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Aop: 309

AOP Title

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Luteinizing hormone receptor antagonism leading to reproductive dysfunction

Short name:

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Luteinizing hormone receptor antagonism

Graphical Representation

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Click to download graphical representation template

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Authors

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Point of Contact

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Young Jun Kim   (email point of contact)

Contributors

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  • Young Jun Kim

Status

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Author status OECD status OECD project SAAOP status
Under Development: Contributions and Comments Welcome


This AOP was last modified on November 29, 2019 11:43

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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.


Background (optional)

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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.


Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
MIE 1691 Antagonism,LH receptor 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
AO 679 Decline, Population trajectory Decline, Population trajectory

Relationships Between Two Key Events
(Including MIEs and AOs)

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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

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Stressors

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Name Evidence Term
Progesterone,estrogen,melatonin,Letrozole Not Specified
glucocorticoids Moderate
Cetrorelix High
Interleukin-6 Moderate

Life Stage Applicability

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Life stage Evidence
3 to < 6 months Not Specified

Taxonomic Applicability

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Term Scientific Term Evidence Link
fish fish Moderate NCBI

Sex Applicability

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Sex Evidence
Female High

Overall Assessment of the AOP

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To do

Expected duration

Building the AOP frame

Development of KEs

3 month

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

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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  1. Control of ovulation in mice by progesterone receptor-regulated gene networks Molecular Human Reproduction, Vol.15, No.12 pp. 821–828, 2009
  2. 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
  3. 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
  4. Control of ovulation in mice by progesterone receptor-regulated gene networks Molecular Human Reproduction, Vol.15, No.12 pp. 821–828, 2009
  5. 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
  6. 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
  7. Perspectives on fish gonadotropins and their receptors. Gen Comp Endocrinol 165: 412–437
  8. Structural aspects of luteinizing hormone action. In: Ascoli M editor. Luteinizing hormone action and receptors. Boca Raton, Florida: CRC Press. 173–198.
  9. 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.
  10. Regulation of oocyte maturation in fish. Develop Growth Differ 50: 195–219.
  11. Regulation of fish gonadotropins. Int Rev Cytol 225: 131–185.
  12. Novel pathways in gonadotropin receptor signaling and biased agonism. Rev Endocr Metab Disord 12: 259–27
  13. Regulation of oocyte maturation in fish. In: Sherwood NM, Hew CL, editors. Fish physiology. New York: Academic Press. 393–439.
  14. Gene knockout of nuclear progesterone receptor provides insights into the regulation of ovulation by Lsignaling in zebrafish. Sci. Rep. 6, 28545–28545
  15. Perspectives on fish gonadotropins and their receptors. Gen Comp Endocrinol 165: 412–437
  16. Structural aspects of luteinizing hormone action. In: Ascoli M editor. Luteinizing hormone action and receptors. Boca Raton, Florida: CRC Press. 173–198.
  17. 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.
  18. Regulation of oocyte maturation in fish. Develop Growth Differ 50: 195–219.
  19. Regulation of fish gonadotropins. Int Rev Cytol 225: 131–185.
  20. Novel pathways in gonadotropin receptor signaling and biased agonism. Rev Endocr Metab Disord 12: 259–27
  21. Regulation of oocyte maturation in fish. In: Sherwood NM, Hew CL, editors. Fish physiology. New York: Academic Press. 393–439.
  22. Gene knockout of nuclear progesterone receptor provides insights into the regulation of ovulation by Lsignaling in zebrafish. Sci. Rep. 6, 28545–28545