This AOP is open for adoption and licensed under the BY-SA license. The BY-SA 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.

This AOP is open for adoption. Please email to indicate your interest in becoming the main point of contact for this AOP.
AOP: 496


A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Training duplicate-Estrogen receptor alpha (ERa) inactivation alters mitochondrial functions and insulin signaling in skeletal muscle and leads to insulin resistance and metabolic syndrome

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
ERa inactivation leads to insulin resistance in skeletal muscle and metabolic syndrome

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool


The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Arthur Author   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Arthur Author
  • Min Ji Kim
  • Jean-Pascal de Bandt
  • Antoine Girardon
  • Etienne Blanc
  • Xavier COUMOUL
  • Karine Audouze


This field is used to identify coaches who supported the development of the AOP. Each coach selected must be a registered author. More help
  • Travis Karschnik


Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Handbook Version OECD status OECD project
This AOP was last modified on June 07, 2023 08:51

Revision dates for related pages

Page Revision Date/Time
Estrogen receptor alpha inactivation April 10, 2023 13:29
Decreased, Mitochondrial fatty acid beta-oxidation September 16, 2017 10:14
Increased, Reactive oxygen species April 10, 2023 14:01
Mitochondrial dysfunction November 02, 2020 07:11
Increased, Oxidative Stress February 03, 2022 14:20
Impaired insulin signaling June 05, 2023 14:42
Insulin resistance June 27, 2022 23:17
Metabolic syndrome June 05, 2023 14:45
ERa inactivation leads to Increased, Reactive oxygen species June 05, 2023 14:12
ERa inactivation leads to Decreased, Mitochondrial fatty acid beta-oxidation June 05, 2023 14:14
Increased, Oxidative Stress leads to Mitochondrial dysfunction June 05, 2023 14:47
Increased, Reactive oxygen species leads to Increased, Oxidative Stress December 03, 2016 16:38
Decreased, Mitochondrial fatty acid beta-oxidation leads to Mitochondrial dysfunction June 05, 2023 14:50
Mitochondrial dysfunction leads to Impaired insulin signaling June 05, 2023 14:51
Increased, Oxidative Stress leads to Impaired insulin signaling June 05, 2023 14:52
Impaired insulin signaling leads to Insulin resistance June 05, 2023 14:53
Insulin resistance leads to Metabolic syndrome June 05, 2023 14:55


A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Estrogens are not only important in the development and functions of the reproductive system, but also play a role in metabolic functions and insulin sensitivity. Thus, before menopause,  women display higher insulin sensitivity and lower propensity to develop metabolic dysfunction-related diseases such as insulin resistance, type 2 diabetes, cancers and cardiovascular diseases than men but, after menopause, incidence of these diseases is similar in both sex [1]. In parallel, hormone replacement therapy has positive effects on insulin resistance [2]. Similarly, men with a mutation in the aromatase gene, who don’t have circulating estrogen, develop insulin resistance that can be reversed by estrogen therapy [3].

Skeletal muscle is known to play a central role in the development of insulin resistance (IR). Due to the important mass of skeletal muscle (30 to 40% of total body mass), any defect in glucose entry into the muscle cells, caused by muscle IR, significantly affects whole body glucose disposition. Subsequently, IR in skeletal muscle favors hyperglycemia and increase the risk of type 2 diabetes [4]. The importance of estrogens and their effects mediated through ERa in insulin resistance was suggested by whole body ERa knock-out (KO) and muscle-specific ERa KO mice that are obese and insulin resistant [5,6]. A negative association between muscle ERa expression and fat mass or insulinemia is observed in women and in genetically obese mice emphasizing the importance of muscle ERa signaling in insulin sensitivity [6]. Thus, the alterations resulting from reduced muscle ERa activity is important to consider to better understand mechanisms leading to muscle insulin resistance.

Decreased mitochondrial oxidative capacity, increased production of reactive oxygen species and impaired insulin signaling should be considered as they are known to be key features of insulin-resistant muscle [7] and are also present in ERa KO mice [5,6].

Thus, the AOP that we propose here links the inactivation of ERa in skeletal muscle to one of the hallmarks of the metabolic syndrome that is insulin resistance taking account the following events “decreased mitochondrial fatty acid oxidation”, “increased reactive oxygen species”, “mitochondrial dysfunction”, “increased oxidative stress” and “impaired insulin signaling”.

AOP Development Strategy


Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help


Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help


Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 2126 Estrogen receptor alpha inactivation ERa inactivation
KE 179 Decreased, Mitochondrial fatty acid beta-oxidation Decreased, Mitochondrial fatty acid beta-oxidation
KE 1115 Increased, Reactive oxygen species Increased, Reactive oxygen species
KE 1816 Mitochondrial dysfunction Mitochondrial dysfunction
KE 1088 Increased, Oxidative Stress Increased, Oxidative Stress
KE 2134 Impaired insulin signaling Impaired insulin signaling
AO 2018 Insulin resistance Insulin resistance
AO 2135 Metabolic syndrome Metabolic syndrome

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help


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

[1]       M.C. Carr, The emergence of the metabolic syndrome with menopause, J Clin Endocrinol Metab. 88 (2003) 2404–2411.

[2]       F. Mauvais-Jarvis, J.E. Manson, J.C. Stevenson, V.A. Fonseca, Menopausal Hormone Therapy and Type 2 Diabetes Prevention: Evidence, Mechanisms, and Clinical Implications, Endocr Rev. 38 (2017) 173–188.

[3]       V. Rochira, B. Madeo, L. Zirilli, G. Caffagni, L. Maffei, C. Carani, Oestradiol replacement treatment and glucose homeostasis in two men with congenital aromatase deficiency: evidence for a role of oestradiol and sex steroids imbalance on insulin sensitivity in men, Diabet Med. 24 (2007) 1491–1495.

[4]       R.A. DeFronzo, D. Tripathy, Skeletal muscle insulin resistance is the primary defect in type 2 diabetes, Diabetes Care. 32 Suppl 2 (2009) S157-163.

[5]       V. Ribas, M.T.A. Nguyen, D.C. Henstridge, A.-K. Nguyen, S.W. Beaven, M.J. Watt, A.L. Hevener, Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice, Am J Physiol Endocrinol Metab. 298 (2010) E304-319.

[6]       V. Ribas, B.G. Drew, Z. Zhou, J. Phun, N.Y. Kalajian, T. Soleymani, P. Daraei, K. Widjaja, J. Wanagat, T.Q. de Aguiar Vallim, A.H. Fluitt, S. Bensinger, T. Le, C. Radu, J.P. Whitelegge, S.W. Beaven, P. Tontonoz, A.J. Lusis, B.W. Parks, L. Vergnes, K. Reue, H. Singh, J.C. Bopassa, L. Toro, E. Stefani, M.J. Watt, S. Schenk, T. Akerstrom, M. Kelly, B.K. Pedersen, S.C. Hewitt, K.S. Korach, A.L. Hevener, Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females, Sci Transl Med. 8 (2016) 334ra54.

[7]       S. Di Meo, S. Iossa, P. Venditti, Skeletal muscle insulin resistance: role of mitochondria and other ROS sources, J Endocrinol. 233 (2017) R15–R42.