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Erik R. Janus; M3 Technical & Regulatory Services; Shepherdstown, WV; <email@example.com>
Kristie Sullivan; Physicians Committee for Responsible Medicine; Washington, DC; <firstname.lastname@example.org>
Katie Paul-Friedman; US Environmental Protection Agency; Research Triangle Park, NC
Mary Gilbert; National Health and Environmental Effects Research Laboratory; US Environmental Protection Agency; Research Triangle Park, NC; <email@example.com>
Kevin M. Crofton; National Center for Computational Toxicology; US Environmental Protection Agenc; Research Triangle Park, NC; <firstname.lastname@example.org>
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This AOP describes one adverse outcome (neurodevelopemental effects) that results from the 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 certain 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. 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, and ultimately cognitive function.
Transthyretin is one of three serum binding proteins found in man that collectively act to transport thyroid hormone (TH) and thus maintain normal homeostasis via modulation of the hypothalamic/pituitary/thyroid axis. In addition to TTR, albumin and thyroxine-binding globulin (TBG) also serve to transport TH in serum and the relative contribution of each binding protein differs across species (although TTR itself is highly conserved). 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, with ALB being most prevalent (42 g/L in serum), followed by TTR (0.25 g/L) and TBG is the least prevalent in serum (0.015 g/L) (Mendel et al 1989, Richardson et al 2015). In rat, TTR is the major serum transport protein (as rats lack TBG); however, in man and primates, only a small fraction of T4 is bound to TTR or albumin.
Summary of the AOP
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Molecular Initiating Event
|Molecular Initiating Event||Support for Essentiality|
|Transthyretin in serum, Binding||Strong|
|Cognitive Function, Decreased|
Relationships Among Key Events and the Adverse Outcome
|Event||Description||Triggers||Weight of Evidence||Quantitative Understanding|
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Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Life Stage Applicability,
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Essentiality of the Key Events
Molecular Initiating Event Summary,
Key Event Summary
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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.
Weight of Evidence Summary
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Considerations for Potential Applications of the AOP (optional)
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.
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.
Kohrle et al 1989
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.
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.
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)
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.
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.
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.