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Event Title

Thyroxine (T4) in serum, Decreased
Short name: Thyroxine (T4) in serum, Decreased

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals KE Strong
Inhibition of Na+/I- symporter (NIS) decreases TH synthesis leading to learning and memory deficits in children KE Strong
Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals KE Strong
XX Inhibition of Sodium Iodide Symporter and Subsequent Adverse Neurodevelopmental Outcomes in Mammals KE Strong
Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals KE Strong
Interference with thyroid serum binding protein transthyretin and subsequent adverse human neurodevelopmental toxicity KE
Thyroperoxidase inhibition leading to reduced young of year survival via anterior swim bladder inflation KE
Thyroperoxidase inhibition leading to altered amphibian metamorphosis KE Strong
Sodium Iodide Symporter (NIS) Inhibition leading to altered amphibian metamorphosis KE Strong
Hepatic nuclear receptor activation leading to altered amphibian metamorphosis KE Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
human Homo sapiens Strong NCBI
rat Rattus sp. 95728 Strong NCBI
mouse Mus sp. Strong NCBI
African clawed frog Xenopus laevis Strong NCBI
chicken Gallus sp. Moderate NCBI

Level of Biological Organization

Biological Organization

How this Key Event works

There are two biological active thyroid hormones (THs) in serum, triiodothyronine (T3) and thyroxine (T4), and a few inactive iodothyronines (rT3, 3,5-T2), which are all derived from the modification of tyrosine molecules (Zoeller et al., 2007). However, the plasma concentrations of the other iodothyronines are significantly lower than those of T3 and T4.

The circulatory system serves as the major transport and delivery system for TH delivery to tissues. The majority of THs in the blood are bound to transport proteins (Bartalena and Robbins, 1993). In serum, it is the unbound, or ‘free’ form of the hormone that is active and available for transport into tissues. Free hormones are approximately 0.03 and 0.3 percent for T4 and T3, respectively. There are major species differences in the predominant binding proteins and their affinities for THs (see below). However, there is broad agreement that changes in serum concentrations of THs is diagnostic of thyroid disease or chemical-induced disruption of thyroid homeostasis (Zoeller et al., 2007).

In rodents, serum TH are low in the fetal circulation, increasing as the fetal thyroid gland becomes functional on gestational day 17, just prior to birth on gestational day 22. After birth serum hormones increase steadily, peaking at two weeks, and falling slightly to adult levels by postnatal day 21 (Zoeller et al., 2007).

How it is Measured or Detected

Serum T3 and T4 can be measured as free (unbound) or total (bound + unbound). Free hormone are considered more direct indicators of T4 and T3 activities in the body, but in animal studies, total T3 and T4 are typically measured as the concentrations of free hormone are very low and difficult to detect. Historically, the most widely used method in toxicology is radioaminoassay (RIA). The method is routinely used in rodent endocrine and toxicity studies. The ELISA method is a commonly used as a human clinical test method. Least common is analytical determination of iodothyronines (T3, T4, rT3, T2) and their conjugates, though methods employing HLPC and mass spectrometry exist (Hornung et al., 2015; DeVito et al., 1999; Spencer, 2013).

Any of these measurements should be evaluated for fit-for-purpose, relationship to the actual endpoint of interest, repeatability, reproducibility, and lower limits of quantification. All three of the methods summarized above would be fit-for-purpose, depending on the number of samples to be evaluated and the associated costs of each method. Both RIA and ELISA measure THs by an indirect methodology, whereas analytical determination is the most direct measurement available. All of these methods, particularly RIA, are repeatable and reproducible.

Evidence Supporting Taxonomic Applicability

The overall evidence supporting taxonomic applicability is strong. THs are evolutionarily conserved molecules present in all vertebrate species (Hulbert, 2000; Yen, 2001). Moreover, their crucial role in amphibian and larbean metamorphoses is well established (Manzon and Youson, 1997; Yaoita and Brown, 1990; Furlow and Neff, 2006). Their existence and importance has also been described in many different animal and plant kingdoms (Eales, 1997; Heyland and Moroz, 2005), while their role as environmental messenger via exogenous routes in echinoderms confirms the hypothesis that these molecules are widely distributed among the living organisms (Heyland and Hodin, 2004). However, the role of TH in the different species depends on the expression and function of specific proteins (e.g receptors or enzymes) under TH control and may vary across species and tissues. As such extrapolation regarding TH action across species should be done with caution.

With few exceptions, vertebrate species have circulating T3 and T4 that are bound to transport proteins in blood. Clear species differences exist in serum transport proteins (Dohler et al., 1979; Yamauchi and Isihara, 2009). There are three major transport proteins in mammals; thyroid binding globulin (TBG), transthyretin (TTR), and albumin. In adult humans, the percent bound to these proteins in adult humans is about 75, 15 and 10 percent, respectively (Schussler 2000). In contrast, the majority of THs are bound to TTR in adult rats. And thyroid binding proteins are developmentally regulated in rats. Thyroxine binding globulin is expressed in rats until approximately postnatal day (PND) 60, with peak expression occurring during weaning (Savu et al., 1989). Low low levels of TBG persist into adult ages in rats and can be experimentally induced by hypothyroidism, malnutrition, or caloric restriction (Rouaze-Romet et al., 1992). While these species differences impact hormone half-life (Capen, 1997) and possibly regulatory feedback mechanisms, there is little information on quantitative dose-response relationships. SerumTHs are still regarded as the most robusts measurable key event causally linked to downstream adverse outcomes.


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Heyland A, Hodin J. (2004). Heterochronic developmental shift caused by thyroid hormone in larval sand dollars and its implications for phenotypic plasticity and the evolution of non-feeding development. Evolution. 58: 524-538.

Heyland A, Moroz LL. (2005). Cross-kingdom hormonal signaling: an insight from thyroid hormone functions in marine larvae. J Exp Biol. 208:4355-4361.

Hornung MW, Kosian P, Haselman J, Korte J, Challis K, Macherla C, Nevalainen E, Degitz S (2015) In vitro, ex vivo and in vivo determination of thyroid hormone modulating activity of benzothiazoles. . Toxicol Sci 146:254-264.

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Zoeller RT, Tan SW, Tyl RW. General background on the hypothalamic-pituitary-thyroid (HPT) axis. Crit Rev Toxicol. 2007 Jan-Feb;37(1-2):11-53