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Relationship: 3468

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Apoptosis leads to Decreased, ovarian reserve

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Apoptosis

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Decreased, ovarian reserve

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Aryl hydrocarbon Receptor (AHR) activation causes Premature Ovarian Insufficiency via Bax mediated apoptosis	adjacent	Moderate		Sapana Kushwaha (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	Moderate	NCBI
baboon	Papio anubis	Low	NCBI
human	Homo sapiens	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Female	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Fetal	High
Adult	Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Apoptosis, a natural process of programmed cell death, is crucial for maintaining cellular homeostasis in the ovary. It plays a significant role during ovarian development by eliminating defective or surplus follicles. However, when apoptosis is dysregulated or excessively induced, it leads to the premature death of ovarian follicles, thereby depleting the ovarian reserve. The ovarian reserve, established during fetal development, represents the finite pool of primordial and primary follicles available throughout a female's reproductive life. This results in the accelerated depletion of follicles. studies in humans and primates confirm that apoptosis is a key driver of follicular atresia. The relationship between apoptosis and decreased ovarian reserve is also supported by findings in AhR-deficient mice, where reduced apoptosis preserves the ovarian follicle pool. This KER establishes how excessive apoptosis disrupts ovarian biology, leading to reduced reproductive capacity and an increased likelihood of conditions such as primary ovarian insufficiency (POI).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

A structured literature search was conducted to compile mechanistic and empirical evidence supporting the linkage between apoptosis and decreased ovarian reserve. Emphasis was placed on peer-reviewed studies involving in vivo rodent models, human ovarian tissue, and in vitro culture systems. Databases such as PubMed, ScienceDirect, and Google Scholar using keywords like “apoptosis,” “ovarian reserve,” “follicle depletion,” “Bax,” “granulosa cell apoptosis,” and “ovarian toxicity”. Key markers of apoptosis such as Bax expression, granulosa cell atresia, follicle count reduction and immunohistochemical localization of Bax and caspase activity were emphasized as mechanistic indicators. Studies those correlating molecular markers (e.g., Bax, Bcl-2, Caspase-3, AMH) with follicle depletion were in brought in inclusion. Evidence spanning developmental to adult life stages was included to ensure relevance across the female reproductive lifespan. Cross-species findings from mice, rats, and humans were considered to assess taxonomic applicability.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The biological plausibility of the KER "Apoptosis leads to Decreased Ovarian Reserve" is moderate and supported by mechanistic evidence. The ovarian reserve is established during fetal development, with oocytes undergoing precise regulation to ensure proper follicle numbers. Apoptosis plays a critical role in regulating this population, as it eliminates defective or superfluous oocytes and granulosa cells. However, excessive or premature apoptosis, triggered by environmental or genetic factors, can deplete the follicle pool, reducing ovarian reserve. Further evidence from rodent and human studies confirms that apoptosis underpins follicular apoptosis. This mechanistic linkage is strengthened by findings in AhR-deficient mice, where reduced apoptosis preserves the primordial follicle pool. Overall, the connection between apoptosis and reduced ovarian reserve is well-grounded in ovarian biology and developmental physiology.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Evidence from Exposure to Benzo[a]pyrene (BaP) to in vitro culture systems has been shown to induce apoptosis in fetal oocytes and significantly increase the expression of Bax, a pro-apoptotic gene. Prenatal exposure to BaP results in permanent reductions in the ovarian reserve at birth, demonstrating the causal link between apoptosis and ovarian reserve depletion (1, 3).
Exposure to QEPE (4(3H)-Quinazolinone-2-ethyl-2-phenyl Ethyl)in mice leads to apoptosis in fetal oocytes via elevated Bax expression. This further highlight how chemical-induced apoptosis during fetal development depletes the primordial follicle pool (2).
In utero exposure to PAHs, including BaP, leads to a significant reduction in the stock of primordial follicles in female mouse fetuses. Extensive rodent studies demonstrate that apoptosis mediated by PAHs causes depletion of the ovarian follicular pool. BaP exposure in fetal mice increases pro-apoptotic Bax expression in oocytes, leading to a 50–70% reduction in primordial follicles at birth. AhR-deficient mice (with reduced apoptosis) retain a significantly higher number of follicles, confirming a negative correlation between apoptosis and ovarian reserve. (4).
Research on ovarian tissues from humans and baboons shows that apoptosis is a key mechanism driving follicular atresia. Immunohistochemical analysis reveals that Bax is abundant in granulosa cells of atretic follicles but undetectable in healthy follicles (5,6).
In AhR-deficient mice, germ cell and primordial follicle numbers are increased, while the number of antral follicles is reduced. This indicates that the absence of AhR signaling reduces apoptosis, preserving the ovarian reserve (7).
Cyclophosphamide (CPA) exposure in mice induces apoptosis within 24 hours, with TUNEL-positive primordial follicles increasing proportionally to the dose. Histological analysis shows a dose-dependent decrease in the number of primordial and growing follicles within 3–7 days post-exposure (8).
Granulosa cell apoptosis rates in DOR patients are 2–3 times higher than in normal ovarian reserve individuals. AMH levels, an ovarian reserve marker, decrease significantly (from 3.48 ng/mL to 1.42 ng/mL) as apoptosis increases (9,11).
Cancer patients undergoing chemotherapy show a dose-dependent increase in apoptotic granulosa cells. A corresponding decrease in follicle numbers and AMH levels is observed post-therapy, leading to premature ovarian insufficiency (POI) (10).
Overexpression of pro apoptotic factors in murine ovarian follicles results in accelerated follicular atresia, with a direct inverse relationship between apoptotic activity and follicle count. Blocking this signaling reduces apoptosis and preserves follicular reserve, confirming the role of apoptosis in ovarian depletion (11).

Higher apoptosis rates (e.g., Bax activation, caspase activation) → Greater follicular depletion → Lower ovarian reserve

Lower apoptosis rates (e.g., Bcl2 overexpression, Bax knockout) → Increased follicle survival → Higher ovarian reserve

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Differences in mechanisms which leads to ovarian reserve depletion may lead to inconsistent correlations like some studies show strong caspase-3, bax activation preceding follicle loss, while others indicate alternative apoptotic pathways (e.g., autophagy-mediated follicular atresia, hormonal influence) (12, 13, 14, 15)
The exact threshold of apoptotic signaling required to significantly deplete ovarian follicles is not well-defined. Dose-response relationships for toxicant-induced apoptosis and subsequent follicle loss show variability across chemicals and exposure durations.(16, 17, 18)

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Currently, the quantitative understanding of the Key Event Relationship (KER) "Apoptosis leads to Decreased Ovarian Reserve" remains incomplete. Although several studies demonstrate a correlation between the degree of apoptosis and the extent of follicular loss, specific quantitative thresholds—such as the level and duration of apoptotic activity needed to significantly impact the ovarian reserve—have not been clearly defined. Further investigation is needed to determine levels of apoptotic signaling that directly correspond to measurable declines in follicle numbers.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

The time scale of ovarian reserve depletion following apoptosis varies depending on the exposure type and severity. In acute exposure models, apoptosis is initiated within hours and peaks within 24–48 hours, leading to rapid follicular depletion. Chronic exposure to apoptotic stimuli, such as environmental toxins, results in a gradual decline in ovarian reserve over weeks to months. In prenatal and neonatal models, apoptotic events induced by toxicant exposure lead to permanent ovarian reserve depletion by birth, with no possibility of recovery. In adult human females, apoptosis-driven follicular atresia occurs progressively over years, contributing to age-related fertility decline, with significantly higher apoptosis rates observed in women diagnosed with DOR.

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Taxonomic: Relevant to mammals, especially humans and rodents.
Life Stage: Applies to fetal, pre-pubertal, reproductive, and perimenopausal stages; less relevant postmenopause.
Sex: Female-specific due to ovarian function.

References

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

Matikainen TM, Moriyama T, Morita Y, Perez GI, Korsmeyer SJ, Sherr DH, Tilly JL. Ligand activation of the aromatic hydrocarbon receptor transcription factor drives Bax-dependent apoptosis in developing fetal ovarian germ cells. Endocrinology. 2002;143(2):615-20.
Lahijani M, Farivar S, Amiri M, Sarhady M. Roles of Bax and Caspase2 genes in fetal ovary germ cell apoptosis induced by 4(3H) quinazolinone-2-ethyl-2-phenyl ethyl. Reproductive Toxicology. 2011;8.
Miller MM, Plowchalk DR, Weitzman GA, London SN, Mattison DR. The effect of benzo(a)pyrene on murine ovarian and corpora lutea volumes. Am J Obstet Gynecol. 1992;166(5):1535-41.
Lim J, Kong W, Lu M, Luderer U. The Mouse Fetal Ovary Has Greater Sensitivity Than the Fetal Testis to Benzo[a]pyrene-Induced Germ Cell Death. Toxicol Sci. 2016;152(2):372-81.
Kugu K, Ratts VS, Piquette GN, Tilly KI, Tao XJ, Martimbeau S, et al. Analysis of apoptosis and expression of bcl-2 gene family members in the human and baboon ovary. Cell Death Differ. 1998;5(1):67-76.
Rhon-Calderón EA, Toro CA, Lomniczi A, Galarza RA, Faletti AG. Changes in the expression of genes involved in the ovarian function of rats caused by daily exposure to 3-methylcholanthrene and their prevention by α-naphthoflavone. Arch Toxicol. 2018;92(2):907-19.
Benedict JC, Lin TM, Loeffler IK, Peterson RE, Flaws JA. Physiological role of the aryl hydrocarbon receptor in mouse ovary development. Toxicol Sci. 2000;56(2):382-8.
Luan Y, Edmonds ME, Woodruff TK, Kim S-Y. Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide. Journal of Endocrinology. 2019;240(2):243-56.
Grive KJ. Pathways coordinating oocyte attrition and abundance during mammalian ovarian reserve establishment. Mol Reprod Dev. 2020;87(8):843-56.
Kashi O, Meirow D. Overactivation or Apoptosis: Which Mechanisms Affect Chemotherapy-Induced Ovarian Reserve Depletion? International Journal of Molecular Sciences. 2023;24(22):16291.
Vital-Reyes V, Rodríguez-Burford C, Chhieng DC, Alvarado-Cabrero I, Reyes-Fuentes A, Grizzle WE. Ovarian expression of markers associated with proliferation or apoptosis in women with diminished ovarian reserve. Fertil Steril. 2006;86(1):176-85.
Cacciottola L, Camboni A, Cernogoraz A, Donnez J, Dolmans MM. Role of apoptosis and autophagy in ovarian follicle pool decline in children and women diagnosed with benign or malignant extra-ovarian conditions. Hum Reprod. 2023;38(1):75-88.
Kumariya S, Ubba V, Jha RK, Gayen JR. Autophagy in ovary and polycystic ovary syndrome: role, dispute and future perspective. Autophagy. 2021;17(10):2706-33.
Ding Z, Shao G, Li M. Regulatory Mechanism of Autophagy in Premature Ovarian Failure. Cell Biochem Funct. 2024;42(7):e4122.
Zhu Q, Li Y, Ma J, Ma H, Liang X. Potential factors result in diminished ovarian reserve: a comprehensive review. J Ovarian Res. 2023;16(1):208.
Sobinoff AP, Nixon B, Roman SD, McLaughlin EA. Staying alive: PI3K pathway promotes primordial follicle activation and survival in response to 3MC-induced ovotoxicity. Toxicol Sci. 2012;128(1):258-71.
Zhou L, Xie Y, Li S, Liang Y, Qiu Q, Lin H, Zhang Q. Rapamycin Prevents cyclophosphamide-induced Over-activation of Primordial Follicle pool through PI3K/Akt/mTOR Signaling Pathway in vivo. J Ovarian Res. 2017;10(1):56.
Perono GA, Petrik JJ, Thomas PJ, Holloway AC. The effects of polycyclic aromatic compounds (PACs) on mammalian ovarian function. Curr Res Toxicol. 2022;3:100070.