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AOP: 535
Title
Binding and activation of GPER leading to learning and memory impairments
Short name
Graphical Representation
Point of Contact
Contributors
- Zedong Ouyang
- Ruifang Fan
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
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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
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
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
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 2029 | protein-coupled estrogen receptor 1 (GPER) activation | GPER activation |
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)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
GPER activation leads to Increased, Intracellular Calcium overload | adjacent | High | |
GPER activation leads to Decreased, ERαβ heterodimers | adjacent | Moderate | |
Increased, Intracellular Calcium overload leads to Oxidative Stress | adjacent | Moderate | |
Oxidative Stress leads to Apoptosis | adjacent | High | |
Apoptosis leads to Aberrant, synaptic formation and plasticity | adjacent | Moderate | |
Apoptosis leads to Disruption, neurotransmitter release | adjacent | Moderate | |
Oxidative Stress leads to Neuroinflammation | adjacent | High | |
Aberrant, synaptic formation and plasticity leads to Impairment, Learning and memory | adjacent | High | |
Disruption, neurotransmitter release leads to Impairment, Learning and memory | adjacent | Moderate | |
Decreased, ERαβ heterodimers leads to Apoptosis | adjacent | Moderate | |
Neuroinflammation leads to Impairment, Learning and memory | adjacent | High | |
Increased, Intracellular Calcium overload leads to Disruption, neurotransmitter release | adjacent | Moderate | |
Apoptosis leads to Neuroinflammation | adjacent | Moderate |
Network View
Prototypical Stressors
Name |
---|
Bisphenol A |
Life Stage Applicability
Life stage | Evidence |
---|---|
Nursing Child | Moderate |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Mixed | Moderate |
Overall Assessment of the AOP
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
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
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
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
调制因子 (MF) | 影响或结果 | 涉及的 KER |
---|---|---|
Quantitative Understanding
Considerations for Potential Applications of the AOP (optional)
References
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