Relationship:305

From AOP-Wiki
Jump to: navigation, search



Key Event Relationship Overview

Please follow link to widget page to edit this section.

If you manually enter text in this section, it will get automatically altered or deleted in subsequent edits using the widgets.

Description of Relationship

Upstream Event Downstream Event/Outcome
Thyroid hormone synthesis, Decreased Thyroxin (T4) in serum, Decreased

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals Directly Leads to Strong Weak
XX Inhibition of Sodium Iodide Symporter and Subsequent Adverse Neurodevelopmental Outcomes in Mammals Directly Leads to Strong Moderate
Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals Directly Leads to Strong Strong
Inhibition of Na+/I- symporter (NIS) decreases TH synthesis leading to learning and memory deficits in children Directly Leads to Strong Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
human Homo sapiens Strong NCBI
rat Rattus sp. Strong NCBI
mouse Mus sp. Strong NCBI
Xenopus laevis Xenopus laevis Strong NCBI

How Does This Key Event Relationship Work

Thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), are synthesized by TPO in the thyroid gland as iodinated thyroglobulin (Tg) and stored in the colloid of thyroid follicles. Secretion from the follicle into serum is a multi-step process. The first involves thyroid stimulating hormone (TSH) stimulation of the separation of the peptide linkage between Tg and TH. The next steps involve endocytosis of colloid, fusion of the endosome with the basolateral membrane of the thyrocyte, and finally release of TH into blood. More detailed descriptions of this process can be found in reviews by Braverman and Utiger (2012) and Zoeller et al. (2007).

Weight of Evidence

The weight of evidence linking these two KEs of decreased TH synthesis and decreased T4 in serum is strong.

Biological Plausibility

The biological relationship between two KEs in this KER is well accepted dogma within the scientific community.

Empirical Support for Linkage

There is limited direct evidence supporting the relationship between decreased TH syntheses and lowered circulating hormone levels during development. Lu and Anderson (1994) followed the time course of TH synthesis, measured as thyroxine secretion rate, in non-treated pregnant rats and correlated it with serum T4 levels. So while empirical data is scarce, it is widely accepted dogma the TPO inhibition leads to declines in serum TH levels. This is due to the fact that the sole source for circulating T4 is thyroid gland synthesis. Indeed, it has been known for decades that insufficient dietary iodine will lead to decreased serum TH concentrations due to inadequate synthesis. Furthermore, a wide variety of drugs and chemicals that inhibit TPO are known to result in decreased release of TH from the thyroid gland, as well as decreased circulating TH concentrations. This is evidenced by a very large number of studies that employed a wide variety of techniques, including thyroid gland explant cultures, tracing organification of 131-I and in vivo treatment of a variety of species with known TPO inhibitors (Atterwill et al., 1990; Brown et al., 1986; Brucker-Davis, 1998; Hornung et al., 2010; Hurley et al., 1998; Kohrle, 2008).

Temporal Evidence: For the current AOP the temporal nature of this developmental, however, there are a lack of studies that measured both TPO synthesis and TH production during development. Recently, serum thyroid hormones recovered in adult athyroid mice following grafting of in-vitro derived follicles (Antonica et al., 2012).

Dose-response Evidence: Dose-response data is lacking from studies that include concurrent measures of both TH synthesis and serum TH concentrations. However, data is available demonstrating correlations between thyroidal TH and serum TH concentrations during gestation and lactation following development exposures (Gilbert et al., 2013). This data was used to develop a rat quantitative biologically-based dose-response model for iodine deficiency (Fisher et al., 2013).

Uncertainties or Inconsistencies

There are no inconsistencies in this KER, but there are some uncertainties. The first uncertainty stems from the paucity of data for quantitative modeling of the relationship between the degree of synthesis decrease and resulting changes in circulating T4 concentrations. In addition, most of the data supporting this KER comes from inhibition of TPO, and there are a number of other processes (e.g., endocytosis, lysosomal fusion, basolateral fusion and release) that are not as well studied.

Quantitative Understanding of the Linkage

Fisher et al. (2013) recently published a quantitative biologically-based dose-response model for iodine deficiency in the rat. This model provides quantitative relationships for thyroidal T4 synthesis (iodine organification) and predictions of serum T4 concentrations in developing rats There are also a few other computational models that include thyroid hormone synthesis. Ekerot et al. (2012) modeled TPO, T3, T4 and TSH in dogs and humans based on exposure to myeloperoxidase inhibitors that also inhibit TPO and was has recently adapted for rat (Leonard et al., 2016). While the original model predicted serum TH and TSH levels as a function of oral dose, it was not used to explicitly predict the relationship between serum hormones and TPO inhibition, or thyroidal hormone synthesis. Leonard et al. (2016) recently incorporated TPO inhibition into the model. Degon et al (2008) developed a human thyroid model that includes TPO, but does not make quantitative prediction of organification changes due to inhibition of the TPO enzyme.

Evidence Supporting Taxonomic Applicability

While a majority of the empirical evidence comes from work with laboratory rodents, there is a large amount of supporting data from humans (with anti-hyperthyroidism drugs including propylthiouracil and methimazole), some amphibian species (e.g., frog), and some avian species (e.g, chicken).

References

Antonica F, Kasprzyk DF, Opitz R, Iacovino M, Liao XH, Dumitrescu AM, Refetoff S, Peremans K, Manto M, Kyba M, Costagliola S. Generation of functional thyroid from embryonic stem cells. Nature. 2012 491(7422):66-71.

Atterwill CK, Fowler KF. A comparison of cultured rat FRTL-5 and porcine thyroid cells for predicting the thyroid toxicity of xenobiotics. Toxicol In Vitro. 1990. 4(4-5):369-74.

Braverman, L.E. and Utiger, R.D. (2012). Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text (10 ed.). Philadelphia, PA: Lippincott Williams & Wilkins. pp. 775-786. ISBN 978-1451120639.

Brown CG, Fowler KL, Nicholls PJ, Atterwill C. Assessment of thyrotoxicity using in vitro cell culture systems. Food Chem Toxicol. 1986 24(6-7):557-62.

Brucker-Davis F. Effects of environmental synthetic chemicals on thyroid function. Thyroid. 1998 8(9):827-56.

Degon, M., Chipkin, S.R., Hollot, C.V., Zoeller, R.T., and Chait, Y. (2008). A computational model of the human thyroid. Mathematical Biosciences 212, 22–53

Ekerot P, Ferguson D, Glämsta EL, Nilsson LB, Andersson H, Rosqvist S, Visser SA. Systems pharmacology modeling of drug-induced modulation of thyroid hormones in dogs and translation to human. Pharm Res. 2013 30(6):1513-24.

Fisher JW, Li S, Crofton K, Zoeller RT, McLanahan ED, Lumen A, Gilbert ME. Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose-response model. Toxicol Sci. 2013 132(1):75-86.

Gilbert ME, Hedge JM, Valentín-Blasini L, Blount BC, Kannan K, Tietge J, Zoeller RT, Crofton KM, Jarrett JM, Fisher JW. An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome. Toxicol Sci. 2013 132(1):177-95.

Hornung MW, Degitz SJ, Korte LM, Olson JM, Kosian PA, Linnum AL, Tietge JE.Inhibition of thyroid hormone release from cultured amphibian thyroid glands by methimazole, 6-propylthiouracil, and perchlorate. Toxicol Sci. 2010 118(1):42-51.

Hurley PM. Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents. Environ Health Perspect. 1998 106(8):437-45.

Köhrle J. Environment and endocrinology: the case of thyroidology. Ann Endocrinol (Paris). 2008 69(2):116-22.

Leonard JA, Tan YM, Gilbert M, Isaacs K, El-Masri H. Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling. Toxicol Sci. 2016 151(1):57-70.

Lu, M-H, and Anderson, RR. Thyroxine secretion rats during pregnancy in the rat. Endo Res. 1994. 20(4):343-364.

Van Herck SL, Geysens S, Delbaere J, Darras VM. Regulators of thyroid hormone availability and action in embryonic chicken brain development. Gen Comp Endocrinol. 2013 190:96-104.

Zoeller, R. T., Tan, S. W., and Tyl, R. W. (2007). General background on the hypothalamic-pituitary-thyroid (HPT) axis. Critical reviews in toxicology 37(1-2), 11-53.