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Succinate dehydrogenase inhibition leading to increased insulin resistance through reduction in circulating thyroxine
Point of Contact
- Simon Thomas
- Prakash Patel
|Handbook Version||OECD status||OECD project|
This AOP was last modified on June 02, 2023 08:12
|Succinate dehydrogenase, inhibited||May 04, 2023 11:49|
|Insulin resistance, increased||May 26, 2023 06:34|
|Thyroxine (T4) in serum, Decreased||October 10, 2022 08:52|
|Superoxide generation, increased||April 17, 2023 06:40|
|Thyroid hormone synthesis, Decreased||November 04, 2022 09:25|
|Increase, Oxidative Stress||March 03, 2022 10:40|
|SDH, inhibited leads to Superoxide generation, increased||May 04, 2023 07:10|
|Superoxide generation, increased leads to Increase, Oxidative Stress||June 01, 2023 17:09|
|Increase, Oxidative Stress leads to TH synthesis, Decreased||May 23, 2023 11:58|
|TH synthesis, Decreased leads to T4 in serum, Decreased||October 10, 2022 08:56|
|T4 in serum, Decreased leads to Insulin resistance, increased||April 20, 2023 08:15|
|Di(2-ethylhexyl) phthalate||November 29, 2016 18:42|
|Mono(2-ethylhexyl) phthalate||November 29, 2016 18:42|
Many environmental contaminants are known or suspected to generate adverse effects through multiple mechanisms, within multiple cell types, and potentially acting across multiple biological systems, thus rendering elucidation of cause and effect highly challenging. The purpose of creating this AOP is to collate evidence for a plausible pathway by which inhibition of a mitochondrial enzyme, succinate dehydrogenase, could, via disruption of the hypothalamus-pituitary-thydroid axis, contribute to the development of a clinically significant metabolic disruption, namely an increase in insulin resistance (IR).
Key to identifying a metabolic effect mediated by thyroid disruption from a direct xenobiotic impact on metabolism is the existence of evidence that qualitatively or quantitatively differentiates between potential impacts via the two routes. Clinical data support the hypothesis that exposure to DEHP - as determined by renal excretion of its major metabolites - has components of both thyroid-mediated (via reduction in circulating free thyroxine concentration) and direct impacts on increase in IR. In vitro data support the hypotheses that (i) inhibition of succinate dehydrogenase can lead to oxidative stress, and (ii) increasing oxidative stress in the thyroid follicular cells can lead to reduction in thyroid hormone secretion. Thus, a plausible link can be established between thyroidal succinate dehydrogenase inhibition and increase in IR.
It must be borne in mind that additional molecular initiating events (MIEs) and alternative pathways to increase in IR are plausible for many xenobiotics.
AOP Development Strategy
This AOP was created in order to collate information, and attempt to drive understanding, around several key issues concerning xenobiotic driven disruption of energy metabolism, and the subsequent development of related pathologies. Specifically, the focus is on the nature and extent of the component of this disruption that can potentially be mediated via alteration of thyroid gland function, and consequent changes in circulating thyroid hormone concentrations (Huang et al, 2021).
Amongst classes of xenobiotics, fragmentary evidence indicates that this is one possible route - amongst many - by which toxicity of phthalate esters could manifest itself. This evidence includes the observations that :
- Phthalate esters can increase reactive oxygen species (ROS) concentrations in multiple in vitro systems and in vivo (see, for example, Mondal and Bandypoadhayay, 2023).
- Phthalate esters can decrease concentrations of thyroid hormones in vivo (Kim et al, 2019).
- Phthalate ester exposure has been correlated to pathologies of energy metabolism, such as insulin resistance (Shoshtari-Yeganeh et al, 2019; Gao et al, 2021).
- Decrease in circulating thyroid hormones has been linked to the development of insulin resistance (Brenta, 2011).
Given the role of thyroid hormones in regulating energy metabolism, including glucose and lipids, the possibility exists for phthalate-induced disruptions in energy metabolism and contribution to subsequent pathologies to be mediated at least, in part, through their impacts on thyroid function.
This AOP was developed as part of the ScreenED project, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 825745.
Identification of molecular initiating event
A significant body of data indicates that:
- Many xenobiotics generate ROS in vitro and/or in vivo (e.g. Amjad et al, 2020; Mondal and Bandypoadhayay, 2023; Unsal et al, 2020; Wang et al, 2023; Yang et al, 2020).
- ROS generation resulting in oxidative stress can be a contributing factor - potentially the most important factor for some xenobiotics - in the induction of toxic, pathological outcomes (e.g. Amjad et al, 2020; Mondal and Bandypoadhayay, 2023; Unsal et al, 2020; Wang et al, 2023; Yang et al, 2020).
- Multiple mechanisms of excess ROS generation are known, including mechanisms specific to particular cell types, and mechanisms specific to particular xenobiotics or xenobiotic classes (see ArulJothi et al, 2023, for review)
- The main source of ROS generation under normal physiological conditions in most cell types is the electron transport chain of the mitochondria (Murphy, 2009).
Consequently, of the multiple potential routes of ROS generation, a mechanism involving increased mitochondrial generation is a strong candidate for a potential MIA.
Identification of adverse outcome
Xenobiotic-induced metabolic disfunction can manifest itself in multiple biochemical and physiolological outcomes. These can be of clinical significance in themselves, of significance when taken in conjunction with other measures, and/or indicators of potential progression to further endpoints that may be of clinical significance. Insulin resistance (IR), a measure of the extent to which cells do not respond normally to insulin, is a component of metabolic syndrome, which, in turn, predisposes to type 2 diabetes and cardiovascular disease. Given this central position in the development of metabolic pathologies, and that it can be determined by simple blood measurements, it represents a quantifiable endpoint of clinical relevance, suitable for identification as a significant adverse outcome in and of itself.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Type||Event ID||Title||Short name|
|MIE||2118||Succinate dehydrogenase, inhibited||SDH, inhibited|
|KE||2120||Superoxide generation, increased||Superoxide generation, increased|
|KE||1969||Increase, Oxidative Stress||Increase, Oxidative Stress|
|KE||277||Thyroid hormone synthesis, Decreased||TH synthesis, Decreased|
|KE||281||Thyroxine (T4) in serum, Decreased||T4 in serum, Decreased|
|AO||2119||Insulin resistance, increased||Insulin resistance, increased|
Relationships Between Two Key Events (Including MIEs and AOs)
|SDH, inhibited leads to Superoxide generation, increased||adjacent||High||Low|
|Superoxide generation, increased leads to Increase, Oxidative Stress||adjacent||High||Low|
|Increase, Oxidative Stress leads to TH synthesis, Decreased||adjacent||Moderate||Low|
|TH synthesis, Decreased leads to T4 in serum, Decreased||adjacent||High|
|T4 in serum, Decreased leads to Insulin resistance, increased||adjacent||Moderate||Moderate|
Life Stage Applicability
Overall Assessment of the AOP
The first iteration of the AOP has been developed in order to outline a plausible route by which stressors that induce oxidative stress could contribute to the global burden of metabolic pathologies acting, specifically, via reduction in thyroid hormone synthesis, and corresponding reduction in circulating thyroxine levels. It was also considered important to identify a particular mechanism that can induce oxidative stress. For phthalate esters, particularly DEHP, there is documented evidence for the chain of events leading from succinate dehydrogenase inhibition, through an increase in thyroid gland oxidative stress and reduction in circulating thyroxine levels, to an increase in insulin resistance (Huang et al, 2021).
Domain of Applicability
In vivo evidence for this AOP supports its applicability to adult humans (Huang et al, 2021).
Essentiality of the Key Events
|Key Event||Defining question||High (strong)||Moderate||Low (weak)|
|Are downstream KEs and/or the AO prevented if an upstream KE is blocked?||Direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important KEs||Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE||No or contradictory experimental evidence of the essentiality of any of the KEs|
|KE 2118 (MIE): Succinate dehydrogenase, inhibited||No direct evidence identified|
|KE 2120: Superoxide generation, increased||No direct evidence identified|
|KE 1969: Increase, Oxidative Stress|
|KE 277: Thyroid hormone synthesis, Decreased||Pharmacological inhibition of thyroid synthesis has been observed to lead to increase in insulin resistance in animals.|
|KE 281: Thyroxine (T4) in serum, Decreased||Reduction in T4 concentration contributing to an increase in insulin resistance in humans has been inferred using mediation analysis (Huang et al, 2021).|
|Key Event Relationship||Defining question||High (strong)||Moderate||Low (weak)|
|Is there a mechanistic (i.e., structural or functional) relationship between KEup and KEdown consistent with established biological knowledge?||Extensive understanding based on extensive previous documentation and broad acceptance -Established mechanistic basis||The KER is plausible based on analogy to accepted biological relationships but scientific understanding is not completely established.||There is empirical support for a statistical association between KEs (See 3.), but the structural or functional relationship between them is not understood.|
|SDH, inhibited leads to superoxide generation, increased||Inhibition of mitochondrial succinate dehydrogenase has been demonstrated to lead to an increase in mitochondrial superoxide generation in in vitro studies|
|Superoxide generation, increased leads to Increase, Oxidative Stress||Activation of superoxide generation, and superoxide dismutase overexpression have been shown to lead, respectively, to increase and decrease of markers of oxidative stress within cells.|
|Increase, Oxidative Stress leads to TH synthesis, Decreased||Increased oxidative stress leads to adverse biochemical and histological outcomes in thyroid cells in vitro and in vivo, including reduced follicular colloidal amounts|
|TH synthesis, Decreased leads to T4 in serum, Decreased||Inhibition of T4 synthesis in vivo is expected to lead to reduction in circulating T4 concentration, though mediated by the counterbalancing effect of negative feedback in the|
|T4 in serum, Decreased leads to Insulin resistance, increased||Decreased T4 serum concentration has been demonstrated to result in increase in insulin resistance in rodent studies and in humans|
Known Modulating Factors
|Modulating Factor (MF)||Influence or Outcome||KER(s) involved|
Quantitative understanding of the AOP is currently low.
Considerations for Potential Applications of the AOP (optional)
Amjad, S. et al (2020), "Role of antioxidants in alleviating bisphenol A toxicity", Biomolecules, Vol 10, 1105.
ArulJothi, K.N. et al (2023), "Implications of reactive oxygen species in lung cancer and exploiting it for therapeutic interventions", Medical Oncology, Vol 40, 43.
Brenta, G. (2011), "Why can insulin resistance be a natural consequence of thyroid dysfunction?", Journal of Thyroid Research, 152850.
Gao, H. et al (2021), "Association between phthalate exposure and insulin resistance: a systemic review and meta-analysis update", Environmental Science and Pollution Research International", Vol 28, pp 55967-55980.
Huang, H-B et al (2021), "Mediation effects of thyroid function in the associations between phthalate exposure and glucose metabolism in adults", Environmental Pollution Vol 278, 116799.
Kim, M.J. et al (2019), "Association between Diethylhexyl phthalate exposure and thyroid function: a meta-analysis", Thyroid, Vol 29, pp 183-192, with correction in Vol 29, 752.
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.
Murphy, M.P. (2009), "How mitochondria produce reactive oxygen species", Biochemical Journal, Vol 417, pp 1-13.
Shoshtari-Yeganeh, B, et al (2019) "Systematic review and meta-analysis on the association between phthalates exposure and insulin resistance", Environmental Science and Pollution Research International", Vol 26, pp 9435-9442.
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.
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.