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Relationship: 2897
Title
Increase, Oxidative Stress leads to TH synthesis, Decreased
Upstream event
Downstream event
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Succinate dehydrogenase inhibition leading to increased insulin resistance through reduction in circulating thyroxine | adjacent | Moderate | Low | Evgeniia Kazymova (send email) | Under development: Not open for comment. Do not cite | |
| AhR activation in the thyroid leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals | adjacent | Moderate | Low | Brendan Ferreri-Hanberry (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
| Term | Scientific Term | Evidence | Link |
|---|---|---|---|
| mammals | mammals | Moderate | NCBI |
Sex Applicability
| Sex | Evidence |
|---|---|
| Male | Moderate |
Life Stage Applicability
| Term | Evidence |
|---|---|
| Adult | Moderate |
Increases in oxidative stress in the thyroid gland in vivo and in thyroid cells or cell lines in vitro have been shown to cause detrimental change to multiple aspects of thyroid structure and function. Within this KER, evidence is collated that such changes could include reduction in thyroxine (T4) synthesis, with consequential reduction in T4 secretion into the blood.
A search of Pubmed was made for the following terms:
((thyroxine[Title] OR thyroid[Title]) AND "oxidative stress"[Title]) OR (thyroxine[Title/Abstract] AND ROS[Title/Abstract])
that retrieved 194 hits on 10/05/2023. The abstracts of these hits were individually inspected for any indication of reference to data relevant to the impact of oxidative stress on thyroid hormone synthesis/release (whether stimuatory, inhibitive or without effect). This inspection resulted in the identification of 33 publications for initial detailed investigation. These publications were reviewed in full, along with any citations within them that indicated further information regarding this KER - supportive or otherwise - could be found within them.
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
The bulk of the empirical evidence described above supports the view that administration of high doses of certain xenobiotics (e.g. bisphenol A, CCL4, DEHP, lambda-cyhalothrin) in vivo results in oxidative stress in the thyroid, frequently with clear histological evidence of structural disruption, including loss of colloidal material, and hypothyroidism; namely reduced plasma concentrations of T3 and T4, and elevated plasma TSH. These compounds are, though, well documented as generators of reactive oxygen species or oxidative stress. Similarly, though, several of the compounds are documented as stimulators of T4 clearance. Furthermore, the relatively long-term duration of the studies, and the high doses used, raises the possibility that any changes in T4 secretion rate are consequences of thyroidal changes brought about by other mechanisms, rather than direct response increased oxidative stress in the thyroid: the thyroidal oxidative stress observed could be a consequence of thyroidal damage, without, itself, necessarily being a cause of reduced T4 synthesis. As a result, the observed changes in plasma T4 concentration could be a consequence of contributions from:
- Increased T4 clearance and/or
- Reduced T4 synthesis and secretion:
- Arising from increase in oxidative stress, and/or
- Arising from other mechanisms that may cause an increase in oxidative stress.
The balance between these contributions can be expected to differ between compounds. Further evidence regarding timings and the chain of events is necessary to determine cause and effect, and the balance of these contributions for different compounds.
In contrast to the empirical evidence presented above, treatment of female wistar rats with 40mg/kg/day bisphenol A for 15 days led to an increase in total T3 of 33% over controls, despite evidence for increase in thyroidal reactive oxygen species (specifically H2O2), reduction in radioactive iodine uptake, and detrimental histological changes in the thyroid gland, including loss of follicular colloid (da Silva et al, 2018).