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Relationship: 3483

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

Decreased, ovarian reserve leads to POI

Upstream event

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

Decreased, ovarian reserve

Downstream event

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

POI

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	High		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 Do not cite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
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
Perinatal	Low
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

Ovarian Reserve refers to the quantity and quality of a woman’s remaining pool of primordial and growing follicles in the ovaries that are capable of developing into mature, fertilizable oocytes. It reflects the reproductive potential of the ovaries and their capacity to support normal endocrine function, ovulation, and fertility. Ovarian reserve naturally declines with age, but can also be diminished prematurely due to genetic, autoimmune, environmental, or iatrogenic factors.This KER describes how the depletion of the ovarian reserve leads to primary ovarian insufficiency (POI). The ovarian reserve, which consists of primordial and primary follicles, is essential for maintaining regular ovarian function. When this reserve is reduced, whether through natural aging or external environmental factors, ovarian failure can occur.

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 targeted literature search was conducted using PubMed, Google Scholar, ResearchGate and ScienceDirect , with keywords: “ovarian reserve,” “primordial follicle loss,” “premature ovarian insufficiency,” “premature ovarian failure”, “PAHs,”, “follicular apoptosis,” “environmental pollutants and POI”.

Inclusion focused on animal and human studies linking environmental or chemical exposure to depletion of ovarian reserve and onset of POI, using validated biomarkers (AMH, FSH, AFC). Studies were prioritized based on mechanistic relevance, and quality of methods (e.g., ELISA, histology, IHC).

Only peer-reviewed data showing direct causality or correlation between decreased ovarian reserve and POI progression were included. Epidemiological studies were considered where experimental evidence aligned.

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

Ovarian reserve refers to the pool of functional primordial and growing follicles within the ovaries that are critical for maintaining normal ovarian function, including steroid hormone production and the release of mature oocytes necessary for reproduction. The quantity and quality of this follicular pool directly determine the ovary's ability to sustain regular menstrual cycles, ovulation, and endocrine balance. As the ovarian reserve declines—either due to natural aging, environmental insults, or pathological factors—follicular depletion disrupts hormonal feedback mechanisms, leading to elevated FSH, reduced estrogen, irregular or absent menstruation, and ultimately, the loss of fertility. These changes are hallmark features of premature ovarian insufficiency (POI). Therefore, the progression from decreased ovarian reserve to POI is biologically plausible and consistent with current understanding of ovarian physiology (15-21).

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

Perinatal exposure to PAHs such as 7,12-dimethylbenz(a)anthracene and benzo[a]pyrene (BaP)accelerates primordial follicle loss, leading to ovarian pool depletion and premature ovarian insufficiency (1).
Prenatal and postnatal exposure to diesel exhaust (PAH chemicals) significantly reduces primordial and primary follicular pools, impairing future reproductive capacity (2,3).
A cross-sectional study of 31,575 women from the NHANES dataset (1999–2008) showed that exposure to endocrine-disrupting chemicals (EDCs), including nine PCBs, three pesticides, one furan, and two phthalates, was significantly associated with an earlier onset of menopause (by 1.9–3.8 years), even after adjusting for confounders such as age, race, smoking, and BMI (4).
Studies confirm that PAHs, particularly those with coplanar structures, activate the Aryl Hydrocarbon Receptor (AhR), leading to granulosa cell and oocyte apoptosis, which reduces the ovarian reserve and triggers early menopause or POI (5).
Direct Evidence of Follicular Depletion between AhR activation, apoptosis, and follicular loss has been consistently observed across rodent studies due to (e.g., Matikainen T.) PAH chemicals significantly reduces the primordial follicle pool in experimental settings, directly impacting reproductive capacity (6).
Evidence demonstrates a dose-response relationship, with higher PAH exposure correlating with faster follicular depletion and earlier onset of ovarian dysfunction.
Cumulative smoking exposure accelerates ovarian aging; women with 11–15 pack-years of smoking exhibit a 4.35-fold increased risk of premature menopause, while those with >15 years of smoking experience ovarian failure 4–6 years earlier than non-smokers (7).
DMBA exposure (50 mg/kg) results in measurable follicular depletion within 5–6 days, establishing a clear dose-response relationship between toxicant exposure and ovarian damage.
Subchronic TBT exposure (500 ng/kg/day for 12 days) induces ovarian dysfunction, while chronic exposure for over 30 days leads to irreversible follicular loss, mimicking natural POI but at an accelerated rate (8).
Women who smoke for more than 15 years exhibit a 15.58-fold increased risk of premature menopause, with every 5 years of smoking leading to an approximate 0.3 ng/mL reduction in AMH. Similarly, exposure to environmental toxins such as 7,12-Dimethylbenz[a]anthracene (DMBA), Tributyltin (TBT), and 4-Vinylcyclohexene Diepoxide (VCD) causes accelerated follicular atresia. Chronic exposure over 30 days results in irreversible ovarian damage, mimicking POI in rodent studies (9).

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

Not all individuals with a reduced ovarian reserve develop POI, suggesting the involvement of compensatory mechanisms or genetic resilience. Some women experience ovarian failure at different rates despite similar environmental exposures, indicating individual variability. Although environmental pollutants like PAHs have been implicated in ovarian toxicity, the precise exposure levels required to trigger significant ovarian reserve depletion are not well-defined. Human studies linking environmental pollutants to early menopause must account for factors such as smoking, lifestyle, diet, and genetic predisposition, which can independently influence ovarian aging. Co-exposure to multiple endocrine-disrupting chemicals makes it challenging to isolate the specific effects of one toxicant. While apoptosis and oxidative stress are known contributors to follicular loss, other potential pathways, such as inflammatory responses and mitochondrial dysfunction, require further exploration.The exact molecular mechanisms linking AhR activation to ovarian follicle loss need further exploration specifically in human tissues.

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

Other causes of POI, acting as modulating factors, include genetic mutations, autoimmune disorders, metabolic conditions, infections, and iatrogenic interventions other than environmental toxicants exposure.

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

Threshold Values for POI Diagnosis:

AMH <0.5 ng/mL → Early POI risk
AFC <5 follicles per ovary → Strong predictor of imminent ovarian failure
FSH >20 IU/L → Transition from diminished ovarian reserve to POI

AMH and FSH levels can be measured on 2–3 of the menstrual cycle. Serum AMH measured using ELISA and chemiluminescence immunoassays, while FSH can be assessed via enzyme-linked fluorescence assay (ELFA) and chemiluminescence assay. Antral Follicle Count (AFC), transvaginal ultrasonography was performed using 4–10 MHz multifrequency probes (11-14).

Hormonal Biomarkers
- AMH Measurement: AMH levels are quantified using enzyme-linked immunosorbent assay (ELISA), which provides sensitivity in detecting early ovarian decline.
- FSH & Estradiol Levels: These are measured using chemiluminescent immunoassay (CLIA) to track hormonal changes as ovarian reserve diminishes.
Ovarian Follicle Analysis
- Antral Follicle Count (AFC): Assessed via transvaginal ultrasound (TVUS) to evaluate the number of small follicles remaining in the ovaries, correlating with AMH levels.
- Histological Follicle Counting: Ovarian sections are stained with hematoxylin and eosin (H&E), allowing precise quantification of follicle numbers across developmental stages.
Gene and Protein Expression Analysis
- mRNA Quantification: Northern blot analysis confirms Bax mRNA elevation post-DMBA exposure, indicating apoptotic pathways contributing to follicular depletion.
- Protein Localization: Immunohistochemical (IHC) staining detects Bax protein accumulation in primordial and primary oocytes, confirming early ovarian damage in chemically exposed mice.

Response-response Relationship

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

Greater depletion of ovarian reserve biomarkers corresponds with higher probability and severity of POI manifestation, though an exact model or BMD (benchmark dose) is not established.

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 transition from decreased ovarian reserve to POI follows a progressive timeline spanning several years, with distinct pre-POI and early POI phases, with AMH declining 1–3 years before FSH elevation. FSH levels (10–20 IU/L) and AFC reduction (<5 follicles) occur 2–4 years before clinical POI onset, marking a critical window for early detection. In cases of environmental and chemical-induced ovarian toxicity, progression occurs on a much faster timescale. Acute DMBA exposure (50 mg/kg) depletes follicles within 5–6 days, while subchronic TBT exposure (500 ng/kg/day) disrupts ovarian function within 2–4 weeks. Chronic toxicant exposure (>30 days) leads to irreversible follicular depletion, mimicking natural POI but at an accelerated rate. Similarly, smokers experience POI 4–6 years earlier than non-smokers, reinforcing the role of lifestyle and environmental factors in ovarian aging.

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

This KER applies primarily to female mammals, with the strongest evidence derived from rodent, human clinical and epidemiological studies. The mechanistic basis of ovarian reserve depletion and subsequent POI is well-conserved across rodents and non-human primates, as demonstrated in experimental models of chemically induced ovarian toxicity. However, interspecies differences in ovarian physiology, follicular dynamics, and hormonal regulation may affect the exact timeline and severity of POI onset. The KER is not applicable to males, as ovarian reserve is a female-specific physiological parameter. Additionally, species with prolonged reproductive longevity or alternative mechanisms of ovarian maintenance may exhibit variations in response.

References

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

Ye X, Pan W, Li C, Ma X, Yin S, Zhou J, Liu J. Exposure to polycyclic aromatic hydrocarbons and risk for premature ovarian failure and reproductive hormones imbalance. J Environ Sci (China). 2020;91:1-9.
Ogliari KS, Lichtenfels AJ, de Marchi MR, Ferreira AT, Dolhnikoff M, Saldiva PH. Intrauterine exposure to diesel exhaust diminishes adult ovarian reserve. Fertil Steril. 2013;99(6):1681-8.
Anderson RA, McIlwain L, Coutts S, Kinnell HL, Fowler PA, Childs AJ. Activation of the aryl hydrocarbon receptor by a component of cigarette smoke reduces germ cell proliferation in the human fetal ovary. Mol Hum Reprod. 2014;20(1):42-8.
Vabre P, Gatimel N, Moreau J, Gayrard V, Picard-Hagen N, Parinaud J, Leandri RD. Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data. Environ Health. 2017;16(1):37.
Morita Y, Tsutsumi O, Taketani Y. Regulatory mechanisms of female germ cell apoptosis during embryonic development. Endocr J. 2001;48(3):289-301.
Matikainen T, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, Ryu HY, et al. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet. 2001;28(4):355-60.
Zhu D, Chung HF, Pandeya N, Dobson AJ, Cade JE, Greenwood DC, et al. Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: A pooled analysis of individual data from 17 observational studies. PLoS Med. 2018;15(11):e1002704.
Sarmento IV, Merlo E, Meyrelles SS, Vasquez EC, Warner GR, Gonsioroski A, et al. Subchronic and Low Dose of Tributyltin Exposure Leads to Reduced Ovarian Reserve, Reduced Uterine Gland Number, and Other Reproductive Irregularities in Female Mice. Toxicol Sci. 2020;176(1):74-85.
Jiao X, Meng T, Zhai Y, Zhao L, Luo W, Liu P, Qin Y. Ovarian Reserve Markers in Premature Ovarian Insufficiency: Within Different Clinical Stages and Different Etiologies. Front Endocrinol (Lausanne). 2021;12:601752.
Hoyer PB, Sipes IG. Assessment of follicle destruction in chemical-induced ovarian toxicity. Annu Rev Pharmacol Toxicol. 1996;36:307-31.
Jaiswar SP, Natu SM, Sujata, Sankhwar PL, Manjari G. Prediction of Poor Ovarian response by Biochemical and Biophysical Markers: A Logistic Regression Model. J Obstet Gynaecol India. 2015;65(6):411-6.
Huang Y, Kuang X, Jiangzhou H, Li M, Yang D, Lai D. Using anti-Müllerian hormone to predict premature ovarian insufficiency: a retrospective cross-sectional study. Front Endocrinol (Lausanne). 2024;15:1454802.
Barbakadze L, Kristesashvili J, Khonelidze N, Tsagareishvili G. The correlations of anti-mullerian hormone, follicle-stimulating hormone and antral follicle count in different age groups of infertile women. Int J Fertil Steril. 2015;8(4):393-8.
Ahmeid M, Khalil M, Algburi F, Alobaidi A. The Predictive Value of Serum Progesterone and Estrogen Recepters as Diagnostic Tool for Premature Ovarian Failure. Medico-Legal Update. 2021;21:481-5.
Zhang H, Yan J. Environment and female reproductive health: Springer; 2021.
Jiang, D.; Meng, F. Cases Study on the Management of Diminished Ovarian Reserve (DOR) and Premature Ovarian Insufficiency (POI) with Traditional Chinese Medicine (TCM). J. Obes. Diabetes 2022
Cui J, Wang Y. Premature ovarian insufficiency: a review on the role of tobacco smoke, its clinical harm, and treatment. J Ovarian Res. 2024;17(1):8.
Vabre P, Gatimel N, Moreau J, Gayrard V, Picard-Hagen N, Parinaud J, Leandri RD. Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data. Environ Health. 2017;16(1):37.
Liu B, Liu Y, Li S, Chen P, Zhang J, Feng L. Depletion of placental brain-derived neurotrophic factor (BDNF) is attributed to premature ovarian insufficiency (POI) in mice offspring. Journal of Ovarian Research. 2024;17(1):141.
Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360(6):606-14.
Adiga P, Marconi N, N R, Vitthala S. Effect of intra-ovarian injection of platelet-rich plasma on the patients with a poor ovarian response (POR) or premature ovarian insufficiency (POI): a systematic review and meta-analysis. Middle East Fertility Society Journal. 2024;29.