This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Interference with thyroid serum binding protein transthyretin and subsequent adverse human neurodevelopmental toxicity
Point of Contact
- Erik Janus
- Timo Hamers
- Kevin Crofton
- Allie Always
|Author status||OECD status||OECD project||SAAOP status|
|Open for adoption||Under Development||1.41||Included in OECD Work Plan|
This AOP was last modified on April 05, 2021 18:16
|Binding, Transthyretin in serum||September 16, 2017 10:16|
|Displacement, Serum thyroxine (T4) from transthyretin||December 17, 2016 17:03|
|Increased, Free serum thyroxine (T4)||September 16, 2017 10:16|
|Increased, Uptake of thyroxine into tissue||December 17, 2016 17:04|
|Increased, Clearance of thyroxine from serum||January 26, 2021 10:41|
|Thyroxine (T4) in serum, Decreased||November 14, 2020 02:14|
|Thyroxine (T4) in neuronal tissue, Decreased||April 04, 2019 09:13|
|Hippocampal gene expression, Altered||August 11, 2018 09:26|
|Hippocampal anatomy, Altered||August 11, 2018 09:36|
|Hippocampal Physiology, Altered||August 11, 2018 09:41|
|Cognitive Function, Decreased||August 09, 2018 11:55|
|Binding, Transthyretin in serum leads to Displacement, Serum thyroxine (T4) from transthyretin||December 09, 2020 14:51|
|Displacement, Serum thyroxine (T4) from transthyretin leads to Increased, Free serum thyroxine (T4)||December 09, 2020 14:51|
|Increased, Free serum thyroxine (T4) leads to Increased, Clearance of thyroxine from serum||January 26, 2021 10:51|
|Increased, Clearance of thyroxine from serum leads to T4 in serum, Decreased||January 26, 2021 10:42|
|Halogenated phenols||March 09, 2017 23:55|
|Polychlorinated biphenyl||November 29, 2016 18:42|
|Polychlorinated dibenzodioxins||March 09, 2017 20:38|
|Polybrominated diphenyl ethers||March 09, 2017 20:40|
|Isoflavones||March 09, 2017 21:14|
|Perflourinated chemicals||March 09, 2017 22:36|
|Phthalates||March 09, 2017 22:37|
|Tetrabromobisphenol A||July 20, 2018 05:36|
|Clonixin||March 10, 2017 00:50|
|Meclofenamic acid||March 10, 2017 00:51|
|2,6-dinitro-p-cresol||March 10, 2017 00:53|
|Triclopyr||March 10, 2017 00:59|
|2,2',4,4'-Tetrahydroxybenzophenone||November 29, 2016 18:42|
This AOP describes adverse neurodevelopemental effects that may result from xenobiotic interference with thyroid serum binding protein transthyretin (TTR). Binding of TTR by a xenobiotic (the MIE) during certain developmental windows may disrupt the normal neurodevelopment of mammals through a transient increase in free thyroxine (T4) levels, permitting increased tissue uptake of thyroid hormone (TH), followed by a decrease in both serum and neuronal tissue concentrations. Due to the highly conserved nature of the TTR protein, birds, reptiles, fish and amphibians can also express TTR and be impacted by interference by xeniobiotics. The adverse consequences of TH insufficiency depend both on the severity and developmental timing, indicating that exposure to thyroid toxicants may produce different effects at different developmental windows of exposure. This AOP discusses the potential for developmental TTR interference to adversely impact hippocampal anatomy, function, gene expression and, ultimately, cognitive function.
Transthyretin is one of three ancient, highly conserved serum binding proteins that collectively act to transport thyroid hormone (TH) and thus help maintain normal homeostasis via modulation of the hypothalamic/pituitary/thyroid axis. In addition to TTR, albumin (ALB) and thyroxine-binding globulin (TBG) also serve to transport TH in serum and the relative contribution of each binding protein differs across species. In man, TBG has the greatest affinity for thyroxine (T4), followed by TTR and ALB shows the lowest affinity for T4 while prevalence in serum is the opposite, while in rat, TTR is the major serum transport protein (as rats lack TBG). Interference with TH serum binding proteins is one of several mechanisms through which xenobiotics and environmental contaminants can disrupt normal thyroid endocrine function ("thyroid disruptors") and development of this AOP is expected to contribute towards a fuller understanding of the mechanism of TTR interference and how it may be measured in vitro as part of a larger screening battery for thyroid toxicants.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||957||Binding, Transthyretin in serum||Binding, Transthyretin in serum|
|2||KE||958||Displacement, Serum thyroxine (T4) from transthyretin||Displacement, Serum thyroxine (T4) from transthyretin|
|3||KE||959||Increased, Free serum thyroxine (T4)||Increased, Free serum thyroxine (T4)|
|4||KE||960||Increased, Uptake of thyroxine into tissue||Increased, Uptake of thyroxine into tissue|
|5||KE||961||Increased, Clearance of thyroxine from serum||Increased, Clearance of thyroxine from serum|
|6||KE||281||Thyroxine (T4) in serum, Decreased||T4 in serum, Decreased|
|7||KE||280||Thyroxine (T4) in neuronal tissue, Decreased||T4 in neuronal tissue, Decreased|
|8||KE||756||Hippocampal gene expression, Altered||Hippocampal gene expression, Altered|
|9||KE||757||Hippocampal anatomy, Altered||Hippocampal anatomy, Altered|
|10||KE||758||Hippocampal Physiology, Altered||Hippocampal Physiology, Altered|
|11||AO||402||Cognitive Function, Decreased||Cognitive Function, Decreased|
Relationships Between Two Key Events (Including MIEs and AOs)
|Binding, Transthyretin in serum leads to Displacement, Serum thyroxine (T4) from transthyretin||adjacent||Moderate||Low|
|Displacement, Serum thyroxine (T4) from transthyretin leads to Increased, Free serum thyroxine (T4)||adjacent||Moderate||Low|
|Increased, Free serum thyroxine (T4) leads to Increased, Clearance of thyroxine from serum||adjacent||Moderate||Low|
|Increased, Clearance of thyroxine from serum leads to T4 in serum, Decreased||adjacent||Moderate||Low|
|Polychlorinated dibenzodioxins||Not Specified|
|Polybrominated diphenyl ethers||High|
|Tetrabromobisphenol A||Not Specified|
|Meclofenamic acid||Not Specified|
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Molecular Initiating Event Summary, Key Event Summary Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.
In vivo evidence for MIE
Kohrle et al (1989) added 10 μmol/L 3-methyl-4’,6-dihydroxy-3’,5-dibromo-flavone (EMD 21388) to pooled rat serum and measured displacement of [125I]-T4 from TTR. EMD21388 was synthesized using “molecular drug design” (and resembles T4) to help confirm previous findings that certain flavonoid deiodinase inhibitors also displaced thyroxine (T4) for TTR (or T3-binding prealbumin). Displacement of [125I] from TTR in rat serum was analyzed by gel electrophoresis (PAGE) and individual serum samples were assayed for T3 and T4 content by RIA and % free TH by equilibrium dialysis (lower limit of detectability 0.3 ug/dL for T4). There was a significant increase in % free T4 (0.031 to 0.124), which was dose-dependent and resulted in complete inhibition of [125I]-T4/TTR at 8-10 umol (radiolabeled TH were displaced primarily to albumin).
One to 4 hours following ip delivery of 2 μmol/100 g BW to euthyroid Sprague-Dawley rats (a dose that is 1000x higher than daily T4 production in rat), inhibition of [125I]-T4/TTR binding was observed. T4 decreased from 5.6 to 2.3 ug/dl after 1 hour and remained low while % free T4 increased from 0.035 to 0.091 and remained high; however, free T4 did not change. TSH decreased to very low values after 2 hours and increased slightly, despite no change in the free TH concentration (hypothyroid rats did not show changes in serum TSH following EMD 21388 administration). Lueprasitsakul et al (1990) performed a series of experiments with Sprague-Dawley rats using smaller doses of EMD 21388 (up to 2 μmol /100 g BW) and the same measurement methods (RIA, equilibrium dialysis). Administration of 2 μmol of EMD 21388 inhibited [125I]-T4/TTR binding within a few minutes, displacing [125I] to albumin to a greater degree of magnitude, due to slight differences in preparing the EMD 21388 solutions. Dose-dependent decreases in displacement were found with decreasing dose.
Following a single dose of 2 μmol, a significant decrease was seen in total serum T4 after 10 minutes that persisted, % free T4 also increased immediately (peaked after 10 minutes) and stayed elevated and a significant increase in free T4 was observed within three minutes that stayed elevated for 60 minutes. Following a single dose of 0.3 μmol, decreased [125I]-T4/TTR binding was observed reaching a nadir after 10 minutes and slowly recovering over the 180-minute experiment. The % free T4 and serum free T4 both increased and returned to normal after 180 minutes as well while total serum T4 hit a nadir after 10 minutes and mostly recovered. Serum TSH decreased after 20 minutes, significantly at the nadir hit after 60 minutes.
Considerations for Potential Applications of the AOP (optional)
Abdalla, S.M. and A.C. Bianco. (2014) Defending plasma T3 is a biological priority. Clin. Endocrinol. (Oxf) 81(5): 633-641.
Alshehri, B., D’Souza, D. G., Lee, J. Y., Petratos, S., & Richardson, S. J. (2015). The Diversity of Mechanisms Influenced by Transthyretin in Neurobiology: Development, Disease and Endocrine Disruption. Journal of Neuroendocrinology, 27(5), 303–323. http://doi.org/10.1111/jne.12271
Andrea, T.A., R.R. Cavalieri, I.D. Goldfine and E.C. Jorgensen (1980) Binding of thyroid hormones and analogues to the human plasma protein prealbumin. Biochemistry 19(1): 55-63.
Aqai, P., C. Fryganas, M. Mizuguchi, W. Haasnoot and M.W. Nielen. (2012) Triple bioaffinity mass spectrometry concept for thyroid transporter ligands. Anal. Chem. 84(15): 6488-6493.
Athanasiadou, M., S.N. Cuadra, G. Marsh, A> Bergman, and K. Jakobsson. (2008) Polybrominated diphenyl ethers (PBDEs) and bioaccumulative hydroxylated PBDE metabolites in young humans from Managua, Nicaragua. Environ. Health Perspect. 116(3): 400-408.
Barter, R.A. and C.D. Klaassen. (1994) Reduction of thyroid hormone levels and alteration of thyroid function by four representative UDP-glucuronosyltransferase inducers in rats. Toxicol. Appl. Pharmacol. 128(1): 9-17.
Blake, C.C., J.M. Burridge and S.J. Oatley. (1978) X-ray analysis of thyroid hormone binding to prealbumin. Biochem Soc. Trans. 6(6): 1114-1118.
Bloom, M.S., J.E. Vena, J.R. Olson and P.J. Kostyniak. (2009) Assessment of polychlorinated biphenyl congeners, thyroid stimulating hormone, and free thyroxine among New York state anglers. Int. J. Hyg. Environ. Health 212(6): 599-611.
Branchi, I., E. Alleva and L.G. Costa. (2002) Effects of perinatal exposure to a polybrominated diphenyl ether (PBDE 99) on mouse neurobehavioural development. Neurotoxicology 23(3): 375-384.
Brouwer, a, & van den Berg, K. J. (1986). Binding of a metabolite of 3,4,3’,4'-tetrachlorobiphenyl to transthyretin reduces serum vitamin A transport by inhibiting the formation of the protein complex carrying both retinol and thyroxin. Toxicology and Applied Pharmacology, 85(3), 301–312.
Calvo, R.M., E. Jauniaux, B. Gulbis, M. Asuncion, C. Gervy, B. Contempre and G. Morreale de Escobar. (2002) Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development. J. Clin. Endocrinol. Metab. 87(4); 1768-1777.
Cao, J., L.H. Guo, B. Wan and Y. Wei. (2011) In vitro fluorescence displacement investigation of thyroxine transport disruption by bisphenol A. J. Environ Sci, (China) 23(2): 315-321.
Cao, J., Y. Lin, L.H. Guo, A.Q. Zhang, Y. Wei and Y. Yang. (2010) Structure-based investigation on the binding interaction of hydroxylated polybrominated diphenyl ethers with thyroxine transport proteins. Toxicology 277(1-3): 20-28.
Chan, S.Y., J.A. Franklyn, H.N. Pemberton, J.N. Bulmer, T.J. Visser, C.J. McCabe and M.D. Kilby. (2006) Monocarboxylate transporter 8 expression in the human placenta: the effects of severe intrauterine growth restriction. J. Endocrinol. 189(3): 465-471.
Chan, S., S. Kachilele, C.J. McCabe, L.A. Tannahill, K. Boelaert, N.J. Gittoes, T.J. Visser, J.A. Franklyn and M.D. Kilby. (2002) Early expression of thyroid hormone deiodinases and receptors in human fetal cerebral cortex. Brain Res. Dev. Brain Res. 138(2): 109-116.
Chang, S.C., J.R. Thibodeaux, M.L. Eastvold, D.J. Ehresman, J.A. Bjork, J.W. Froehlich, C. Lau, R.J. Singh, K.B. Wallace and J.L. Butenhoff. (2008) Thyroid hormone status and pituitary function in adult rats given oral doses of perfluorooctanesulfonate (PFOS). Toxicology 243(3): 330-339.
Chanoine, J.-P., Alex, S., Fang, S. L., Stone, S., Leonard, J. L., Kohrle, J., & Braverman, L. E. (1992). Role of transthyretin in the transport of thyroxine from the blood to the choroid plexus, the cerebrospinal fluid and the brain. Endocrinology, 130(2), 933–938.
Chauhan, K. R., Kodavanti, P. R. S., & McKinney, J. D. (2000). Assessing the Role of ortho-Substitution on Polychlorinated Biphenyl Binding to Transthyretin, a Thyroxine Transport Protein. Toxicology and Applied Pharmacology, 162(1), 10–21. http://doi.org/10.1006/taap.1999.8826
Cheek, A.O., K. Kow, J. Chen and J.A. McLachlan. (1999) Potential mechanisms of thyroid disruption in humans: interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid-binding globulin. Environ. Health Perspect. 107(4): 273-278.
Chevrier, J., K.G. Harley, A. Bradman, M. Gharbi, A. Sjodin and B. Eskenazi. (2010) Polybrominated diphenyl ether (PBDE) flame retardants and thyroid hormone during pregnancy. Environ. Health Perspect. 118(10) : 1444-1449.
Chopra, I.J., P. Taing and L. Mikus. (1996) Direct determination of free triiodothyronine (T3) in undiluted serum by equilibrium dialysis/radioimmunoassay (RIA). Thyroid 6(4): 255-259.
Costa, L.G., R. de Laat, S. Tagliaferri and C. Pellacani. (2014) A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity. 230(2): 282-294.
Dallaire, R., G. Muckle, E. Dewailly, S.W. Jacobson, J.L. Jacobson, T.M. Sandanger, C.D. Sandau and P. Ayotte. (2009a) Thyroid hormone levels of pregnant inuit women and their infants exposed to environmental contaminants. Environ. Health Perspect. 117(6): 1014-1020.
Dallaire, R., E. Dewailly, D. Pereg, S. Dery and P. Ayotte. (2009b) Thyroid function and plasma concentrations of polyhalogenated compounds in Inuit adults. Environ. Health Perspect. 117(9): 1380-1386.
Darnerud, P.O., D. Morse, E. Klasson-Wehler and A Brouwer. (1996) Binding of a 3,3', 4,4'-tetrachlorobiphenyl (CB-77) metabolite to fetal transthyretin and effects on fetal thyroid hormone levels in mice. Toxicology 106(1-3): 105-114.
De Escobar, G.M., M.J. Obregon and F.E. del Rey. (2004) Maternal thyroid hormones early in pregnancy and fetal brain development. Best Pract. Res. Clin. Endocrinol. Metab. 18(2): 225-248.
Dirinck, E., A.C. Dirtu, G. Malarvanna, A. Covaci, P.G. Jorens and L.F. Van Gall. (2016) A Preliminary Link between Hydroxylated Metabolites of Polychlorinated Biphenyls and Free Thyroxin in Humans. Int. J. Environ. Res. Public Health 13(4): 421.
Eguchi, A., K. Nomiyama, N. Minh Tue, P.T. Trang, P. Hung Viet, S. Takahashi and S. Tanabe. (2015) Residue profiles of organohalogen compounds in human serum from e-waste recycling sites in North Vietnam: Association with thyroid hormone levels. Environ. Res. 137: 440-449.
Emerson, C.H., J.H. Cohen III, R.A Yung, S. Alex and S.L. Fang. (1990) Gender-related differences of serum thyroxine-binding proteins in the rat. Acta Endocrinol. (Copenh) 123(1): 72-78.
Erratico, C.A., A. Steitz and S.M. Bandiera. (2013) Biotransformation of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) by human liver microsomes: identification of cytochrome P450 2B6 as the major enzyme involved. Chem. Res. Toxicol. 26(5): 721-731.
Erratico, C.A., S.C. Moffatt and S.M. Bandiera. (2011) Comparative oxidative metabolism of BDE-47 and BDE-99 by rat hepatic microsomes. Toxicol. Sci. 123(1): 37-47.
Eskenazi, B., J. Chevrier, S.A. Rauch, K. Kogul, K.G. Harley, C. Johnson, C. Trujillo, A. Sjodin and A. Bradman. (2013) In utero and childhood polybrominated diphenyl ether (PBDE) exposures and neurodevelopment in the CHAMACOS study. 121(2) : 257-262.
Feo, M.L., M.S. Gross, B.P. McGarrigle, E. Eljarrat, D. Barcelo, D.S. Aga and J.R. Olson. (2013) Biotransformation of BDE-47 to potentially toxic metabolites is predominantly mediated by human CYP2B6. Environ. Health Persepct. 121(4): 440-446.
Ferguson, R.N., H. Edelhoch, H.A. Saroff, J. Robbins and H.J. Cahnmann (1975) Negative cooperativity in the binding of thyroxine to human serum prealbumin. Preparation of tritium-labeled 8-anilino-1-naphthalenesulfonic acid. Biochemistry 14(2): 282-289.
Friesema EC, Jansen J, Jachtenberg JW, Visser WE, Kester MH, Visser TJ 2008 Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Molecular endocrinology (Baltimore, Md 22:1357-1369
Friesema EC, Kuiper GG, Jansen J, Visser TJ, Kester MH 2006 Thyroid hormone transport by the human monocarboxylate transporter 8 and its rate-limiting role in intracellular metabolism. Molecular endocrinology (Baltimore, Md 20:2761-2772
Friesma, E.C., J. Jansen and T.J. Visser. (2005) Thyroid hormone transporters. Biochem. Soc. Trans. 33(part 1): 228-232.
Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ 2003 Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 278:40128-40135
Grimm, F. a., Lehmler, H. J., He, X., Robertson, L. W., & Duffel, M. W. (2013). Sulfated metabolites of polychlorinated biphenyls are high-affinity ligands for the thyroid hormone transport protein transthyretin. Environmental Health Perspectives, 121(6), 657–662.
Gutshall, D.M., G.D. Pilcher and A.E. Langley. (1989) Mechanism of the serum thyroid hormone lowering effect of perfluoro-n-decanoic acid (PFDA) in rats. J. Toxicol. Environ. Health 28(1): 53-65.
Hagenbuch, B. (2007) Cellular entry of thyroid hormones by organic anion transporting polypeptides. Best Pract. Res. Clin. Endocrinol. Metab. 21(2): 209-221.
Hagenbuch B, Meier PJ 2004 Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch 447:653-665
Hagmar, L., L. Rylander, E. Dyremark, E. Klasson-Wehler and E.M. Erfurth. (2001a). Plasma concentrations of persistent organochlorines in relation to thyrotropin and thyroid hormone levels in women. Int. Arch. Occup. Environ. Health 74(3): 184-188.
Hagmar, L., J. Bjork, A. Sjodin, A. Bergman and E.M. Erfurth. (2001b) Plasma levels of persistent organohalogens and hormone levels in adult male humans. Arch. Environ. Health 56(2): 138-143.
Hallgren, S., T. Sinjari, H. Hakansson and P.O. Darnerud. (2001) Effects of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) on thyroid hormone and vitamin A levels in rats and mice. 75(4): 200-208.
Hallgren, S. and P.O. Darnerud. (2002) Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and chlorinated paraffins (CPs) in rats-testing interactions and mechanisms for thyroid hormone effects. Toxicology 177(203): 227-243.
Hamers, T., J.H. Kamstra, E. Sonneveld, A.J. Murk, M.H. Kester, P.L. Andersson, J. Legler and A. Brouwer. (2006) In vitro profiling of the endocrine-disrupting potency of brominated flame retardants. Toxicol. Sci. 92(1): 157-173.
Hamers, T., Kamstra, E. Sonneveld, A.J. Murk, T.J. Visser, M.J. Van Velzen, A. Brouwer and A. Bergman. (2008) Biotransformation of brominated flame retardants into potentially endocrine-disrupting metabolites, with special attention to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47). Mol. Nutr. Food Res. 52(2): 284-298.
Harley, K.G., A.R. Marks, J. Chevrier, A. Bradman, A. Sjodin and B. Eskenazi. (2010) PBDE concentrations in women's serum and fecundability. Environ. Health Perspect. 118(5): 699-704.
Henneman, G., R. Docter, E.C. Friesma, M. de Jong, E.P. Krenning and T.J. Visser. (2001) Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr. Rev. 22(4): 451-476.
Heuer, H. (2007) The importance of thyroid hormone transporters for brain development and function. Best Pract. Res. Clin. Endocrinol. Metab. 21(2): 265-276.
Hood, A. and C.D. Klaassen. (2000a) Differential effects of microsomal enzyme inducers on in vitro thyroxine (T(4)) and triiodothyronine (T(3)) glucuronidation. Toxicol. Sci. 55(1): 78-84.
Hood, A. and C.D. Klaassen. (2000b) Effects of microsomal enzyme inducers on outer-ring deiodinase activity toward thyroid hormones in various rat tissues. Toxicol. Appl. Pharmacol. 163(3): 240-248.
Hovander, L., M. Athanasiadou, L. Asplund, S. Jensen and E.K. Wehler. (2000). Extraction and cleanup methods for analysis of phenolic and neutral organohalogens in plasma. 24(8): 696-703.
Hume, R., J. Simpson, C. Delahunty, H. van Toor, S.Y. Wu, F.L. Williams, T.J. Visser et al. (2004) Human fetal and cord serum thyroid hormones: developmental trends and interrelationships. J. Clin. Endocrinol. Metab. 89(8): 4097-4103.
Inoue, K., F. Okada, R. Ito, S. Kato, S. Sasaki, S. Nakajima, A. Uno, Y. Saijo, F. Sata, Y. Yoshimura, R. Kishi and H. Nakazawa. (2004) Perfluorooctane sulfonate (PFOS) and related perfluorinated compounds in human maternal and cord blood samples: assessment of PFOS exposure in a susceptible population during pregnancy. Environ. Health Perspect. 112(11): 1204-1207.
Kato, Y., K. Haraguchi, M. Onishi, S. Ikushiro, T. Endo, C. Ohta, N. Koga, S Yamada and M. Degawa. (2014) 3,3',4,4'-Tetrachlorobiphenyl-mediated decrease of serum thyroxine level in C57BL/6 and DBA/2 mice occurs mainly through enhanced accumulation of thyroxine in the liver. Biol. Pharm. Bull. 37(3) 504-509.
Kato, Y., M. Onishi, K. Haraguchi, S. Ikushiro, C. Ohta, N. Koga, T. Endo, S. Yamada and M. Degawa. (2013) A possible mechanism for 2,3',4,4',5'-pentachlorobiphenyl-mediated decrease in serum thyroxine level in mice. Biol. Pharm. Bull. 36(10): 1594-1601.
Kato, Y., S. Tamaki, K. Haraguchi, S. Ikushiro, M. Sekimoto, C. Ohta, T. Endo, N. Koga, S. Yamada and M. Degawa. (2012) Comparative study on 2,2',4,5,5'-pentachlorobiphenyl-mediated decrease in serum thyroxine level between C57BL/6 and its transthyretin-deficient mice. Toxicol. Appl. Pharmacol. 263(3): 323-329.
Kato, Y., M. Onishi, K. Haraguchi, S. Ikushiro, C. Ohta, N. Koga, T. Endo, S. Yamada and M. Degawa. (2011) A possible mechanism for 2,2',4,4',5,5'-hexachlorobiphenyl-mediated decrease in serum thyroxine level in mice. Toxicol. Appl. Pharmacol. 254(1): 48-55.
Kato, Y., K. Haraguchi, M. Kubota, Y. Seto, S. Ikushiro, T. Sakaki, N. Koga, S. Yamada and M. Degawa. (2009) 4-Hydroxy-2,2',3,4',5,5',6-heptachlorobiphenyl-mediated decrease in serum thyroxine level in mice occurs through increase in accumulation of thyroxine in the liver. Drug Metab. Dispos. 37(10): 2095-2102.
Kato, Y., S. Ikushiro, R. Takiguchi, K. Haraguchi, N. Koga, S. Uchida, T. Sakaki, S. Yamada, J. Kanno and M. Degawa. (2007) A novel mechanism for polychlorinated biphenyl-induced decrease in serum thyroxine level in rats. Drug Metab. Dispos. 35(10) : 1949-1955.
Kato, Y., S. Ikushiro, K. Haraguchi, T. Yamazaki, Y. Ito, H. Suzuki, R. Kimura, S. Yamada, T. Inoue and M. Degawa. (2004) A possible mechanism for decrease in serum thyroxine level by polychlorinated biphenyls in Wistar and Gunn rats. Toxicol. Sci. 81(2): 309-315.
Kato, Y., K. Haraguchi, T. Yamazuki, Y. Ito, S. Miyajima, K. Nemoto, N. Koga, R. Kimura and M. Degawa. (2003) Effects of polychlorinated biphenyls, kanechlor-500, on serum thyroid hormone levels in rats and mice. Toxicol. Sci. 72(2): 235-241.
Kim, S.Y., E.S. Choi, H.J. Lee, C. Moon and E. Kim. (2015) Transthyretin as a new transporter of nanoparticles for receptor-mediated transcytosis in rat brain microvessels. Colloids Surf B Biointerfaces 136: 989-996.
Kim do K, Kanai Y, Matsuo H, Kim JY, Chairoungdua A, Kobayashi Y, Enomoto A, Cha SH, Goya T, Endou H 2002 The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. Genomics 79:95-103
Kohrle, J., S.L. Fang, Y. Yang, K. Irmscher, R.D. Hesch, S. Pino, S. Alex, and L.E. Braverman. (1989). Rapid effects of the flavonoid EMD 21388 on serum thyroid hormone binding and thyrotropin regulation in the rat. Endocrinoloy 125: 532-537
Koopman-Essenboom, C., D.C. Morse, N. Weisglas-Kuperus, I.J. Lutkeschipholt, C.G. Van der Paauw, L.G. Tuinstra, A. Brouwer and P.J. Sauer. (1994) Effects of dioxins and polychlorinated biphenyls on thyroid hormone status of pregnant women and their infants. Pediatr. Res. 36(4): 468-473.
Lans, M. C., Klasson-Wehler, E., Willemsen, M., Meussen, E., Safe, S., & Brouwer, A. (1993). STRUCTURE-DEPENDENT, COMPETITIVE INTERACTION OF HYDROXY-POLYCHLOROBIPHENYLS, -DIBENZO-p-DIOXINS AND -DIBENZOFURANS WITH HUMAN TRANSTHYRETIN. Chemico-Biological Interactions, 88, 7–21.
Lans, M. C., Spiertz, C., Brouwer, a, & Koeman, J. H. (1994). Different competition of thyroxine binding to transthyretin and thyroxine-binding globulin by hydroxy-PCBs, PCDDs and PCDFs. European Journal of Pharmacology, 270(2-3), 129–136. http://doi.org/10.1016/0926-6917(94)90054-X
Larsson, M., Pettersson, T., & Carlström, a. (1985). Thyroid hormone binding in serum of 15 vertebrate species: isolation of thyroxine-binding globulin and prealbumin analogs. General and Comparative Endocrinology, 58(3), 360–375.
Loubiere, L.S., E. Vasilopoulou, J.N. Bulmer, P.M. Taylor, B. Stieger, F. Verrey, C.J. McCabe, J.A. Franklyn, M.D. Kilby and S.Y. Chan. (2010) Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction. Placenta 31(4): 295-304.
Lueprasitsakul, W., Alex, S., Fang, S. L., Pino, S., Irmscher, K., Köhrle, J., & Braverman, L. E. (1990). Flavonoid administration immediately displaces thyroxine (T4) from serum transthyretin, increases serum free T4, and decreases serum thyrotropin in the rat. Endocrinology 126 (6)
Lupton, S.J., P. McGarrigle, J.R. Olson, T.D. Wood and D.S. Aga. (2010) Analysis of hydroxylated polybrominated diphenyl ether metabolites by liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry. Rapid Commun. Mass. Spectrom. 24(15): 2227-2235.
Lupton, S.J., B.P. McGarrigle, J.R. Olson, T.D. Wood and D.S. Aga. (2009) Analysis of hydroxylated polybrominated diphenyl ether metabolites by liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry. 22(11): 1802-1809.
Malmberg, T., M. Athanasiadou, G. Marsh, I. Brandt and A. Bergman. (2005) Identification of hydroxylated polybrominated diphenyl ether metabolites in blood plasma from polybrominated diphenyl ether exposed rats. 39(14): 5342-5348.
Marchesini, G.R., E. Meulenberg, W. Haasnoot, M. Mizuguchi and H. Irth. (2006) Biosensor recognition of thyroid-disrupting chemicals using transport proteins. Anal. Chem. 78(4): 1107-1114.
Marchesini, G.R., A. Meimaridou, W. Haasnoot, E. Meulenberg, F. Albertus, M. Mizuguchi, M. Takeuchi, H. Irth and A.J. Murk. (2008) iosensor discovery of thyroxine transport disrupting chemicals. Toxicol. Appl. Pharmacol. 232(1): 150-160.
Martin, L.A., D.T. Wilson, K.R> Reuhl, M.A. Gallo and C.D. Klaassen. (2012) Polychlorinated biphenyl congeners that increase the glucuronidation and biliary excretion of thyroxine are distinct from the congeners that enhance the serum disappearance of thyroxine. Drug Metab. Dispos. 40(3): 588-595.
Martin, L. and C.D. Klaassen. (2010) Differential effects of polychlorinated biphenyl congeners on serum thyroid hormone levels in rats. Toxicol. Sci. 117(1): 36-44.
Meerts, I.A., Y. Assink, P.H. Cenjin, J.H. Van Den Berg, B.M. Weijers, A. Bergman, J.H. Koeman and A. Brouwer. (2002) Placental transfer of a hydroxylated polychlorinated biphenyl and effects on fetal and maternal thyroid hormone homeostasis in the rat. Toxicol. Sci. 68(2): 361-371.
Meerts, I.A., J.J. van Zanden, E.A. Lujiks, I. van Leeuwen-Bol, G. Marsh, E. Jakobsson, A. Bergman and A. Brouwer. (2000) Potent competitive interactions of some brominated flame retardants and related compounds with human transthyretin in vitro. Toxicol. Sci. 56(1): 95-104.
Mendel, C. M. (1989). Modeling thyroxine transport to liver : rejection of the “enhanced dissociation” hypothesis as applied to thyroxine. Am J Physiol, 257(Endocrinol Metab 20), E764–E771.
Mendel, C. M., Cavalieri, R. R., & Kohrle, J. (1992). Thyroxine (T4) transport and distribution in rats treated with EMD 21388, a synthetic flavonoid that displaces T4 from transthyretin. Endocrinology, 130(3), 1525–1532.
Midgley, J. E. (2001) Direct and indirect free thyroxine assay methods: theory and practice. Clin. Chem. 47(8): 1353-1363.
Miksys, S. and R.F. Tyndale. (2004) The unique regulation of brain cytochrome P450 2 (CYP2) family enzymes by drugs and genetics. Drug Metab. Rev. 36(2): 313-333.
Montano, M., E. Coccco, C. Guignard, G. Marsh, L. Hoffmann, A. Bergman, A.C. Gutleb and A.J. Murk. (2012) New approaches to assess the transthyretin binding capacity of bioactivated thyroid hormone disruptors. Toxicol. Sci. 130(1): 94-105.
Morse, D.C., E.K. Wehler, W. Wesseling, J.H. Koeman and A. Brouwer. (1996) Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254). Toxicol. Appl. Pharmacol. 136(2): 269-279.
Morse, D.C., D. Groen, M. Veerman, C.J. van Amerongen, H.B. Koeter, A.E. Smits van Proojie, T.J. Visser, J.H. Koeman and A. Brouwer. (1993) Interference of polychlorinated biphenyls in hepatic and brain thyroid hormone metabolism in fetal and neonatal rats. Toxicol. Appl. Pharmacol. 122(1) :27-33.
Munro, S.L., C.F. Lim, J.G. Hall, J.W. Barlow, D.J. Craik, D.J. Topliss and J.R. Stockigt (1989) Drug competition for thyroxine binding to transthyretin (prealbumin): comparison with effects on thyroxine-binding globulin. J. Clin. Endocrinol. Metab. 68(6): 1141-1147,
Nishimura M, Naito S 2008 Tissue-specific mRNA expression profiles of human solute carrier transporter superfamilies. Drug Metab Pharmacokinet 23:22-44
Pedraza, P., Calvo, R., Obregón, M. J., Asuncion, M., Escobar Del Rey, F., & Morreale De Escobar, G. (1996). Displacement of T4 from transthyretin by the synthetic flavonoid EMD 21388 results in increased production of T3 from T4 in rat dams and fetuses. Endocrinology, 137(11), 4902–4914. http://doi.org/10.1210/en.137.11.4902
Purkey, H.E., M.I. Dorrell and J.W. Kelly. (2001) Evaluating the binding selectivity of transthyretin amyloid fibril inhibitors in blood plasma. Proc. Natl. Acad. Sci. USA 98(10): 5566-5571.
Refetoff, S., N.I. Robin and V.S. Fang. (1970) Parameters of thyroid function in serum of 16 selected vertebrate species: a study of PBI, serum T4, free T4, and the pattern of T4 and T3 binding to serum proteins. Endocrinology 86(4): 793-805.
Refetoff, S. (2015) Thyroid Hormone Serum Transport Proteins. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000.
Ren, X.M., L.H. Guo, Y. Gao, B.T. Zhang and B. Wan. (2013) Hydroxylated polybrominated diphenyl ethers exhibit different activities on thyroid hormone receptors depending on their degree of bromination. Toxicol. Appl. Pharamacol. 268(3): 256-263.
Ren, X. M., & Guo, L. H. (2012). Assessment of the binding of hydroxylated polybrominated diphenyl ethers to thyroid hormone transport proteins using a site-specific fluorescence probe. Environmental Science and Technology, 46(8), 4633–4640. http://doi.org/10.1021/es2046074
Rerat, C. and H.G. Schwick (1967) [Crystallographic data of blood plasma prealbumin]. [Article in French] Acta Crystallogr. 22(3): 441-442.
Richardson, S. J. (2007). Cell and molecular biology of transthyretin and thyroid hormones. International Review of Cytology, 258(January), 137–93. http://doi.org/10.1016/S0074-7696(07)58003-4
Richardson, S. J., Wijayagunaratne, R. C., D’Souza, D. G., Darras, V. M., & Van Herck, S. L. J. (2015). Transport of thyroid hormones via the choroid plexus into the brain: the roles of transthyretin and thyroid hormone transmembrane transporters. Frontiers in Neuroscience, 9(March), 1–8.
Rickenbacher, U., McKinney, J. D., Oatley, S. J., & Blake, C. C. (1986). Structurally specific binding of halogenated biphenyls to thyroxine transport protein. Journal of Medicinal Chemistry, 29(5), 641–648.
Ritchie, J.W. and P.M. Taylor. (2001) Role of the System L permease LAT1 in amino acid and iodothyronine transport in placenta. Biochem. J. 356(Part 3); 719-725.
Riu, A., J.P. Cravedi, L. Debrauwer, A. Garcia, C. Canlet, I. Jouanin and D. Zalko. (2008) Environ. Int. 34(3): 318-329.
Roberts LM, Woodford K, Zhou M, Black DS, Haggerty JE, Tate EH, Grindstaff KK, Mengesha W, Raman C, Zerangue N 2008 Expression of the thyroid hormone transporters MCT8 (SLC16A2) and OATP14 (SLCO1C1) at the blood-brain barrier. Endocrinology 149:6251-6261
Rotroff, D.M., B.A. Wetmore, D.J. Dix, S.S. Ferguson, H.J. Clewell, K.A. Houck, E.L. Lecluyse, M.E. Anersen, R.S. Judson, C.M. Smith, M.A. Sochaski, R.J. Kavlock, F. Boellmann, M.T. Martin, D.M. Reif, J.F. Wambaugh and R.S. Thomas. (2010) Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening. 117(2): 348-358.
Sato, K., J. Sugawara, T. Sato, H. Mizutamari, T. Suzuki, A. Ito, T. Mikkaichi, T. Onogawa, M. Tanemoto, M. Unno, T. Abe and K. Okamura. (2003) Expression of organic anion transporting polypeptide E (OATP-E) in human placenta. Placenta 24(2-3): 144-148.
Schreiber, G. (2002). The evolutionary and integrative roles of transthyrein in thyroid hormone homeostasis. Journal of Endocrinology, 175(1), 61–73. http://doi.org/10.1677/joe.0.1750061
Schroder van der Elst, J.P., D. van der Heide, H. Rokos, G. Morreale de Escobar and J. Kohrlre. (1998) Synthetic flavonoids cross the placenta in the rat and are found in fetal brain. Am. J. Physiol. 274(2 Psrt 1): E253-E256.
Schroder van der Elst, J.P., D. van der Heide, H. Rokos, J. Kohrle and G. Morreale de Escobar. (1997) Different tissue distribution, elimination, and kinetics of thyroxine and its conformational analog, the synthetic flavonoid EMD 49209 in the rat. Endocrinology 138(1): 79-84.
Schuur, A.G., F.M. Boekhorst, A. Brouwer and T.J. Visser. (1997) Extrathyroidal effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on thyroid hormone turnover in male Sprague-Dawley rats. Endocrinology 138(9): 3727-3734.
Sinjari, T. and P.O. Darnerud. (1998) Hydroxylated polychlorinated biphenyls: placental transfer and effects on thyroxine in the foetal mouse. Xenobiotica 28(1): 21-30.
Sparkes, R.S., H. Sasaki, T. Mohandas, K. Yoshioka, I. Kilsak, Y. Sasaki, C. Heinzmann and M.I. Simon. (1987) Assignment of the prealbumin (PALB) gene (familial amyloidotic polyneuropathy) to human chromosome region 18q11.2-q12.1. Hum. Genet. 75(2): 151-154.
Stapleton, H.M., S.M. Kelly, R. Pei, R.J. Letcher and C. Gunsch. (2009) Metabolism of polybrominated diphenyl ethers (PBDEs) by human hepatocytes in vitro. Environ. Health Perspect. 117(2): 197-202.
Tohyama K, Kusuhara H, Sugiyama Y 2004 Involvement of multispecific organic anion transporter, Oatp14 (Slc21a14), in the transport of thyroxine across the blood-brain barrier. Endocrinology
Ucan-Marin, F., A. Arukwe, A.S. Mortensen, G.W. Gabrielsen and R.J. Letcher. (2010) Recombinant albumin and transthyretin transport proteins from two gull species and human: chlorinated and brominated contaminant binding and thyroid hormones. Environ. Sci. Technol. 44(1): 497-504.
Van Birgelen, A.P., E.A. Smit, I.M. Kampen, C.N. Groeneveld, K.M. Case, J. Van der Kolk, H. Poiger, M. Van den Berg, J.H. Koeman and A. Brouwer. (1995) Subchronic effects of 2,3,7,8-TCDD or PCBs on thyroid hormone metabolism: use in risk assessment. Eur. J. Pharmacol. 293(1) : 77-85.
Van den Berg, K. J. (1990). Interaction of chlorinated phenols with thyroxine binding sites of human transthyretin, albumin and thyroid binding globulin. Chemico-Biological Interactions, 76(1), 63–75.
Van den Berg, K. J., Van Raaij, J. a G. M., Bragt, P. C., & Notten, W. R. F. (1991). Interactions of halogenated industrial chemicals with transthyretin and effects on thyroid hormone levels in vivo. Archives of Toxicology, 65(1), 15–19.
Viberg, H., A. Fredriksson and P. Eriksson. (2002) Neonatal exposure to the brominated flame retardant 2,2',4,4',5-pentabromodiphenyl ether causes altered susceptibility in the cholinergic transmitter system in the adult mouse. Toxicol. Sci. 67(1): 104-107.
Viollon-Abadie, C., D. Lassere, E. Debruyne, L. Nicod, N. Carmichael and L. Richert. (1999) Phenobarbital, beta-naphthoflavone, clofibrate, and pregnenolone-16alpha-carbonitrile do not affect hepatic thyroid hormone UDP-glucuronosyl transferase activity, and thyroid gland function in mice. Toxicol. Appl. Pharmacol. 155(1) 1-12.
Visser, T.J. and R.P. Peeters. (2012) Metabolism of thyroid hormone. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.
Visser, T. J. (2010). Cellular Uptake of Thyroid Hormones. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.
Visser, T.J. (1996) Role of sulfate in thyroid hormone sulfation. Eur. J. Endocrinol. 134(1): 12-14.
Visser, T.J., E. Kaptein, J.A. van Raaij, C.T. Joe, T. Ebner and B. Burchell. (1993)
Multiple UDP-glucuronyltransferases for the glucuronidation of thyroid hormone with preference for 3,3',5'-triiodothyronine (reverse T3). FEBS Lett. 315(1): 65-68.
Weiss, J.M., P.L. Andersson, M.H. Lamoree, P.E. Leonards, S.P. van Leeuwen and T. Hamers. (2009) Competitive binding of poly- and perfluorinated compounds to the thyroid hormone transport protein transthyretin. Toxicol. Sci. 109(2): 206-216.
Weiss, J. M., Andersson, P. L., Zhang, J., Simon, E., Leonards, P. E. G., Hamers, T., & Lamoree, M. H. (2015). Tracing thyroid hormone-disrupting compounds: database compilation and structure-activity evaluation for an effect-directed analysis of sediment. Analytical and Bioanalytical Chemistry, 5625–5634. http://doi.org/10.1007/s00216-015-8736-9
Yamauchi, K., A. Ishihara, H. Fukazawa and Y. Terao. (2003) Competitive interactions of chlorinated phenol compounds with 3,3',5-triiodothyronine binding to transthyretin: detection of possible thyroid-disrupting chemicals in environmental waste water. Toxicol. Appl. Pharmacol. 187(2): 110-117.
Yen, P. M. (2001). Physiological and molecular basis of thyroid hormone action. Physiological Reviews, 81(3), 1097–1142.
Zhang, J., J.H. Kamstra, M. Ghorbanzadeh, J.M. Weiss, T. Hamers and P.L. Andersson. (2015) In Silico Approach To Identify Potential Thyroid Hormone Disruptors among Currently Known Dust Contaminants and Their Metabolites. Environ. Sci. Technol. 49(16): 10099-10107.
Zoeller, R. T., Tan, S. W., & Tyl, R. W. (2007). General background on the hypothalamic-pituitary-thyroid (HPT) axis. Critical Reviews in Toxicology, 37(1-2), 11–53.
Zoeller, R.T. and J. Rovet. (2004) Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings. J. Neuroendocrinol. 16(10): 809-818.