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Relationship: 3274
Title
Oxidative Stress leads to TH synthesis, Decreased
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 |
---|---|---|---|---|---|---|
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 Do not cite | |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 Do not cite |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
Term | Scientific Term | Evidence | Link |
---|---|---|---|
mammals | mammals | Moderate | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Male | Moderate |
Life Stage Applicability
Term | Evidence |
---|---|
Adult | Moderate |
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.
Biological Plausibility
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.
Empirical Evidence
Male albino rats treated with 3mg/kg carbon tetrachloride (CCL4) intraperitonally (ip) on two occasions 3 days apart showed significantly reduced serum triiodithyronine (T3) and thyroxine (T4) and increase in TSH. Thyroid weight, and relative thyroid weight increased, as did thyroidal DNA damage. Follicular colloid was depleted, blood thyroidal blood vessels were congested and follicular cells showed hyperplasia. Thyroidal glutathione (GSH) decreased, but thyroidal TBARS (thiobarbituric acid reactive substances), hydrogen peroxide (H2O2) and nitrites increased. Protein content of thyroid 12000g supernatant decreased. Catalase and peroxidase activities and superoxide dismutase specific activities were significantly reduced, as were the specific activities of glutathione transferase, glutathione reductase, glutathione peroxidase and quinone reductase. The specific activity of gamma-glutamyl transferase, an enzyme of the glutathione cycle, involved in the synthesis of glutathione, was increased. The decrease in glutathione, and the increases in TBARS and H2O2 demonstrate an increase in oxidative stress, supported by the observation of increased DNA damage. The enzyme changes observed could be contributory factors in that oxidative stress increase. The histological observations indicate significant changes in thyroidal form and function, potentially leading to a decrease in net T4 synthesis and secretion. All observed and measured changes were mitigated by administration of a methanolic extract of Sonchus asper, an effect hypothesised to be mediated by anti-oxidant compounds (sesquiterpene lactone alkaloids, ascorbic acid and carotenoids) in the plant. Most effects were mitigated in a dose-dependent manner (using 100 or 200mg/kg of extract administered orally). Sonchus asper extract given alone did not significantly effect any of the biochemical measurements or histological observations (Khan 2012).
Male Sprague-Dawley rats treated with DEHP (250, 500, 750mg/kg/day)for 30 days showed a decrease in plasma total free and total triiodothyronine (fT3 and tT3), free and total thyroxine (fT4 and tT4) and thyrotropin releasing hormone (TRH), with unchanged levels of plasma TSH. Histological assessment of the thyroid showed dose-dependent increases in the number of follicular cells and reduction in the follicular cavity volume. Ultrastructural changes observed with TEM included changes to nucleus, dilation of the RER and appearance of vacuoles. Reactive oxygen species (ROS) were generated in the liver. In vitro, Nthy-ori 3-1 cells treated with 400µM for 24hours showed an increase in ROS generation over controls that was largely diminished by the presence of 1mM N-acetyl cycteine, a ROS scavenger (Ye et al, 2017).
Male Wistar rats treated with the synthetic pyrethroid insecticide lambda-cyhalothrin (α-cyano-3-phenoxy -benzyl-3-(2-chloro-3, 3,3-trifluoro-1-propenyl)-2, 2-dimethylcyclopropanecarboxylate, LCT) at 0.79mg/kg (1% of the LD50) for 3 days/week for 4 weeks for a total study duration of 30 days showed significant decreases in plasma T3 and T4 and a significant increase in TSH. Investigations of the thyroid in treated rats showed multiple structural, biochemical and pathological alterations, including degeneration of thyroid follicles; reduction in periodic acid-Schiff staining in colloid and mercury bromophenol blue staining in colloid and follicular cells indicating, respectively, reduction in carbohydrate-containing macromolecules and protein content; reduction of mean follicular diameter from 35µm to 23µm; statistically significant increases in measures of DNA damage (tail length and percent of DNA damaged) determined in the comet assay. Statistical increases in plasma malondialdehyde (MDA, a marker of reactive oxygen species (ROS) activity), superoxide dismutase and catalase indicate an increase in the body burden of ROS caused by LCT treatment (Al-Amoudi et al, 2018). All of these changes were ameliorated by co-administration of ginger extract with LCT, an effect ascribed to the anti-oxidant propeties of compounds in the ginger extract.
Male albino rats treated with 200mg/kg/day bisphenol A (BPA) orally for 35 days showed significant increase in serum TSH and decrease in T3 and T4 compared to control animals. Thyroid weight, but not body weight was significantly reduced. Markers of increased oxidative stress or damage in the thyroid include inreased malondialdehyde concentration, DNA damage (increased tail length and moment, and increased % damaged DNA in the comet assay) and decreased reduced glutathione concentration. Thyroidal gene or protein expression changes included increased induction of myeloperoxidase, decrease in nuclear factor erythroid-derived 2-like 2 (Nrf-2) gene expression and protein concentration and haem-oxygenase 1 (HO-1) expression, and increase in inducible nitric oxide synthase (iNOS) compared to control. mRNA levels of TSHR, TPO and NIS were all reduced. Histological evaluation of the thyroid revealed BPA-induced congestion of capillaries, increased lymphocyte infiltration, increase in variability of follicle size and marked decrease in colloid content compared to control animals. Nearly all effects were wholly or partially ameliorated by co-administration of ginger extract (Mohammed et al, 2020).
Male Wistar rates exposed to PCB118 for 13 weeks showed a dose-dependent decrease in plasma free triiodothyronine (fT3), plasma free thyroxine (fT4) and increase in plasma thyroid stimulating hormone (TSH) over doses of 0,10,100 and 1000µg/kg/day. Thyroids from treated rats, and FRTL-5 cells treated with a range of concentrations up to 25nM showed histological and biochemical signs of disruption, and evidence for generation of reactive oxygen species (Xu et al, 2022).
These compounds have been shown to generate reactive oxygen species or oxidative stress in vivo (Amjad et al, 2020; Mondal and Bandyopadhyay, 2023; Unsal et al, 2020; Wang et al, 2023; Yang et al, 2020).
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
Quantitative Understanding of the Linkage
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
References
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.