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Structure–activity relations in binding of perfluoroalkyl compounds to human thyroid hormone T3 receptor

  • Molecular Toxicology
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Abstract

Perfluoroalkyl compounds (PFCs) have been shown to disrupt thyroid functions through thyroid hormone receptor (TR)-mediated pathways, but direct binding of PFCs with TR has not been demonstrated. We investigated the binding interactions of 16 structurally diverse PFCs with human TR, their activities on TR in cells, and the activity of perfluorooctane sulfonate (PFOS) in vivo. In fluorescence competitive binding assays, most of the 16 PFCs were found to bind to TR with relative binding potency in the range of 0.0003–0.05 compared with triiodothyronine (T3). A structure–binding relationship for PFCs was observed, where fluorinated alkyl chain length longer than ten, and an acid end group were optimal for TR binding. In thyroid hormone (TH)-responsive cell proliferation assays, PFOS, perfluorohexadecanoic acid, and perfluorooctadecanoic acid exhibited agonistic activity by promoting cell growth. Furthermore, similar to T3, PFOS exposure promoted expression of three TH upregulated genes and inhibited three TH downregulated genes in amphibians. Molecular docking analysis revealed that most of the tested PFCs efficiently fit into the T3-binding pocket in TR and formed a hydrogen bond with arginine 228 in a manner similar to T3. The combined in vitro, in vivo, and computational data strongly suggest that some PFCs disrupt the normal activity of TR pathways by directly binding to TR.

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References

  • Benninghoff AD, Bisson WH, Koch DC, Ehresman DJ, Kolluri SK, William DE (2011) Estrogen-like activity of perfluoroalkyl acids in vivo and interaction with human and rainbow trout estrogen receptors in vitro. Toxicol Sci 120(1):42–58

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bjork JA, Butenhoff JL, Wallace KB (2011) Multiplicity of nuclear receptor activation by PFOA and PFOS in primary human and rodent hepatocytes. Toxicology 288(1):8–17

    Article  CAS  PubMed  Google Scholar 

  • Boas M, Feldt-Rasmussen U, Skakkebaek NE, Main KM (2006) Environmental chemicals and thyroid function. Eur J Endocrinol 154(5):599–611

    Article  CAS  PubMed  Google Scholar 

  • Calafat AM, Wong LY, Kuklenyik Z, Reidy JA, Needham LL (2007) Polyfluoroalkyl chemicals in the U.S. population: data from the national health and nutrition examination survey (NHANES) 2003–2004 and comparisons with NHANES 1999–2000. Environ Health Perspect 115(11):1596–1602

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chang SC, Thibodeaux JR, Eastvold ML, Ehresman DJ, Bjork JA, Froehlich JW, Lau C, Singh RJ, Wallace KB, Butenhoff JL (2008) Thyroid hormone status and pituitary function in adult rats given oral doses of perfluorooctane sulfonate (PFOS). Toxicology 243(3):330–339

    Article  CAS  PubMed  Google Scholar 

  • Chen YM, Guo LH (2009) Fluorescence study on site-specific binding of perfluoroalkyl acids to human serum albumin. Arch Toxicol 83(3):255–261

    Article  CAS  PubMed  Google Scholar 

  • Cheng Y, Cui Y, Chen HM, Xie WP (2011) Thyroid disruption effects of environmental level perfluorooctane sulfonates (PFOS) in Xenopus laevis. Ecotoxicology 20(8):2069–2078

    Article  CAS  PubMed  Google Scholar 

  • Chiellini G, Apriletti JW, Yoshihara HA, Baxter JD, Ribeiro RCJ, Scanlan TS (1998) A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor. Chem Biol 5(6):299–306

    Article  CAS  PubMed  Google Scholar 

  • Dallaire R, Dewailly E, Pereg D, Dery S, Ayotte P (2009) Thyroid function and plasma concentrations of polyhalogenated compounds in inuit adults. Environ Health Perspect 117(9):1380–1386

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Domingo JL, Ericson-Jogsten I, Perello G, Nadal M, Van Bavel B, Karrman A (2012) Human exposure to perfluorinated compounds in catalonia, spain: contribution of drinking water and fish and shellfish. J Agric Food Chem 60(17):4408–4415

    Article  CAS  PubMed  Google Scholar 

  • Du G, Hu J, Huang H, Qin Y, Han X, Wu D, Song L, Xia Y, Wang X (2013) Perfluorooctane sulfonate (PFOS) affects hormone receptor activity, steroidogenesis, and expression of endocrine-related genes in vitro and in vivo. Environ Toxicol Chem 32(2):353–360

    Article  CAS  PubMed  Google Scholar 

  • Fromme H, Tittlemier SA, Voelkel W, Wilhelm M, Twardella D (2009) Perfluorinated compounds-exposure assessment for the general population in western countries. Int J Hyg Environ Health 212(3):239–270

    Article  CAS  PubMed  Google Scholar 

  • Gao Y, Li X, Guo LH (2013) Assessment of estrogenic activity of perfluoroalkyl acids based on ligand-induced conformation state of human estrogen receptor. Environ Sci Technol 47(1):634–641

    Article  CAS  PubMed  Google Scholar 

  • Gutleb AC, Meerts IA, Bergsma JH, Schriks M, Murk AJ (2005) T-Screen as a tool to identify thyroid hormone receptor active compounds. Environ Toxicol Pharmacol 19(2):231–238

    Article  CAS  PubMed  Google Scholar 

  • Gutshall DM, Pilcher GD, Langley AE (1989) Mechanism of the serum thyroid-hormone lowering effect of perfluoronormaldecanoic acid (PFDA) in rats. J Toxicol Environ Health 28(1):53–65

    Article  CAS  PubMed  Google Scholar 

  • Harvey CB, Willians GR (2002) Mechanism of thyroid hormone action. Thyroid 12:441–448

    Article  CAS  PubMed  Google Scholar 

  • Inoue A, Yamamoto N, Morisawa Y, Uchimoto T, Yukioka M, Morisawa S (1989) Unesterified long-chain fatty-acids inhibit thyroid-hormone binding to the nuclear receptor-solubilized receptor and the receptor in cultured-cells. Eur J Biochem 183(3):565–572

    Article  CAS  PubMed  Google Scholar 

  • Kitamura S, Jinno N, Ohta S, Kuroki H, Fujimoto N (2002) Thyroid hormonal activity of the flame retardants tetrabromobisphenol a and tetrachlorobisphenol a. Biochem Biophys Res Commun 293(1):554–559

    Article  CAS  PubMed  Google Scholar 

  • Lau C (2012) Perfluorinated compounds. EXS 101:47–86

    PubMed  Google Scholar 

  • Lau C, Butenhoff JL, Rogers JM (2004) The developmental toxicity of perfluoroalkyl acids and their derivatives. Toxicol Appl Pharmacol 198(2):231–241

    Article  CAS  PubMed  Google Scholar 

  • Lau C, Anitole K, Hodes C, Lai D, Pfahles-Hutchens A, Seed J (2007) Perfluoroalkyl acids: a review of monitoring and toxicological findings. Toxicol Sci 99(2):366–394

    Article  CAS  PubMed  Google Scholar 

  • Li QL, Yamamoto N, Morisawa S, Inoue A (1993) Fatty acyl-CoA binding-activity of the nuclear thyroid-hormone receptor. J Cell Biochem 51(4):458–464

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Wang J, Fang X, Zhang H, Dai J (2011) The thyroid-disrupting effects of long-term perfluorononanoate exposure on zebrafish (Danio rerio). Ecotoxicology 20(1):47–55

    Article  PubMed  Google Scholar 

  • Long MH, Ghisari M, Bonefeld-Jorgensen EC (2013) Effects of perfluoroalkyl acids on the function of the thyroid hormone and the aryl hydrocarbon receptor. Environ Sci Pollut Res Int 20(11):8045–8056

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Espinosa MJ, Mondal D, Armstrong B, Bloom MS, Fletcher T (2012) Thyroid function and perfluoroalkyl acids in children living near a chemical plant. Environ Health Perspect 120(7):1036–1041

    Article  PubMed Central  PubMed  Google Scholar 

  • Lou QQ, Zhang YF, Zhou Z, Shi YL, Ge YN, Ren DK, Xu HM, Zhao YX, Wei WJ, Qin ZF (2013) Effects of perfluorooctanesulfonate and perfluorobutanesulfonate on the growth and sexual development of Xenopus laevis. Ecotoxicology 22(7):1133–1144

    Article  CAS  PubMed  Google Scholar 

  • Luebker DJ, Hansen KJ, Bass NM, Butenhoff JL, Seacat AM (2002) Interactions of flurochemicals with rat liver fatty acid-binding protein. Toxicology 176(3):175–185

    Article  CAS  PubMed  Google Scholar 

  • Melzer D, Rice N, Depledge MH, Henley WE, Galloway TS (2010) Association between serum perfluorooctanoic acid (PFOA) and thyroid disease in the U.S. national health and nutrition examination survey. Environ Health Perspect 118(5):686–692

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nieuwkoop PD, Faber J (1994) Normal table of Xenopus laevis (Daudin). Garland, New York

    Google Scholar 

  • Norman MF, Lavin TN (1989) Antagonism of thyroid-hormone action by amiodarone in rat pituitary-tumor cells. J Clin Invest 83(1):306–313

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Olsen GW, Burris JM, Burlew MM, Mandel JH (2003) Epidemiologic assessment of worker serum perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) concentrations and medical surveillance examinations. J Occup Environ Med 45(3):260–270

    Article  CAS  PubMed  Google Scholar 

  • Olsen GW, Burris JM, Ehresman DJ, Froehlich JW, Seacat AM, Butenhoff JL, Zobel LR (2007) Half-life of serum elimination of perfluorooctanesulfonate, perfluorohexanesulfonate, and perfluorooctanoate in retired fluorochemical production workers. Environ Health Perspect 115(9):1298–1305

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ren XM, Guo LH, Gao Y, Zhang BT, Wan B (2013) Hydroxylated polybrominated diphenyl ethers exhibit different activities on thyroid hormone receptors depending on their degree of bromination. Toxicol Appl Pharmacol 268(3):256–263

    Article  CAS  PubMed  Google Scholar 

  • Smith DS (1977) Enhancement fluoro-immunoassay of thyroxine. FEBS Lett 77(1):25–27

    Article  CAS  PubMed  Google Scholar 

  • Stahl TMD, Brunn H (2011) Toxicology of perfluorinated compounds. Environ Sci Eur 23:38–89

    Article  Google Scholar 

  • Steenland K, Fletcher T, Savitz DA (2010) Epidemiologic evidence on the health effects of perfluorooctanoic acid (PFOA). Environ Health Perspect 118(8):1100–1108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Takacs ML, Abbott BD (2007) Activation of mouse and human peroxisome proliferator-activated receptors (alpha, beta/delta, gamma) by perfluorooctanoic acid and perfluorooctane sulfonate. Toxicol Sci 95(1):108–117

    Article  CAS  PubMed  Google Scholar 

  • Vongphachan V, Cassone CG, Wu D, Chiu S, Crump D, Kennedy SW (2011) Effects of perfluoroalkyl compounds on mRNA expression levels of thyroid hormone-responsive genes in primary cultures of avian neuronal cells. Toxicol Sci 120(2):392–402

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wagner RL, Apriletti JW, McGrath ME, West BL, Baxter JD, Fletterick RJ (1995) A structural role for hormone in the thyroid hormone receptor. Nature 378:690–697

    Article  CAS  PubMed  Google Scholar 

  • Weiss JM, Andersson PL, Lamoree MH, Leonards PEG, van Leeuwen SPJ, Hamers T (2009) Competitive binding of poly- and perfluorinated compounds to the thyroid hormone transport protein transthyretin. Toxicol Sci 109(2):206–216

    Article  CAS  PubMed  Google Scholar 

  • Wolf CJ, Takacs ML, Schmid JE, Lau C, Abbott BD (2008) Activation of mouse and human peroxisome proliferator-activated receptor alpha by perfluoroalkyl acids of different functional groups and chain lengths. Toxicol Sci 106(1):162–171

    Article  CAS  PubMed  Google Scholar 

  • Wolf CJSJ, Lau C, Abbott BD (2012) Activation of mouse and human peroxisome proliferator-activated receptor-alpha (PPARα) by perfluoroalkyl acids (PFCAs): further investigation of C4–C12 compounds. Reprod Toxicol 33(4):546–551

    Article  CAS  PubMed  Google Scholar 

  • Yu WG, Liu W, Jin YH (2009a) Effects of perfluorooctane sulfonate on rat thyroid hormone biosynthesis and metabolism. Environ Toxicol Chem 28(5):990–996

    Article  CAS  PubMed  Google Scholar 

  • Yu WG, Liu W, Jin YH, Liu XH, Wang FQ, Liu L, Nakayama SF (2009b) Prenatal and postnatal impact of perfluorooctane sulfonate (PFOS) on rat development: a cross-foster study on chemical burden and thyroid hormone system. Environ Sci Technol 43(21):8416–8422

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Ren XM, Guo LH (2013) Structure-based investigation on the interaction of perfluorinated compounds with human liver fatty acid binding protein. Environ Sci Technol 47(19):11293–11301

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Basic Research Program of China (2011CB936001), National Natural Science Foundation of China (21077125), Research Center of Eco-environmental Sciences (YSW2013A01), and Young Scientists Fund of RCEES (RCEES-QN-20130004F).

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None of the authors have any conflict of interest to declare.

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Authors and Affiliations

  1. State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Centre for Eco-environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, P.O. Box 2871, Beijing, 100085, China

    Xiao-Min Ren, Yin-Feng Zhang, Liang-Hong Guo, Zhan-Fen Qin, Qi-Yan Lv & Lian-Ying Zhang

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  1. Xiao-Min Ren
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  2. Yin-Feng Zhang
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Correspondence to Liang-Hong Guo or Zhan-Fen Qin.

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Ren, XM., Zhang, YF., Guo, LH. et al. Structure–activity relations in binding of perfluoroalkyl compounds to human thyroid hormone T3 receptor. Arch Toxicol 89, 233–242 (2015). https://doi.org/10.1007/s00204-014-1258-y

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  • DOI: https://doi.org/10.1007/s00204-014-1258-y

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