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Relationship: 3467

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

increased, Bax leads to Apoptosis

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
increased, Bax
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Apoptosis

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 Do not cite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 High NCBI
human Homo sapiens Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

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

Bax, a pro-apoptotic member of the Bcl-2 family, plays a crucial role in the intrinsic apoptotic pathway. Upon activation, Bax translocates to the mitochondrial outer membrane, inducing cytochrome c release and caspase activation, ultimately leading to apoptosis. Under normal conditions, Bax resides in the cytoplasm in an inactive form. In response to apoptotic stimuli (such as DNA damage, growth factor withdrawal, or oxidative stress), Bax undergoes a conformational change and translocates to the mitochondrial outer membrane. Bax oligomerizes within the membrane, forming pores that allow the release of cytochrome C and other pro-apoptotic factors.

In ovarian cells, increased Bax expression disrupts mitochondrial integrity, triggering follicular cell death. Evidence from rodent and human studies demonstrates a strong correlation between elevated Bax levels and apoptosis in oocytes and granulosa cells. Additionally, environmental toxicants, such as PAHs, activate Bax via the AhR pathway, further accelerating apoptosis. 

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

This Key Event Relationship (KER) was developed through a structured review of mechanistic and empirical data from peer-reviewed studies. Literature searches were conducted across databases including PubMed, Science direct, and Google Scholar and various journals  using targeted keywords such as “Bax,” “apoptosis,” “mitochondrial pathway,” “Bcl-2 family,”  “Bax knockout,”  “bax and apoptosis in ovary” and “Bax overexpression.” Studies involving both in vivo and in vitro models across different tissues and species were examined to generalize the KER beyond specific organs.

Particular emphasis was placed on experimental evidence from Bax-deficient (Bax⁻/⁻), Bax-KO-knockout animal models studies, which provided strong causal insights into the role of Bax in initiating apoptosis. These were supplemented by immunohistochemical and gene expression analyses showing spatial and temporal Bax expression during apoptotic events. While this KER is canonical and broadly applicable across tissues, particular focus was given on ovarian study models which consistently demonstrated that increased Bax expression contributes to apoptosis in granulosa cells and oocytes, reinforcing the general relevance of this KER in tissue homeostasis and degeneration. This comprehensive approach ensured the KER reflects the canonical, evolutionarily conserved function of Bax in apoptosis, as supported by diverse mechanistic data.

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 connection between increased Bax expression and apoptosis is well-documented in cellular biology. Bax, a pro-apoptotic protein within the Bcl-2 family, plays a pivotal role in the mitochondrial-mediated apoptosis pathway. When upregulated, Bax translocates to the mitochondria, facilitating cytochrome c release, which subsequently activates caspases, leading to programmed cell death. This process is essential for maintaining tissue homeostasis by eliminating damaged or unnecessary cells. This well-conserved mechanism supports the strong biological plausibility of this KER ( 1, 2).

In ovarian physiology, apoptosis is a natural mechanism that governs follicular atresia. However, excessive activation of Bax disrupts this equilibrium, accelerating follicular loss. Research indicates that environmental toxicants, such as PAHs, stimulate Bax expression via the AhR pathway, promoting apoptosis in granulosa cells, follicles and oocytes. Since the ovarian reserve is established at birth, increased apoptosis leads to premature depletion of follicles, contributing to conditions like premature ovarian failure (POF) and primary ovarian insufficiency (POI). The balance between pro-apoptotic (BAX, BCL-XS) and anti-apoptotic (BCL-2, BCL-XL) proteins plays a critical role in determining follicle and oocyte survival or degeneration. Studies have shown that BAX expression is generally high in the mammalian ovary, while BCL-2 levels are low or undetectable. This supports the high rate of programmed cell death (PCD) in the ovary, leading to extensive follicular loss, particularly in humans, where over 99% of oocytes are lost by puberty. The continuous elimination of follicles through apoptosis highlights its fundamental role in ovarian function and regulation. Literature studies and experimental evidence shows that deletion of Bax results in increased oocyte survival. These findings strongly support the mechanistic link between increased Bax expression and apoptosis in ovarian follicles (3,4,5,6).

Besides ovary, mutations or controlled downregulation and upregulation of Bax alter apoptosis, allowing regulation of cell proliferation causing cancer (7). Excessive Bax activation contributes to wider range of disorders,  neuronal apoptosis, playing a role in conditions like Alzheimer’s and Parkinson’s disease and other autoimmune disorders and organogenesis (8,9,10).

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

While Bax is a key pro-apoptotic protein, the balance between pro-apoptotic (BAX, BCL-Xs) and anti-apoptotic (BCL-2, BCL-Xl) factors influences apoptosis. High BCL-2 expression can counteract Bax-induced apoptosis, leading to variability in responses across different cellular environments (8, 19). Although studies in humans, rats, mice, and bovine ovarian tissues confirm Bax’s role in apoptosis, species-specific differences exist in ovarian follicle dynamics, apoptosis rates, and compensatory mechanisms that may affect the generalizability of findings. While PAH-induced upregulation of Bax has been well-documented, other toxicants and endogenous regulatory pathways (e.g., hormonal fluctuations, inflammatory cytokines) may independently influence apoptosis, making it challenging to attribute apoptosissolely to increased Bax expression (20,21,22,23).

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

The balance between BAX and BCL-2/BCL-Xl determines whether apoptosis occurs. While ovarian tissues typically have low BCL-2 expression, its presence may reduce Bax-mediated apoptosis.

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

​​​​​Although numerous studies support the association between increased Bax expression and induction of apoptosis, current evidence lacks quantitative dose–response data. Most findings are qualitative or comparative, and therefore, a definitive response–response relationship cannot be established at this stage.

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

Apoptosis is observed within hours to days of Bax upregulation, but quantitative data is lacking currently. In case of ovaries, apoptosis begins within hours to days post-Bax upregulation and leads to long-term follicular depletion over weeks to months.

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 to multiple mammalian species, including humans, rats, mice, and bovines, as demonstrated by immunohistochemical and genetic knockout studies. The strongest evidence supports Bax-mediated apoptosis in fetal and neonatal ovaries, where excessive Bax expression leads to premature germ cell depletion. Its role in post-pubertal ovarian function and aging remains an area for further research.  The KER is relevant to both males and females as the phenomenon of apoptosis is widely studied across several species in both sexes.

References

List of the literature that was cited for this KER description. More help
  1. Renault TT, Manon S. Bax: Addressed to kill. Biochimie. 2011;93(9):1379-91.
  2. Lalier L, Cartron PF, Juin P, Nedelkina S, Manon S, Bechinger B, Vallette FM. Bax activation and mitochondrial insertion during apoptosis. Apoptosis. 2007;12(5):887-96.
  3. Tilly JL. Apoptosis and ovarian function. Rev Reprod. 1996;1(3):162-72.
  4. Pawlowski J, Kraft AS. Bax-induced apoptotic cell death. Proc Natl Acad Sci U S A. 2000;97(2):529-31.
  5. Albamonte MS, Willis MA, Albamonte MI, Jensen F, Espinosa MB, Vitullo AD. The developing human ovary: immunohistochemical analysis of germ-cell-specific VASA protein, BCL-2/BAX expression balance and apoptosis. Hum Reprod. 2008;23(8):1895-901.
  6. Tai YT, Lee S, Niloff E, Weisman C, Strobel T, Cannistra SA. BAX protein expression and clinical outcome in epithelial ovarian cancer. J Clin Oncol. 1998;16(8):2583-90.
  7. Liu Z, Ding Y, Ye N, Wild C, Chen H, Zhou J. Direct Activation of Bax Protein for Cancer Therapy. Med Res Rev. 2016;36(2):313-41.
  8. Solary E, Dubrez L, Eymin B. The role of apoptosis in the pathogenesis and treatment of diseases. European Respiratory Journal.9(6):1293-305.
  9. MacGibbon GA, Lawlor PA, Sirimanne ES, Walton MR, Connor B, Young D, et al. Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus. Brain Res. 1997;750(1-2):223-34.
  10. Sun F, Akazawa S, Sugahara K, Kamihira S, Kawasaki E, Eguchi K, Koji T. Apoptosis in normal rat embryo tissues during early organogenesis: the possible involvement of Bax and Bcl-2. Arch Histol Cytol. 2002;65(2):145-57.
  11. Jurisicova A, Taniuchi A, Li H, Shang Y, Antenos M, Detmar J, et al. Maternal exposure to polycyclic aromatic hydrocarbons diminishes murine ovarian reserve via induction of Harakiri. J Clin Invest. 2007;117(12):3971-8.
  12. Greenfeld CR, Pepling ME, Babus JK, Furth PA, Flaws JA. BAX regulates follicular endowment in mice. Reproduction. 2007;133(5):865-76.
  13. 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.
  14. Tilly JL, Tilly KI, Kenton ML, Johnson AL. Expression of members of the bcl-2 gene family in the immature rat ovary: equine chorionic gonadotropin-mediated inhibition of granulosa cell apoptosis is associated with decreased bax and constitutive bcl-2 and bcl-xlong messenger ribonucleic acid levels. Endocrinology. 1995;136(1):232-41.
  15. Rueda BR, Tilly KI, Botros IW, Jolly PD, Hansen TR, Hoyer PB, Tilly JL. Increased bax and interleukin-1beta-converting enzyme messenger ribonucleic acid levels coincide with apoptosis in the bovine corpus luteum during structural regression. Biol Reprod. 1997;56(1):186-93.
  16. 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.
  17. Perez GI, Jurisicova A, Wise L, Lipina T, Kanisek M, Bechard A, et al. Absence of the proapoptotic Bax protein extends fertility and alleviates age-related health complications in female mice. Proc Natl Acad Sci U S A. 2007;104(12):5229-34.
  18. Lee DH, Szczepanski M, Lee YJ. Role of Bax in quercetin-induced apoptosis in human prostate cancer cells. Biochem Pharmacol. 2008;75(12):2345-55.
  19. Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR. Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J Biol Chem. 1999;274(4):2225-33.
  20. Sugino N, Okuda K. Species-related differences in the mechanism of apoptosis during structural luteolysis. J Reprod Dev. 2007;53(5):977-86.
  21. 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.
  22. Ke F, Bouillet P, Kaufmann T, Strasser A, Kerr J, Voss AK. Consequences of the combined loss of BOK and BAK or BOK and BAX. Cell Death Dis. 2013;4(6):e650.
  23. Kaur S, Kurokawa M. Regulation of Oocyte Apoptosis: A View from Gene Knockout Mice. Int J Mol Sci. 2023;24(2).