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Increase, Oxidative Stress leads to TH synthesis, Decreased
Key Event Relationship Overview
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 Do not cite|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 Do not cite|
Life Stage Applicability
Key Event Relationship Description
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
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
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.
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
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).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.