This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 2897


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, Oxidative Stress leads to TH synthesis, Decreased

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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 Simon Thomas (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 Do not cite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 Prakash Patel (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
mammals mammals Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

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.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Evidence is provided in terms of (i) the biological plausibility of the KER, and (ii) empirical evidence that supports, quantitatively or qualitatively, the manifestation of the relationship in mammals in vivo, or in mammalian ex vivo or in vitro systems.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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, as is observed in a wide range of organs, tissues and cells or cell lines, and are implicaated in the aetiology of numerous thyroid disorders, including the development of thyroid nodules, Hashimoto's thyroiditis, Graves disease and thyroid cancer (see Kochman et al (2021) and Macvanin et al (2023) for overviews).

Given that one of the major functions of the thyroid is to generate thyroxine (along with its structural analogue triiodothyronine (T3)), it is plausible that cellular dysfunction can lead to a reduction in the synthesis of T4 and T3.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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:

  1. Increased T4 clearance and/or
  2. Reduced T4 synthesis and secretion:
    1. Arising from increase in oxidative stress, and/or
    2. 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).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help

Al-Amoudi, W.M. (2018), "Toxic effects of lambda-cyalothrin on the rat thyroid: involvement of oxidative stress and ameliorative effect of ginger extract", Toxicology Reports, Vol 5, pp 728-736.

Amjad, S. et al (2020), "Role of antioxidants in alleviating bisphenol A toxicity", Biomolecules, Vol 10, 1105.

da Silva, M.M. et al (2018), "Bisphenol A increases hydrigen peroxide generation by thyrocytes both in vivo and in vitro", Endocrine Connections, Vol 7, pp 1196-1207.

Khan, R.A. (2012), "Protective effects of Sonchus asper (L.) Hill, (Asteraceae) against CCl4-induced oxidative stress in the thyroid tissue of rats", BMC Complementary and Alternative Medicine, Vol 12, 181.

Kochman, J. et al (2012), "The influence of oxidative stress on thyroid diseases", Antioxidants, Vol 10, 1442.

Macvanin, M.T. et al (2023), "The protective role of nutritional antioxidants against oxidative stress in thyorid disorders", Frontiers in Endocrinology, Vol 13, 1092837.

Mohammed, E.T. et al (2020), "Ginger extract ameliorates bisphenol A (BPA)-induced disruption in thyroid hormones synthesis and metabolism: involvement of Nr-2/HO-1 pathway", Science of the Total Environment, Vol 73, 134664.

Mondal, S. and Bandyopadhyay, A. (2023), "From oxidative imbalance to compromised standard sperm parameters: toxicological aspects of phthalate esters on spermatozoa", Environmental Toxicology and Pharmacology, Vol 98, 104085.

Unsal, V. et al (2020), "Toxicity of carbon tetrachloride, free radicals and role of antioxidants", Research in Environmental Health, Vol 36, pp279-295.

Wang, Q.-Y. et al (2023), "2,3',4,4',5-Pentachlorophenol induces mitochondria-dependent apoptosis mediated by AhR/Cyp1a1 in mouse germ cells", Journal of Hazard Materials, Vol 445, 130457.

Xu, W. et al (2022), "2,3’,4,4’,5-Pentachlorobiphenyl induced thyroid dysfunction by increasing mitochondrial oxidative stress", The Journal of Toxicological Sciences, Vol 47, pp 555-565.

Yang, C. et al (2020), "Mediation of oxidative stress toxicity induced by pyrethroid pesticides in fish", Comp Biochem Physiol C Toxicol Pharmacol., Vol 234, 108758.

Ye, H. et al (2017), "Di2-ethylhexyl phthalate disrupts thyroid hormone homeostasis through activating the Ras/Akt/TRHr pathway and inducing hepatic enzymes", Scientific Reports, Vol 7, 40153.