohn LD, Suzuki K, Nakazato M, Royaux I, Green ED (2001) Effects of thyroglobulin and pendrin on iodide flux through the thyrocyte. Trends Endocrinol Metab 12:10–16

    Article  CAS  Google Scholar 

  • Lee E, Ahn MY, Kim HJ, Kim IY, Han SY, Kang TS, Hong JH, Park KL, Lee BM, Kim HS (2007) Effect of Di (n-butyl) phthalate on testicular oxidative damage and antioxidant enzymes in hyperthyroid rats. Environ Toxicol 22:245–255

    Article  CAS  Google Scholar 

  • Lin JD (2008) Thyroglobulin and human thyroid cancer. Clin Chim Acta 388:15–21

    Article  CAS  Google Scholar 

  • Liu C, Shi Y, Li H, Wang Y, Yang K (2011) p, p’-DDE disturbs the homeostasis of thyroid hormones via thyroid hormone receptors, transthyretin, and hepatic enzymes. Horm Metab Res 43:391–396

    Article  CAS  Google Scholar 

  • Liu C, Ha M, Cui Y, Wang C, Yan M, Fu W, Quan C, Zhou J, Yang K (2012) JNK pathway decreases thyroid hormones via TRH receptor: a novel mechanism for disturbance of thyroid hormone homeostasis by PCB153. Toxicology 302:68–76

    Article  CAS  Google Scholar 

  • Liu C, Li L, Ha M, Qi S, Duan P, Yang K (2015) The PI3K/Akt and ERK pathways elevate thyroid hormone receptor β1 and TRH receptor to decrease thyroid hormones after exposure to PCB153 and p, p’-DDE. Chemosphere 118:229–238

    Article  CAS  Google Scholar 

  • Meeker JD, Calafat AM, Hauser R (2007) Di (2-ethylhexyl) phthalate metabolites may alter thyroid hormone levels in men. Environ Health Perspect 115:1029–1034

    Article  CAS  Google Scholar 

  • Mendiola J, Jørgensen N, Andersson AM, Calafat AM, Silva MJ, Redmon JB, Sparks A, Drobnis EZ, Wang C, Liu F, Swan SH (2011) Associations between urinary metabolites of di(2-ethylhexyl) phthalate and reproductive hormones in fertile men. Int J Androl 34:369–378

    Article  CAS  Google Scholar 

  • SCMPMD, European Union Scientific Committee on Medicinal Products and Medical Devices (2002) Opinion on medical devices containing DEHP Plasticised PVC; neonates and other groups possibly at risk from DEHP toxicity. Doc.SANCO/SCMPMD/2002/0010 Final. European Commission, Brussels

  • Webb CM, McNabb FM (2008) Polychlorinated biphenyl effects on avian hepatic enzyme induction and thyroid function. Gen Comp Endocrinol 155:650–657

    Article  CAS  Google Scholar 

  • Wenzel A, Franz C, Breous E, Loos U (2005) Modulation of iodide uptake by dialkyl phthalate plasticisers in FRTL-5 rat thyroid follicular cells. Mol Cell Endocrinol 244:63–71

    Article  CAS  Google Scholar 

  • Wirth JJ, Rossano MG, Potter R, Puscheck E, Daly DC, Paneth N, Krawetz SA, Protas BM, Diamond MP (2008) A pilot study associating urinary concentrations of phthalate metabolites and semen quality. Syst Biol Reprod Med 54:143–154

    Article  CAS  Google Scholar 

  • Zhou T, Ross DG, DeVito MJ, Crofton KM (2001) Effects of short-term in vivo exposure to polybrominated diphenyl ethers on thyroid hormones and hepatic enzyme activities in weanling rats. Toxicol Sci 61:76–82

    Article  CAS  Google Scholar 

  • Zoeller RT (2005) Environmental chemicals as thyroid hormone analogues: new studies indicate that thyroid hormone receptors are targets of industrial chemicals? Mol Cell Endocrinol 242:10–15

    Article  CAS  Google Scholar 

Download references


This work was supported by grants from the Chongqing Population and Family Planning Science and Technology Research Institute (CSTC-JBKY-1701401).

Conflict of interest


Author information

Authors and Affiliations


Corresponding author

Correspondence to Lianbing Li.

Additional information

Responsible editor: Markus Hecker

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liu, C., Zhao, L., Wei, L. et al. DEHP reduces thyroid hormones via interacting with hormone synthesis-related proteins, deiodinases, transthyretin, receptors, and hepatic enzymes in rats. Environ Sci Pollut Res 22, 12711–12719 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • DEHP
  • Thyroid hormone
  • Receptor
  • Hepatic enzyme
  • Deiodinase
  • Transthyretin
  • Biosynthesis