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Relationship: 2038
Title
T4 in serum, Decreased leads to Decreased, Triiodothyronine (T3) in serum
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Thyroperoxidase inhibition leading to increased mortality via reduced anterior swim bladder inflation | adjacent | Moderate | Moderate | Dries Knapen (send email) | Open for adoption | Under Development |
Thyroperoxidase inhibition leading to increased mortality via altered eye structure | adjacent | Lucia Vergauwen (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | High |
Life Stage Applicability
Term | Evidence |
---|---|
Juvenile | Moderate |
larvae | Moderate |
Key Event Relationship Description
When serum thyroxine (T4) levels are decreased, less T4 is available for conversion to the more biologically active triiodothyronine (T3). While some thyroid hormone (TH) disrupting mechanisms can immediately affect T3 levels, including deiodinase inhibition, other mechanisms reduce T4 levels, for example through inhibition of TH synthesis, leading to decreased T3 levels.
Since in fish early life stages TH are typically measured on a whole body level, it is currently uncertain whether TH levels changes occur at the serum and/or tissue level. Pending more dedicated studies, whole body TH levels are considered a proxy for serum TH levels.
This key event relationship is not always evident. This could be due to feedback/compensatory mechanisms that in some cases seem to be able to maintain T3 levels even though T4 levels are reduced, for example through increased conversion of T4 to T3 by deiodinases.
Evidence Supporting this KER
Biological Plausibility
When serum thyroxine (T4) levels are decreased, less T4 is available for conversion to the more biologically active triiodothyronine (T3). It is plausible to assume that while some thyroid hormone (TH) disrupting mechanisms can immediately affect T3 levels, including deiodinase inhibition, other mechanisms reduce T4 levels, for example through inhibition of TH synthesis, leading to decreased T3 levels.
Empirical Evidence
- A decrease in whole-body T4 and T3 was observed in zebrafish exposed to methimazole from fertilization until the age of 21 and 32 days and to propylthiouracil until the age of 14, 21 and 32 days (Stinckens et al., 2020). Additionally, a strong correlation was observed between T4 and T3 levels. Both compounds are thyroperoxidase inhibitors expected to inhibit thyroid hormone synthesis.
- A dose-dependent decrease in whole-body T4 and T3 was observed in zebrafish exposed to perfluorooctanoic acid and perfluoropolyether carboxylic acids from fertilization until the age of 5 days (Wang et al., 2020). The exact mechanisms by which PFAS disrupt the thyroid hormone system remain uncertain.
- While T4 measurements could not be acquired in fathead minnows exposed to 1 mg/L 2-mercaptobenzothiazole, a thyroperoxidase inhibitor, for 14 days, a significant decrease in T3 was observed (Nelson et al., 2016). The decreased T3 levels were likely the result of reduced T4 synthesis.
Uncertainties and Inconsistencies
- Since in fish early life stages THs are typically measured on a whole body level, it is currently uncertain whether TH levels changes occur at the serum and/or tissue level. Pending more dedicated studies, whole body TH levels are considered a proxy for serum TH levels.
- This relationship depends on the MIE that is causing the decrease in T3. For example, deiodinase inhibition results in reduced activation of T4 to T3 and thus in reduced T3 levels; increased T4 levels have been observed, probably as a compensatory mechanism in response to the lower T3 levels. For example, Cavallin et al. (2017) exposed fathead minnows to iopanoic acid, a deiodinase inhibitor, and observed T4 increases together with T3 decreases.
- This key event relationship is not always evident. This could be due to feedback/compensatory mechanisms that in some cases seem to be able to maintain T3 levels even though T4 levels are reduced, for example through increased conversion of T4 to T3 by deiodinases. Examples of studies showing reduced T4 levels in the absence of reduced T3 levels:
- Zebrafish exposed to 0.35 mg/L 2-mercaptobenzothiazole, a thyroperoxidase inhibitor, through 32 dpf showed decreased whole-body T4, but T3 levels showed particularly large variation and overall were not significantly decreased (Stinckens et al., 2016).
- Although T4 content of 28 dpf larval fathead minnows exposed to 32 or 100 µg/l methimazole, a thyroperoxidase inhibitor, was reduced, these fish showed no change in whole body T3 content (Crane et al., 2006). Significantly higher T3/T4 ratios in fish held in 100 µg/l methimazole suggest an increased conversion of T4 to T3 or reduced degradation and conjugation during continued exposure to methimazole
Quantitative Understanding of the Linkage
Stinckens et al. (2020, supplementary information) showed a significant linear relationship between whole body T3 and T4 concentrations at 21 and 32 days post fertilization after continuous exposure of zebrafish to methimazole and propylthiouracil, two inhibitors of TH synthesis.
Response-response Relationship
Time-scale
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
This key event relationship is not always evident. This could be due to feedback/compensatory mechanisms that in some cases seem to be able to maintain T3 levels even though T4 levels are reduced, for example through increased conversion of T4 to T3 by deiodinases. Examples of studies showing reduced T4 levels in the absence of reduced T3 levels:
- Zebrafish exposed to 0.35 mg/L 2-mercaptobenzothiazole, a thyroperoxidase inhibitor, through 32 dpf showed decreased whole-body T4, but T3 levels showed particularly large variation and overall were not significantly decreased (Stinckens et al., 2016).
- Although T4 content of 28 dpf larval fathead minnows exposed to 32 or 100 µg/l methimazole, a thyroperoxidase inhibitor, was reduced, these fish showed no change in whole body T3 content (Crane et al., 2006). Significantly higher T3/T4 ratios in fish held in 100 µg/l methimazole suggest an increased conversion of T4 to T3 or reduced degradation and conjugation during continued exposure to methimazole
This relationship depends on the MIE that is causing the decrease in T3. For example, deiodinase inhibition results in reduced activation of T4 to T3 and thus in reduced T3 levels; increased T4 levels have been observed, probably as a compensatory mechanism in response to the lower T3 levels. For example, Cavallin et al. (2017) exposed fathead minnows to iopanoic acid, a deiodinase inhibitor, and observed T4 increases together with T3 decreases.
Domain of Applicability
Taxonomic: The evidence for a relationship between circulating T4 and T3 levels currently comes from work on zebrafish and fathead minnow.
Life stage: This key event relationship is applicable to late larvae and juveniles rather than to embryos, because of the presence of maternal TH in embryos.
Uncertainties during embryonic lifestage:
- A decrease in T4 was observed in fathead minnows exposed to 1 mg/L 2-mercaptobenzothiazole (MBT), a thyroperoxidase inhibitor, through 6 dpf (Nelson et al., 2016). In contrast, there was no observed effect on T3 in fathead minnows exposed to MBT through 6 dpf. Comparably, zebrafish exposed to 0.4 or 0.7 mg/L MBT through 120 hpf showed decreased T4 but not T3 (Stinckens et al., 2016). During this early larval life stage, T3 may have been derived from maternal T4. In addition, it could be produced from further depletion of any T4 still produced by the thyroid gland (as thyroperoxidase may not have been fully inhibited at the tested exposure concentrations).
- Since exposure to PFAS did result in decreased whole-body T4 and T3 in 5 day old zebrafish, the life-stage specificity possibly depends on the mechanism that lies at the basis of the TH changes (Wang et al., 2020). The exact mechanisms by which PFAS disrupt the thyroid hormone system remain uncertain. Compounds that directly reduce T3 levels (e.g., deiodinase inhibitors) in addition to reducing T4 levels via another mechanism can be expected to result in decreased T4 and T3 levels.
Sex: This KER is probably not sex-dependent since both females and males have the same mechanisms of TH synthesis and conversion. Additionally, zebrafish are undifferentiated gonochorists, and gonad differentiation starts only around 23-25 dpf (Uchida et al., 2002), and the current data is based on larvae younger than or around that age.
References
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.
Crane, H.M., Pickford, D.B., Hutchinson, T.H., Brown, J.A., 2006. The effects of methimazole on development of the fathead minnow, pimephales promelas, from embryo to adult. Toxicological Sciences 93, 278-285.
Nelson, K., Schroeder, A., Ankley, G., Blackwell, B., Blanksma, C., Degitz, S., Flynn, K., Jensen, K., Johnson, R., Kahl, M., Knapen, D., Kosian, P., Milsk, R., Randolph, E., Saari, T., Stinckens, E., Vergauwen, L., Villeneuve, D., 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part I: Fathead minnow. Aquatic Toxicology 173, 192-203.
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.
Stinckens, E., Vergauwen, L., Schroeder, A., Maho, W., Blackwell, B., Witters, H., Blust, R., Ankley, G., Covaci, A., Villeneuve, D., Knapen, D., 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part II: Zebrafish. Aquatic Toxicology 173, 204-217.
Wang, J.X., Shi, G.H., Yao, J.Z., Sheng, N., Cui, R.N., Su, Z.B., Guo, Y., Dai, J.Y., 2020. Perfluoropolyether carboxylic acids (novel alternatives to PFOA) impair zebrafish posterior swim bladder development via thyroid hormone disruption. Environment International 134.