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AOP: 309

Title

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

Luteinizing hormone receptor antagonism leading to reproductive dysfunction

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

Luteinizing hormone receptor antagonism

The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help

Handbook Version v2.0

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

Authors

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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

Young Jun Kim (email point of contact)

Contributors

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

Young Jun Kim
June-Woo Park

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on April 29, 2023 16:03

Revision dates for related pages

Page	Revision Date/Time
Antagonism,LH receptor	October 03, 2019 11:03
Reduction, Progesterone synthesis	October 03, 2019 11:04
Reduction, Plasma progesterone concentration	October 03, 2019 11:06
Reduction, progesterone uptake, decresed maturation	October 03, 2019 11:09
Impaired ovulation	October 03, 2019 11:10
Decrease of egg production and cummulative fecundity	October 03, 2019 11:13
Decline, Population trajectory	December 03, 2016 16:37
Antagonism,LH receptor leads to Reduction, Progesterone synthesis	October 03, 2019 11:14
Reduction, Progesterone synthesis leads to Reduction, Plasma progesterone concentration	October 03, 2019 11:15
Reduction, Plasma progesterone concentration leads to Reduction, progesterone uptake, decresed maturation	October 03, 2019 11:15
Reduction, progesterone uptake, decresed maturation leads to Impaired ovulation	October 03, 2019 11:16
Impaired ovulation leads to Decrease of egg production and cummulative fecundity	October 03, 2019 11:17
Decrease of egg production and cummulative fecundity leads to Decline, Population trajectory	October 03, 2019 11:17
Progesterone,estrogen,melatonin,Letrozole	October 03, 2019 11:39
glucocorticoids	October 03, 2019 12:06
Cetrorelix	October 03, 2019 12:09
Interleukin-6	October 03, 2019 12:28

Abstract

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This AOP is designed to detect changes in cumulative fecundity and egg production resulted from the inhibition of LHR by its antagonisms. Alteration of fecundity and ovulation in fish is the critical endpoint for reproductive toxicity caused by endocrine disrupting chemicals. This endpoint is essential and useful for screening of the potential endocrine disrupting chemicals and/or risk assessment. Therefore, this AOP can be applied to the prediction of reproductive toxicity caused by the inhibition of LHR.

AOP Development Strategy

Context

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

This AOP describes an adverse outcome that results from the Luteinizing hormone (LH) receptor antagonism leading to reproductive dysfunction in female fish. Luteinizing hormone (LH) is glycoprotein hormones, called gonadotropins, that control gonadal functions. Gonadotropins exert their action through gonadotropin receptors, the LH receptor. In many species, LHR is primarily expressed in reproductive organs and function coordinately to control steroidogenesis and ovulation. It is well known that in teleosts, LHR is expressed primarily in the theca and granulosa cells of preovulatory ovarian follicles. LH regulates the expression of a variety of genes essential for ovulation, such as genes that code for steroidogenic enzymes (CYP11A1) which convert from cholesterol to pregnelone resulting the synthesis of progesterone. It is well organized that the luteinizing hormone triggers ovulation through progesterone binding to the progesterone receptor. The nuclear progesterone receptor, which is a member of the nuclear receptor transcription factor superfamily, has been suggested as an essential factor for LH-dependent ovulation in fish. In conclusion, LHR inhibition leads to a reduction of the synthesis of Progesterone, which is indispensable for ovulation and fertility in fish.

Acknowledgements: This research was supported by the National Research Council of Science & Technology(NST) grant by the Korea government (MSIP) (No. CAP-17-01-KIST Europe)

Strategy

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

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Events:

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

1691

Antagonism,LH receptor

KE	1692	Reduction, Progesterone synthesis	Reduction, Progesterone synthesis
KE	1693	Reduction, Plasma progesterone concentration	Reduction, Plasma progesterone concentration
KE	1694	Reduction, progesterone uptake, decresed maturation	Reduction, progesterone uptake, decresed maturation
KE	1695	Impaired ovulation	Impaired ovulation
KE	1696	Decrease of egg production and cummulative fecundity	Decrease of egg production and cummulative fecundity

679

Decline, Population trajectory

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

Title	Adjacency	Evidence	Quantitative Understanding

Antagonism,LH receptor leads to Reduction, Progesterone synthesis	adjacent	Moderate	Moderate
Reduction, Progesterone synthesis leads to Reduction, Plasma progesterone concentration	adjacent	High	Moderate
Reduction, Plasma progesterone concentration leads to Reduction, progesterone uptake, decresed maturation	adjacent	High	Moderate
Reduction, progesterone uptake, decresed maturation leads to Impaired ovulation	adjacent	High	High
Impaired ovulation leads to Decrease of egg production and cummulative fecundity	adjacent	High	Moderate
Decrease of egg production and cummulative fecundity leads to Decline, Population trajectory	adjacent	High	High

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

Name
Progesterone,estrogen,melatonin,Letrozole
glucocorticoids
Cetrorelix
Interleukin-6

Life Stage Applicability

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

Life stage	Evidence
3 to < 6 months	Not Specified

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

Term	Scientific Term	Evidence	Link
fish	fish	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Female	High

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

To do		Expected duration
Building the AOP frame	Development of KEs	3 month
Building the AOP frame	Production of experimental data	18 month
Overall assessment of the AOP	Biological domain of applicability	3 month
	Essentiality of all KEs	3 month
	Evidence supporting all KERs	5 month
	Quantitative WoE considerations	5 month
	Quantitative understanding for each KER	6 month

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

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

References

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

Control of ovulation in mice by progesterone receptor-regulated gene networks Molecular Human Reproduction, Vol.15, No.12 pp. 821–828, 2009
Peroxisome Proliferator-Activated Receptor γ Is a Target of Progesterone Regulation in the Preovulatory Follicles and Controls Ovulation in Mice MOLECULAR AND CELLULAR BIOLOGY, Mar. 2008, p. 1770–178
Discovery of BAY-298 and BAY-899: Tetrahydro-1,6-naphthyridine-Based, Potent, and Selective Antagonists of the Luteinizing Hormone Receptor Which Reduce Sex Hormone Levels in Vivo J. Med. Chem. 2019, 62, 22, 10321-10341
Control of ovulation in mice by progesterone receptor-regulated gene networks Molecular Human Reproduction, Vol.15, No.12 pp. 821–828, 2009
Peroxisome Proliferator-Activated Receptor γ Is a Target of Progesterone Regulation in the Preovulatory Follicles and Controls Ovulation in Mice MOLECULAR AND CELLULAR BIOLOGY, Mar. 2008, p. 1770–178
A new biological marker candidate in female reproductive system diseases: Matrix metalloproteinase with thrombospondin motifs (ADAMTS) Journal of the Turkish German Gynecology Association 15(4):250-1
Perspectives on fish gonadotropins and their receptors. Gen Comp Endocrinol 165: 412–437
Structural aspects of luteinizing hormone action. In: Ascoli M editor. Luteinizing hormone action and receptors. Boca Raton, Florida: CRC Press. 173–198.
Hormones of the adenohypophesis. The gonadotropins and thyrotropin (and related placental hormones). In: The Biochemistry of the Polypeptide Hormones. New York: John Wiley and Sons. 147–183.
Regulation of oocyte maturation in fish. Develop Growth Differ 50: 195–219.
Regulation of fish gonadotropins. Int Rev Cytol 225: 131–185.
Novel pathways in gonadotropin receptor signaling and biased agonism. Rev Endocr Metab Disord 12: 259–27
Regulation of oocyte maturation in fish. In: Sherwood NM, Hew CL, editors. Fish physiology. New York: Academic Press. 393–439.
Gene knockout of nuclear progesterone receptor provides insights into the regulation of ovulation by Lsignaling in zebrafish. Sci. Rep. 6, 28545–28545
Perspectives on fish gonadotropins and their receptors. Gen Comp Endocrinol 165: 412–437
Structural aspects of luteinizing hormone action. In: Ascoli M editor. Luteinizing hormone action and receptors. Boca Raton, Florida: CRC Press. 173–198.
Hormones of the adenohypophesis. The gonadotropins and thyrotropin (and related placental hormones). In: The Biochemistry of the Polypeptide Hormones. New York: John Wiley and Sons. 147–183.
Regulation of oocyte maturation in fish. Develop Growth Differ 50: 195–219.
Regulation of fish gonadotropins. Int Rev Cytol 225: 131–185.
Novel pathways in gonadotropin receptor signaling and biased agonism. Rev Endocr Metab Disord 12: 259–27
Regulation of oocyte maturation in fish. In: Sherwood NM, Hew CL, editors. Fish physiology. New York: Academic Press. 393–439.
Gene knockout of nuclear progesterone receptor provides insights into the regulation of ovulation by Lsignaling in zebrafish. Sci. Rep. 6, 28545–28545