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

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

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

欧阳泽东、庞启华、范瑞芳^*

中国广州华南师范大学生命科学学院

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

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

Zedong Ouyang
Ruifang Fan

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

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 March 09, 2026 03:40

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
Increase, Oxidative Stress	February 11, 2026 07:05
Apoptosis	May 31, 2025 08:50
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 Increase, Oxidative Stress	June 19, 2024 04:23
Increase, 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
Increase, 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

该AOP描述了BPA与膜受体GPER结合与GPER激活之间的关系，导致学习和记忆障碍。

作为一种跨膜蛋白，G蛋白偶联雌激素受体（GPER）被认为是雌激素在全身快速非基因组信号传导事件的主要介导者，这些事件在包括神经细胞在内的多种组织类型中表达。由于其在细胞膜上的丰度和表达量高，它更容易被内源性或外源性雌激素激活。双酚A（BPA）作为常见的内分泌干扰物，进入体内时可产生类似雌激素的作用。BPA对GPER的结合和激活可以作为分子起始事件（MIE）。GPER激活后，它促进细胞内^Ca2+浓度作为关键事件1（KE1）的增加，减少ERαβ的异聚化，导致细胞凋亡/焦凋亡，并诱导细胞氧化应激。这进而影响神经元形态发生和神经递质稳态。因此，这些变化会引发神经系统的炎症反应，最终导致学习和记忆能力（AO）下降等不良后果。

我们已识别出沿该不良结局路径的多个关键事件，并确认了这些关键事件之间的联系。基于此，我们开发了AOP以描述GPER的结合和激活，这会导致学习和记忆能力下降。

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是塑料中常见添加剂，常在人体体液中检测到，包括血液、尿液和母乳。BPA可能通过影响芳香烃受体（AhR）或雌激素受体（ERs）在体内诱发芳香化合物的代谢和内分泌疾病（Shi 等，2024），表现出生殖毒性、代谢综合征和神经毒性。大量流行病学研究和毒理学研究表明，BPA可以穿越血脑屏障，低剂量的BPA暴露与多种神经退行性疾病和神经心理障碍相关（Hyun等，2022）。因此，有必要根据AOP框架评估BPA的健康风险。

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

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	Increase, Oxidative Stress	Increase, 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

341

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

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 Increase, Oxidative Stress	adjacent	Moderate
Increase, 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
Increase, 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

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

Name
Bisphenol A

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

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

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

此前关于内分泌干扰物的研究，如双酚A（BPA），主要集中在雌激素受体α（ERα）和β（ERβ）上，而该不良结局通路（AOP）则关注BPA激活G蛋白雌激素受体（GPER），对此有大量证据支持。然而，低剂量BPA对神经发育的影响仍不确定。当BPA在环境中以低剂量存在时，首先结合并激活细胞膜上的跨膜蛋白受体GPER，介导快速的细胞调控，这可能是BPA即使在低剂量下仍可能对细胞造成毒性影响的原因。然而，还需要更多关于敲入、敲除和抑制剂的研究，以探讨剂量与毒性效应之间的相关性。

该AOP由GPER激活启动。BPA可以直接激活GPER，导致细胞内游离^Ca2+浓度增加（L. Wang 等，2023），同时减少雌激素受体α和β的二聚化（Babiloni-Chust等，2022）。实验支持可从多种模型中获得，包括实验动物、小鼠和细胞系，其中敲入、敲除、拮抗和激活等证据可以证实MIE与KER 之间的联系。

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

在胰岛细胞中，研究发现低剂量BPA可结合并激活GPER，抑制雌激素受体α和β的二聚/异二聚化，进而导致程序性细胞死亡（Babiloni-Chust等，2022）。同样的结果也在神经母细胞瘤细胞和原发海马神经元中观察到（Meng等，2023;C. C. Wang等，2022）。

在大鼠模型中，观察到暴露BPA会导致小鼠空间学习和记忆能力下降，且雄性大鼠的影响更为明显（Zhang 等，2019）。使用GPER抑制剂可以有效缓解此病（Meng等，2023）。

同时，结合流行病学调查和实验研究结果，怀孕和婴儿期是人体神经系统发育的最关键窗口期，且对污染物暴露相对敏感，尤其是在神经系统发育方面（Braun，2017;Shin 等，2024）。BPA对行为有显著影响，这一点在学龄男孩中已被观察到（Rodríguez-Carrillo 等，2019）。还有证据表明，产前暴露于BPA及其类似物可能影响儿童的神经发育，男孩相关性更高（Jiang等，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：蛋白偶联雌激素受体1（GPER）激活：雌激素（如17β-雌二醇）结合GPER上的特定结合位点，激活GPER，GPER与细胞内G蛋白，特别是Gα亚基相互作用。这种相互作用会产生第二信使，并触发一系列细胞反应。

KE1：细胞内钙含量增加：储存在内质网中的钙离子接收来自上方的信号，释放Ca2+进入细胞质，调控细胞凋亡和代谢调控等多种细胞功能。

KE2：减少的ERα/β异源体：ERα和ERβ的二聚体在细胞中扮演多种关键角色，包括细胞周期的转录调控、细胞分化和细胞代谢。此外，ERα和ERβ二聚体还与其他细胞信号通路相互作用。ERα和ERβ的二聚体形式还通过影响细胞凋亡相关基因的表达或调控抗凋亡因子的活性，从而维持细胞存活能力，从而与细胞存活和凋亡过程相关。在神经系统中，ERβ的激活被认为能保护神经元免受氧化应激和炎症损伤，这可能涉及ERβ二聚体的调控机制。

KE3：氧化应激：氧化应激是指细胞或生物体内氧化还原（氧化还原）平衡被破坏，导致氧化分子（如氧自由基）产生，超过抗氧化防御系统的清除能力。

KE4：细胞凋亡增多，凋亡是一个高度有组织和受控的细胞死亡过程，受内在和外在信号调控，允许有序地消灭不必要的或受损细胞而不引发炎症反应。这一过程在生物体发育、免疫调节和组织稳态中起着关键作用。凋亡细胞表现出典型的形态变化，包括膜剥蚀、细胞萎缩、染色质缩合和核分裂。最终，细胞被降解成称为凋亡体的小片段，随后被邻近的巨噬细胞或其他吞噬细胞吞噬并降解。

KE5：异常、突触形成与可塑性：突触形成和可塑性异常涉及神经系统内突触的结构和功能变化，影响神经元间信息的传递和处理。突触形成异常可能指突触形态的不规则变化，如突触数量、形状或大小异常。例如，突触形成过多或稀疏会影响神经网络的正常连接性和功能。

突触可塑性是神经系统中的关键特征，使神经连接的强度和效率能够调节。异常可塑性可能表现为突触前和突触后神经元之间信号传递调控不当，导致神经网络功能受损或破坏。

KE6：神经递质的紊乱，神经递质释放：神经递质释放功能障碍涉及神经元在突触之间传递信息的过程中出现异常，包括神经递质的释放、传递和接收。

KE7：神经炎症：神经炎症是发生在中枢神经系统的一种免疫反应，涉及神经细胞（如神经元）和免疫细胞（如小胶质细胞）的激活，导致局部炎症。在神经炎症期间，炎症介质会释放，如IL-1β、TNF-α和活性氧，这些物质会进一步放大炎症反应并加重炎症。

Evidence Assessment

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

KE的必要性	定义性问题	高（强）	中等	低（弱）
	如果上游的动能被阻断，下游的KE和/或AO会被阻止吗？	来自专门设计的实验研究的直接证据，表明至少有一种重要的KE是必需的	间接证据表明，预期调制因子的足够修饰会削弱或增强动能	没有或有相反的实验证据证明任何KE的必要性。
KE1 细胞内钙含量升高	高	细胞外信号分子结合GPER，激活G蛋白，进而激活磷脂酶C，催化PIP2水解，生成第二信使IP3和DAG。IP3在细胞内扩散，结合并打开内质网膜上的Ca²⁺通道，导致细胞内游离^Ca2+浓度增加。
KE2 ERαβ异二聚体减少	高	BPA和G1诱导的GPER激活干扰ERα和ERβ之间的串扰。
KE3 氧化应激	高	细胞内游离钙离子浓度升高会导致内质网应激，而线粒体钙过载则可能增加ROS的产生。
KE4 加重，凋亡	高	细胞内活性氧（ROS）的生成与清除平衡被打破，导致氧化剂水平升高。ROS会触发线粒体释放细胞色素c并激活半胱天冬酶-3，导致细胞凋亡。
KE5 异常、突触形成与可塑性	中等	神经元凋亡可能影响突触的数量和功能，从而影响突触中神经递质的释放和传递。凋亡可能导致突触丧失或重塑，可能改变特定突触处神经递质释放的效率。
KE6 破坏，神经递质释放	中等	神经元凋亡会影响突触的数量和功能，从而影响突触间神经递质的释放和传递。凋亡导致突触丧失或重塑，可能降低或增加特定突触神经递质释放的效率。
KE7 神经炎症	高	氧化应激引起的炎症反应可通过激活如NF-κB通路和释放促炎细胞因子如TNF-α和IL-6，导致神经元细胞损伤和炎症。凋亡还可以通过释放炎症介质并激活炎症信号通路，间接促进神经炎症的发生和进展。
AO 障碍、学习与记忆	高	神经炎症引起的生物体学习和记忆能力障碍通常与神经系统的结构和功能异常相关，直接影响与学习和记忆相关的神经回路和信号传递通路。

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

巴比洛尼-楚斯特，I.，桑托斯，R.S.，梅迪纳-加利，R.M.，佩雷斯-塞尔纳，A.A.，恩西纳尔，J.A.，马丁内斯-皮纳，J.，......纳达尔，A.（2022）。双酚A激活G蛋白偶联雌激素受体，破坏胰腺β细胞中雌激素受体ERα和ERβ所提供的细胞凋亡保护。环境国际，164。doi：ARTN 107250 10.1016/j.envint.2022.107250

布劳恩，J. M.（2017）。早期暴露于EDCs：在儿童肥胖和神经发育中的作用。《自然评论内分泌学》，13（3），161-173。doi：10.1038/nrendo.2016.186

玄S. A.、高M. Y.、张S.、李B. S.、罗J.、金K. K.等卡，M.（2022）。双酚A通过RGS4介导的大脑皮层BDNF信号调控，从而损害突触形成和功能。疾病模型与机制，15（7）。doi：ARTN dmm049177 10.1242/dmm.049177

江永启、李志斐、徐志康、周永启、赵浩志、李永荣......夏，W.（2020）。产前暴露于双酚A及其替代品，以及2岁时儿童神经发育。《危险物质杂志》，388页。doi：ARTN 121774 10.1016/j.jhazmat.2019.121774

孟隆隆、桂志浩、欧阳志明、吴永志、庄永荣、庞启浩、范荣荣（2023）。低剂量双酚暴露于性特异性中诱导幼年大鼠的神经发育毒性，并抑制EGCG。《危险物质杂志》，459页。doi：ARTN 132074 10.1016/j.jhazmat.2023.132074

罗德里格斯-卡里略，A.，穆斯蒂耶莱斯，V.，佩雷斯-洛巴托，R.，莫利纳-莫利纳，J. M.，雷纳-佩雷斯，I.，韦拉-索里亚，F.，......费尔南德斯，M. F.（2019）。双酚A与学龄男孩的认知功能：BPA主要与行为相关吗？神经毒理学，74,162-171。DOI：10.1016/J.Neuro.2019.06.006

石宇宇、胡伟大、李晓晓、葛永义、余晓洁、赵宇（2024）。双酚a通过激活芳基烃受体，下调GLUT4表达，加重多囊卵巢综合征。《细胞通信与信号传导》，22（1）。doi：ARTN 28 10.1186/s12964-023-01410-y

申志英、崔文、李弘世、郑弘明、李文文、权志志......申，J. Y.（2024）。孕期或婴儿早期抗生素暴露与儿童自闭症谱系障碍、智力障碍、语言障碍和癫痫风险的关联：基于人群的队列研究。《英国医学杂志》，385页。doi：ARTN e076885 10.1136/BMJ-2023-076885

王志康、王志明、黄志明、刘永嘉、刘志、匡浩熙......范，R. F.（2022）。NLRP3/Caspase-1/GSDMD依赖性皖아凋亡在BPA诱导人类神经母细胞瘤细胞凋亡中的参与。《生化药理学》，200页。doi：ARTN 115042 10.1016/j.bcp.2022.115042

王立、黄志明、李志志、庞启宏、王志志、范荣荣（2023）。体外及计算机实验室评估新兴双酚的GPER依赖性神经细胞毒性。《整体环境科学》，862页。doi：ARTN 160762 10.1016/j.scitotenv.2022.160762

张浩（H. B.）、匡（Kuang）、罗（Y. F.）、刘（Liu， S. H.）、孟（L. X.）、庞（Pang）和范（R. F.）（2019）。低剂量双酚A暴露会损害大鼠的学习和记忆能力，并改变神经形态和神经递质。《整体环境科学》，第697页。doi：ARTN 134036 10.1016/j.scitotenv.2019.134036