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Inhibition, Deiodinase 2 leads to Decreased, Triiodothyronine (T3)
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Deiodinase 2 inhibition leading to increased mortality via reduced posterior swim bladder inflation||adjacent||Moderate||Low||Dries Knapen (send email)||Under Development: Contributions and Comments Welcome||WPHA/WNT Endorsed|
|Deiodinase 2 inhibition leading to increased mortality via reduced anterior swim bladder inflation||adjacent||Moderate||Low||Dries Knapen (send email)||Under Development: Contributions and Comments Welcome||WPHA/WNT Endorsed|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
The two major thyroid hormones are thyroxine (T4) and the more biologically active triiodothyronine (T3), both iodinated derivatives of tyrosine. Active and inactive THs are tightly regulated by enzymes called iodothyronine deiodinases (DIO). The activation occurs via outer ring deiodination (ORD), i.e. removing iodine from the outer, phenolic ring of T4 to form T3, while inactivation occurs via inner ring deiodination (IRD), i.e. removing iodine from the inner tyrosol ring of T4 or T3.
Three types of iodothyronine deiodinases (DIO1-3) have been described in vertebrates that activate or inactivate THs and are therefore important mediators of TH action. All deiodinases are integral membrane proteins of the thioredoxin superfamily that contain selenocysteine in their catalytic centre. Type I deiodinase is capable of converting T4 into T3, as well as to convert rT3 to the inactive thyroid hormone 3,3’ T2, through outer ring deiodination. rT3, rather than T4, is the preferred substrate for DIO1. furthermore, DIO1 has a very high Km (µM range, compared to nM range for DIO2) (Darras and Van Herck, 2012). Type II deiodinase (DIO2) is only capable of ORD activity with T4 as a preferred substrate (i.e., activation of T4 tot T3). DIO3 can inner ring deiodinate T4 and T3 to the inactive forms of THs, reverse T3, (rT3) and 3,3’-T2 respectively (Darras and Van Herck, 2012). DIO2 and DIO3 expression customize the timing and intensity of TH signalling in an organ/tissue-specific way (Russo et al 2021).
Evidence Collection Strategy
Evidence Supporting this KER
Inhibition of DIO2 activity is widely accepted to directly decrease T3 levels, since the conversion of T4 to T3 is inhibited. The importance of DIO2 inhibition in altering serum and/or tissue T3 levels depends on the relative role of different deiodinases in regulating serum versus tissue T3 levels and in negative feedback within the HPT axis. Both aspects appear to vary among vertebrate taxa.
Inhibition of DIO2 activity is widely accepted to directly decrease T3 levels, since the conversion of T4 to T3 is inhibited.
Uncertainties and Inconsistencies
Since in fish early life stages THs are typically measured on a whole-body level, it is currently uncertain whether T3 level changes occur at the serum and/or tissue level.
The importance of DIO2 inhibition in altering serum or tissue T3 levels depends on the relative role of different deiodinases in regulating serum versus tissue T3 levels and in negative feedback within the HPT axis. Both aspects appear to vary among vertebrate taxa. The high level of DIO2 activity and its expression in the liver of teleosts are unique among vertebrates (Orozco and Valverde, 2005). It is thought that DIO2 is important for local T3 production in several tissues but also contributes to circulating T3, especially in fish and amphibians (Darras et al., 2015).
Deiodinase 2 inhibition may not always directly lead to decreased T3 levels as there may be age-specific, exposure window-specific, and exposure duration-specific effects that may deviate from that dynamic. Differences in feedback mechanisms may be an important contributor. In DIO2 knockout mice it seemed that the negative feedback system was blocked resulting in increased levels of T4 and TSH and in normal rather than decreased T3 levels compared to WT.
In the study of Cavallin et al. (2017) fathead minnow embryos were exposed to IOP, a model iodothyronine deiodinase inhibitor that is assumed to inhibit all three deiodinase enzymes (DIO1,2,3). The authors observed increased whole-body T3 concentrations in 4 and 6 day old embryos, while they observed decreased T3 concentrations in 10 to 21 day old larvae exposed to IOP as of the age of 6 days. One possible explanation for the elevated T3 concentrations may be the potential impact of IOP exposure on DIO3. DIO3 is an inactivating enzyme that removes iodine from the inner ring of both T4 and T3, resulting in reverse T3 (rT3) and 3,5-diiodo-L- thyronine (T2), respectively (Bianco and Kim, 2006). Maternal sources of thyroid hormones are known to include both T4 and T3 (Power et al., 2001; Walpita et al., 2007). Consequently, reduced conversion of maternal T3 to inactive forms may be one plausible explanation for the increase. Another explanation may result from the role of deiodinases in the negative feedback system of the HPT axis. Inhibition of deiodinase (unclear which isoforms) may block the negative feedback system and result in increased release of T4. Increased levels of T4 were indeed observed by Cavallin et al. (2017).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Thyroid hormone levels are regulated via negative feedback, in part via regulation of the expression of all three DIO isoforms in response to deviating TH levels. This feedback mechanism influences this KER. Additionally, deiodinases regulate the activity of thyroid hormones, not only in serum and target organs, but also in the thyroid gland. On top of that, deiodinases themselves are mediators of the negative feedback system that results in increased TSH levels when the levels of T4 (and also T3) in serum are low (Schneider et al., 2001), resulting in an even more complicated impact on this KER. Increased TSH levels then stimulate increased T4 release from the thyroid gland, resulting in a compensatory increase of serum T4 levels. In DIO2 knockout mice it seemed that the negative feedback system was blocked resulting in increased levels of T4 and TSH and in normal rather than decreased T3 levels compared to WT. By inhibiting DIO1 using a PTU exposure, Schneider et al. (2001) showed that DIO2 played a role in the increased TSH levels in response to T3 or T4 injection in mice.
Domain of Applicability
Taxonomic: Deiodinases are important for the activation of T4 to T3 across vertebrates. Therefore, this KER is plausibly applicable across vertebrates. There appear to be differences among vertebrate classes relative to the role of the different deiodinase isoforms in regulating thyroid hormone levels. Maia et al. (2005) determined that in a normal physiological situation in humans the contribution of DIO2 to plasma T3 levels is twice that of DIO1. A DIO2 knockout (KO) mouse however showed a very mild gross phenotype with only mild growth retardation in males (Schneider et al., 2001). It seemed that by blocking the negative feedback system, DIO2 KO resulted in increased levels of T4 and TSH and in normal rather than decreased T3 levels compared to WT. Potential differences in the role of the deiodinase isoforms in the negative feedback system and the final consequences for TH levels across vertebrates is currently not entirely clear. These differences make it difficult to exactly evaluate the importance of DIO2 in regulating serum/tissue T3 levels across vertebrates. Mol et al. (1998) concluded that deiodinases in teleosts were more similar to mammalian deiodinases than had been generally accepted, based on the similarities in susceptibility to inhibition and the agreement of the Km values.
Life stage: Deiodinases are important for the activation of T4 to T3 across all life stages.
Sex: The KE is plausibly applicable to both sexes. Thyroid hormones are essential in both sexes and the components of the HPT-axis are identical in both sexes. There can however be sex-dependent differences in the sensitivity to the disruption of thyroid hormone levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (Hernandez‐Mariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in thyroid hormone levels and mRNA expression of regulatory genes including corticotropin releasing hormone (crh), thyroid stimulating hormone (tsh) and deiodinase 2 after exposure to organophosphate flame retardants. The underlying mechanism of any sex-related differences remains unclear.
Bianco, A.C., Kim, B.W., 2006. Deiodinases: implications of the local control of thyroid hormone action. Journal of Clinical Investigation 116, 2571-2579.
Cavallin, J.E., Ankley, G.T., Blackwell, B.R., Blanksma, C.A., Fay, K.A., Jensen, K.M., Kahl, M.D., Knapen, D., Kosian, P.A., Poole, S.T., Randolph, E.C., Schroeder, A.L., Vergauwen, L., Villeneuve, D.L., 2017. Impaired swim bladder inflation in early life stage fathead minnows exposed to a deiodinase inhibitor, iopanoic acid. Environmental Toxicology and Chemistry 36, 2942-2952.
Darras, V.M., Houbrechts, A.M., Van Herck, S.L.J., 2015. Intracellular thyroid hormone metabolism as a local regulator of nuclear thyroid hormone receptor-mediated impact on vertebrate development.
Darras, V.M., Van Herck, S.L.J., 2012. Iodothyronine deiodinase structure and function: from ascidians to humans. Journal of Endocrinology 215, 189-206.
Hernandez-Mariano JA, Torres-Sanchez L, Bassol-Mayagoitia S, Escamilla-Nunez M, Cebrian ME, Villeda-Gutierrez EA, Lopez-Rodriguez G, Felix-Arellano EE, Blanco-Munoz J. 2017. Effect of exposure to p,p '-dde during the first half of pregnancy in the maternal thyroid profile of female residents in a mexican floriculture area. Environmental Research. 156:597-604.
Houbrechts, A.M., Delarue, J., Gabriels, I.J., Sourbron, J., Darras, V.M., 2016. Permanent Deiodinase Type 2 Deficiency Strongly Perturbs Zebrafish Development, Growth, and Fertility. Endocrinology 157, 3668-3681.
Liu XS, Cai Y, Wang Y, Xu SH, Ji K, Choi K. 2019. Effects of tris(1,3-dichloro-2-propyl) phosphate (tdcpp) and triphenyl phosphate (tpp) on sex-dependent alterations of thyroid hormones in adult zebrafish. Ecotoxicology and Environmental Safety. 170:25-32.
Maia, A.L., Kim, B.W., Huang, S.A., Harney, J.W., Larsen, P.R., 2005. Type 2 iodothyronine deiodinase is the major source of plasma T-3 in euthyroid humans. Journal of Clinical Investigation 115, 2524-2533.
Mol, K.A., Van der Geyten, S., Burel, C., Kuhn, E.R., Boujard, T., Darras, V.M., 1998. Comparative study of iodothyronine outer ring and inner ring deiodinase activities in five teleostean fishes. Fish Physiology and Biochemistry 18, 253-266.
Orozco, A., Valverde, R.C., 2005. Thyroid hormone deiodination in fish. Thyroid 15, 799-813.
Power, D.M., Llewellyn, L., Faustino, M., Nowell, M.A., Bjornsson, B.T., Einarsdottir, I.E., Canario, A.V., Sweeney, G.E., 2001. Thyroid hormones in growth and development of fish. Comp Biochem Physiol C Toxicol Pharmacol 130, 447-459.
Schneider, M.J., Fiering, S.N., Pallud, S.E., Parlow, A.F., St Germain, D.L., Galton, V.A., 2001. Targeted disruption of the type 2 selenodeiodinase gene (D102) results in a phenotype of pituitary resistance to T-4. Molecular Endocrinology 15, 2137-2148.
Stinckens, E., Vergauwen, L., Blackwell, B.R., Anldey, G.T., Villeneuve, D.L., Knapen, D., 2020. Effect of Thyroperoxidase and Deiodinase Inhibition on Anterior Swim Bladder Inflation in the Zebrafish. Environmental Science & Technology 54, 6213-6223.
Walpita, C.N., Van der Geyten, S., Rurangwa, E., Darras, V.M., 2007. The effect of 3,5,3'-triiodothyronine supplementation on zebrafish (Danio rerio) embryonic development and expression of iodothyronine deiodinases and thyroid hormone receptors. Gen Comp Endocrinol 152, 206-214.
Webster GM, Venners SA, Mattman A, Martin JW. 2014. Associations between perfluoroalkyl acids (pfass) and maternal thyroid hormones in early pregnancy: A population-based cohort study. Environmental Research. 133:338-347.
Winata, C.L., Korzh, S., Kondrychyn, I., Korzh, V., Gong, Z. 2010. The role of vasulature and blood circulation in zebrafish swim bladder development. Dev. Biol. 10:3.
Winata, C.L., Korzh, S., Kondrychyn, I., Zheng, W., Korzh, V., Gong, Z. 2009. Development of zebrafish swimbladder: the requirement of Hedgehog signaling in specification and organization of the three tissue layers. Dev. Biol.331, 222–236, http://dx.doi.org/10.1016/j.ydbio.2009.04.035.