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Erik R. Janus; M3 Technical & Regulatory Services; Shepherdstown, WV; <firstname.lastname@example.org>
Kristie Sullivan; Physicians Committee for Responsible Medicine; Washington, DC; <email@example.com>
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; <firstname.lastname@example.org>
Kevin M. Crofton; National Center for Computational Toxicology; US Environmental Protection Agenc; Research Triangle Park, NC; <email@example.com>
Point of Contact
Erik Janus (email point of contact)
- Erik Janus
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite||Under Development||1.41||Included in OECD Work Plan|
This AOP was last modified on March 20, 2017 09:47
|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 tissues||September 16, 2017 10:16|
|Thyroxine (T4) in serum, Decreased||April 04, 2019 09:05|
|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|
|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
Events: Molecular Initiating Events (MIE)
|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 tissues||Increased, Clearance of thyroxine from tissues|
|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)
|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)
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