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AOP: 535

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

Binding and activation of GPER leading to learning and memory impairments

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Binding and activation of GPER leading to learning and memory impairments
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 v2.7

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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Zedong Ouyang, Qihua Pang, Ruifang Fan*

School of Life Sciences, South China Normal University, Guangzhou, China

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
Zedong Ouyang   (email point of contact)

Contributors

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  • Zedong Ouyang
  • Ruifang Fan

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 July 16, 2024 22:54

Revision dates for related pages

Page Revision Date/Time
protein-coupled estrogen receptor 1 (GPER) activation July 18, 2022 05:03
Increased, Intracellular Calcium overload June 26, 2020 04:45
Decreased, ERαβ heterodimers June 19, 2024 04:19
Oxidative Stress November 15, 2024 10:33
Apoptosis February 28, 2024 09:40
Aberrant, synaptic formation and plasticity January 25, 2024 21:18
Disruption, neurotransmitter release July 21, 2023 16:35
Neuroinflammation July 15, 2022 09:54
Impairment, Learning and memory July 26, 2024 09:54
GPER activation leads to Increased, Intracellular Calcium overload June 19, 2024 04:21
GPER activation leads to Decreased, ERαβ heterodimers June 19, 2024 04:23
Increased, Intracellular Calcium overload leads to Oxidative Stress June 19, 2024 04:23
Oxidative Stress leads to Apoptosis June 19, 2024 04:24
Apoptosis leads to Aberrant, synaptic formation and plasticity June 19, 2024 04:24
Apoptosis leads to Disruption, neurotransmitter release June 19, 2024 04:24
Oxidative Stress leads to Neuroinflammation June 19, 2024 04:24
Aberrant, synaptic formation and plasticity leads to Impairment, Learning and memory June 19, 2024 04:25
Disruption, neurotransmitter release leads to Impairment, Learning and memory April 11, 2024 15:20
Decreased, ERαβ heterodimers leads to Apoptosis June 19, 2024 20:36
Neuroinflammation leads to Impairment, Learning and memory June 19, 2024 20:36
Increased, Intracellular Calcium overload leads to Disruption, neurotransmitter release June 19, 2024 20:44
Apoptosis leads to Neuroinflammation June 19, 2024 20:52
Bisphenol A December 29, 2019 18:38

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This AOP describes the connection between BPA binding to the membrane receptor GPER and the activation of GPER leads to learning and memory impairments.

As a transmembrane protein, G protein-coupled estrogen receptor (GPER) is considered the primary mediator of rapid non-genomic signaling events of estrogen throughout the body, expressed in various tissue types, including neural cells. Due to its high abundance and expression on the cell membrane, it is preferentially activated by endogenous or exogenous estrogens. Bisphenol A (BPA), as a common endocrine disruptor, can exert estrogen-like effects upon entering the organism. The binding and activation of GPER by BPA can serve as the molecular initiating event (MIE). After GPER activation, it promotes an increase in intracellular Ca2+ concentration as a key event 1 (KE1), reduces the heterodimerization of ERαβ, leads to apoptosis/pyroptosis of cells, and induces cellular oxidative stress. This subsequently influences neuronal morphogenesis and neurotransmitter homeostasis. As a result, these changes induce an inflammatory response in the nervous system, ultimately leading to adverse outcomes of decreased learning and memory ability (AO).

We have identified multiple key events along this adverse outcome pathway and confirmed the connections between these key events. Based on this, we have developed an AOP to describe the binding and activation of GPER, which results in a decline in  learning and memory abilities.

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

BPA, a common additive in plastics, has been commonly detected in human fluids, including human blood, urine and breast milk. BPA may induce metabolic and endocrine disorders of aromatic compounds in vivo by affecting the aromatic hydrocarbon receptor (AhR) or estrogen receptor (ERs) (Shi et al., 2024), exhibiting reproductive toxicity, metabolic syndrome, and neurotoxicity. Numerous epidemiological investigations and toxicological studies have shown that BPA can cross the blood-brain barrier and low dose of BPA exposure is associated with a variety of neurological disorders in neurodegenerative diseases and neuropsychological disorders (Hyun et al., 2022). Hence, it is necessary to assess the health risks of BPA based on the AOP framework.

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

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

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
KE 389 Increased, Intracellular Calcium overload Increased, Intracellular Calcium overload
KE 2233 Decreased, ERαβ heterodimers Decreased, ERαβ heterodimers
KE 1392 Oxidative Stress Oxidative Stress
KE 1262 Apoptosis Apoptosis
KE 2208 Aberrant, synaptic formation and plasticity Aberrant, synaptic formation and plasticity
KE 2151 Disruption, neurotransmitter release Disruption, neurotransmitter release
KE 188 Neuroinflammation Neuroinflammation
AO 341 Impairment, Learning and memory Impairment, Learning and memory

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

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

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Nursing Child Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens Low NCBI
mouse Mus musculus High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed Moderate

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

Previous studies on endocrine disruptors, such as bisphenol A (BPA), have largely focused on the estrogen receptors alpha (ERα) or beta (ERβ), while this Adverse Outcome Pathway (AOP) is concerned with BPA's activation of G-protein estrogen receptor (GPER), for which there is substantial evidence. However, the impact of low doses of BPA on neurodevelopment remains uncertain. When BPA is present in the environment at low doses, it first binds to and activates the transmembrane protein receptor GPER on the cell membrane, mediating rapid cellular regulation, which may be the reason why BPA can still cause toxic effects on cells even at low doses. However, more studies involving knock-in, knock-out, and inhibitors are needed to explore the correlation between dose and toxic effects.

This AOP is initiated by the activation of GPER. BPA can directly activate GPER, causing an increase in the concentration of intracellular free Ca2+ (L. Wang et al., 2023), and at the same time reduce the dimerization of estrogen receptors alpha and beta (Babiloni-Chust et al., 2022). Experimental support can be obtained from various models including laboratory animals, mice, and cell lines, among which evidence from knock-in, knock-out, antagonism, and activation can substantiate the connection between the MIE and the KER.

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

In islet cells, it has been found that low doses of BPA can bind to and activate GPER, inhibiting the dimerization/heterodimerization of estrogen receptors alpha and beta, which in turn leads to programmed cell death (Babiloni-Chust et al., 2022). The same outcome has also been observed in neuroblastoma cells and primary hippocampal neurons (Meng et al., 2023; C. C. Wang et al., 2022).

In rat models, BPA exposure has been observed to lead to a decline in spatial learning and memory abilities in mice, with the effect being more pronounced in male rats (Zhang et al., 2019). The use of a GPER inhibitor can effectively alleviate this condition (Meng et al., 2023).

At the same time, combining the results of epidemiological surveys and experimental research, pregnancy and infancy are the most critical windows for the development of the body's nervous system and are relatively sensitive to exposure to pollutants, especially in terms of the development of the nervous system (Braun, 2017; Shin et al., 2024). BPA can have a significant impact on behavior, which has been observed in school-age boys (Rodríguez-Carrillo et al., 2019). There is also evidence that prenatal exposure to BPA and its analogs may affect the neurodevelopment of children, with a higher correlation in boys (Jiang et al., 2020).

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

MIE: Protein-coupled estrogen receptor 1 (GPER) activation: Estrogen (such as 17β-estradiol) binds to specific binding sites on GPER, activating GPER, which interacts with intracellular G proteins, particularly the Gα subunit. This interaction generates second messengers and triggers a series of cellular responses.

KE1: Increased, intracellular calcium: Calcium ions stored in the endoplasmic reticulum receive signals from above, releasing Ca2+ into the cytoplasm to regulate various cellular functions such as apoptosis and metabolic control.

KE2: Decreased, ERα/β heterodimers: The dimeric forms of ERα and ERβ play various crucial roles in cells, including transcriptional regulation of the cell cycle, cell differentiation, and cellular metabolism. Additionally, ERα and ERβ dimers interact with other cellular signaling pathways. The dimeric forms of ERα and ERβ are also associated with cell survival and apoptosis processes by influencing the expression of apoptosis-related genes or regulating the activity of anti-apoptotic factors, thereby maintaining cellular viability. In the nervous system, activation of ERβ is believed to protect neurons from oxidative stress and inflammatory damage, potentially involving regulatory mechanisms of ERβ dimers.

KE3: Oxidative Stress: Oxidative stress refers to the disruption of the oxidative-reductive (redox) balance within cells or organisms, leading to the generation of oxidative molecules (such as oxygen free radicals) that surpass the clearing capacity of antioxidant defense systems.

KE4: Increased, apoptosis: Apoptosis is a highly organized and controlled process of cell death regulated by intrinsic and extrinsic signals, allowing unnecessary or damaged cells to be orderly eliminated without triggering an inflammatory response. This process plays a critical role in organism development, immune regulation, and tissue homeostasis. Apoptotic cells exhibit characteristic morphological changes, including membrane blebbing, cell shrinkage, chromatin condensation, and nuclear fragmentation. Ultimately, cells are degraded into small fragments called apoptotic bodies, which are then engulfed and degraded by neighboring macrophages or other phagocytic cells.

KE5: Aberrant, synaptic formation and plasticity: Synaptic formation and plasticity abnormalities involve structural and functional changes in synapses within the nervous system, affecting the transmission and processing of information between neurons. Abnormal synaptic formation may refer to irregular changes in synaptic morphology, such as abnormal numbers, shapes, or sizes of synapses. For instance, excessive or sparse synaptic formation can impact the normal connectivity and function of neuronal networks.

Synaptic plasticity is a crucial feature in the nervous system, allowing for the adjustable strength and efficiency of neuronal connections. Abnormal plasticity may manifest as improper regulation of signal transmission between pre- and postsynaptic neurons, leading to impaired or disrupted neuronal network function.

KE6: Disruption, neurotransmitter release: Neurotransmitter release dysfunction involves abnormalities in the process where neurons transmit information between synapses, including the release, transmission, and reception of neurotransmitters.

KE7: Neuroinflammation: Neuroinflammation is an immune response occurring in the central nervous system, involving activation of neural cells (such as neurons) and immune cells (such as microglia), leading to localized inflammation. During neuroinflammation, inflammatory mediators are released, such as cytokines like IL-1β, TNF-α, and reactive oxygen species, which can further amplify the inflammatory response and exacerbate inflammation.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Essentiality of KEs

Defining question

High (Strong)

Moderate

Low (Weak)

 

Are downstream KEs and/or the AO prevented if an upstream KE is blocked?

Direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important KEs

Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE

No or contradictory experimental evidence of the essentiality of any of the KEs.

KE1

Increased, intracellular calcium

High

Extracellular signaling molecules bind to GPER, activating G proteins, which in turn activate phospholipase C, catalyzing the hydrolysis of PIP2 to generate the second messengers IP3 and DAG. IP3 diffuses intracellularly, binds to and opens Ca2+ channels on the endoplasmic reticulum membrane, leading to an increase in intracellular free Ca2+ concentration.

KE2

Decreased, ERαβ heterodimers

High

BPA and G1-induced GPER activation interferes with the crosstalk between ERα and ERβ.

KE3

Oxidative Stress

High

Elevated intracellular free calcium ion concentration leads to endoplasmic reticulum stress, while mitochondrial calcium overload can increase the production of ROS.

KE4

Increased, Apoptosis

High

The balance between generation and clearance of intracellular reactive oxygen species (ROS) is disrupted, leading to elevated levels of oxidants. ROS trigger mitochondrial release of cytochrome c and activation of caspase-3, resulting in cell apoptosis.

KE5

Aberrant, synaptic formation and plasticity

Moderate

Neuronal apoptosis may impact both the quantity and function of synapses, thereby influencing the release and transmission of neurotransmitters at synapses. Apoptosis can lead to synaptic loss or remodeling, potentially altering the efficiency of neurotransmitter release at specific synapses.

KE6

Disruption, neurotransmitter release

Moderate

Neuronal apoptosis can impact both the quantity and function of synapses, thereby influencing the release and transmission of neurotransmitters between synapses. Apoptosis leads to synaptic loss or remodeling, potentially reducing or increasing the efficiency of neurotransmitter release at specific synapses.

KE7

Neuroinflammation

High

Oxidative stress-induced inflammatory responses can lead to neuronal cell damage and inflammation by activating inflammatory pathways such as the NF-κB pathway and releasing pro-inflammatory cytokines such as TNF-α and IL-6. Apoptosis can also indirectly promote the occurrence and progression of neuroinflammation by releasing inflammatory mediators and activating inflammatory signaling pathways.

AO

Impairment, Learning and memory

High

Neuroinflammation-induced impairment of organismal learning and memory abilities is typically associated with structural and functional abnormalities in the nervous system, directly affecting neural circuits and signal transmission pathways relevant to learning and memory.

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
调制因子 (MF) 影响或结果 涉及的 KER
     

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

Babiloni-Chust, I., dos Santos, R. S., Medina-Gali, R. M., Perez-Serna, A. A., Encinar, J. A., Martinez-Pinna, J., . . . Nadal, A. (2022). G protein-coupled estrogen receptor activation by bisphenol-A disrupts the protection from apoptosis conferred by the estrogen receptors ERα and ERβ in pancreatic beta cells. Environment International, 164. doi:ARTN 107250 10.1016/j.envint.2022.107250

Braun, J. M. (2017). Early-life exposure to EDCs: role in childhood obesity and neurodevelopment. Nature Reviews Endocrinology, 13(3), 161-173. doi:10.1038/nrendo.2016.186

Hyun, S. A., Ko, M. Y., Jang, S., Lee, B. S., Rho, J., Kim, K. K., . . . Ka, M. (2022). Bisphenol-A impairs synaptic formation and function by RGS4-mediated regulation of BDNF signaling in the cerebral cortex. Disease Models & Mechanisms, 15(7). doi:ARTN dmm049177 10.1242/dmm.049177

Jiang, Y. Q., Li, J. F., Xu, S. Q., Zhou, Y. Q., Zhao, H. Z., Li, Y. Y., . . . Xia, W. (2020). Prenatal exposure to bisphenol A and its alternatives and child neurodevelopment at 2 years. Journal of Hazardous Materials, 388. doi:ARTN 121774 10.1016/j.jhazmat.2019.121774

Meng, L. X., Gui, S. H., Ouyang, Z. D., Wu, Y. J., Zhuang, Y. L., Pang, Q. H., & Fan, R. F. (2023). Low-dose bisphenols exposure sex-specifically induces neurodevelopmental toxicity in juvenile rats and the antagonism of EGCG. Journal of Hazardous Materials, 459. doi:ARTN 132074 10.1016/j.jhazmat.2023.132074

Rodríguez-Carrillo, A., Mustieles, V., Pérez-Lobato, R., Molina-Molina, J. M., Reina-Pérez, I., Vela-Soria, F., . . . Fernández, M. F. (2019). Bisphenol A and cognitive function in school-age boys: Is BPA predominantly related to behavior? Neurotoxicology, 74, 162-171. doi:10.1016/j.neuro.2019.06.006

Shi, J., Hu, K. L., Li, X. X., Ge, Y. M., Yu, X. J., & Zhao, J. (2024). Bisphenol a downregulates GLUT4 expression by activating aryl hydrocarbon receptor to exacerbate polycystic ovary syndrome. Cell Communication and Signaling, 22(1). doi:ARTN 28 10.1186/s12964-023-01410-y

Shin, J. Y., Choi, A., Lee, H. Y. S., Jeong, H. E., Lee, S. Y., Kwon, J. S., . . . Shin, J. Y. (2024). Association between exposure to antibiotics during pregnancy or early infancy and risk of autism spectrum disorder, intellectual disorder, language disorder, and epilepsy in children: population based cohort study. Bmj-British Medical Journal, 385. doi:ARTN e076885 10.1136/bmj-2023-076885

Wang, C. C., Wang, L., Huang, C. M., Liu, Y. G., Liu, J., Kuang, H. X., . . . Fan, R. F. (2022). Involvement of NLRP3/Caspase-1/GSDMD-Dependent pyroptosis in BPA-Induced apoptosis of human neuroblastoma cells. Biochemical Pharmacology, 200. doi:ARTN 115042 10.1016/j.bcp.2022.115042

Wang, L., Huang, C. M., Li, L. Z., Pang, Q. H., Wang, C. C., & Fan, R. F. (2023). In vitro and in silico assessment of GPER-dependent neurocytotoxicity of emerging bisphenols. Science of the Total Environment, 862. doi:ARTN 160762 10.1016/j.scitotenv.2022.160762

Zhang, H. B., Kuang, H. X., Luo, Y. F., Liu, S. H., Meng, L. X., Pang, Q. H., & Fan, R. F. (2019). Low-dose bisphenol A exposure impairs learning and memory ability with alterations of neuromorphology and neurotransmitters in rats. Science of the Total Environment, 697. doi:ARTN 134036 10.1016/j.scitotenv.2019.134036