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AOP: 522

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

Estrogen antagonism leading to increased risk of autism-like behavior

Short name

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Handbook Version v2.6

Graphical Representation

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Authors

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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

Kanglong Cui (email point of contact)

Contributors

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Kanglong Cui

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 January 25, 2024 21:58

Revision dates for related pages

Page	Revision Date/Time
Antagonism, Estrogen receptor	September 16, 2017 10:14
inhibition, EKR1/2 signaling pathway	January 25, 2024 21:13
Inhibition, NMDARs	September 16, 2017 10:14
Aberrant, synaptic formation and plasticity	January 25, 2024 21:18
Decrease of neuronal network function	May 28, 2018 11:36
autism-like behavior	January 25, 2024 21:20
Antagonism, Estrogen receptor leads to inhibition, EKR1/2 signaling pathway	January 25, 2024 21:21
inhibition, EKR1/2 signaling pathway leads to Aberrant, synaptic formation and plasticity	January 25, 2024 21:21
Aberrant, synaptic formation and plasticity leads to Neuronal network function, Decreased	January 25, 2024 21:22
Neuronal network function, Decreased leads to autism-like behavior	January 25, 2024 21:22
Inhibition, NMDARs leads to Aberrant, synaptic formation and plasticity	January 25, 2024 21:23
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

Autism spectrum disorder (ASD), also known as autism, is a common, highly hereditary and heterogeneous neurodevelopmental disorder. The prevalence of ASD is high globally and rising from 758 per 100,000 in 2010 to 1,000 in 2022^{[1, 2]}. Emerging evidence suggests that environmental factors contribute to the occurrence and development of ASD and that approximately 41% of the etiology of ASD are related to environmental factors directly or indirectly, for example, by the interaction with genetic factors^[3-5]. Epidemiologic studies have found association between exposure to environmental endocrine disruptors (EDCs) and ASD^[6-9]

On AOP-Wiki, there have been 14 reported AOPs linked to neurodevelopmental toxicity. These encompass a range of adverse outcomes, including learning and memory impairment (5 AOPs), cognitive dysfunction (4 AOPs), neural tube defects (3 AOPs), hearing loss (1 AOP), and periventricular heterotopia (1 AOP). Intriguingly, no AOPs directly related to ASD have been identified yet.

We chose two widespread plastic-derived EDCs, diethylhexyl phthalate (DEHP) and bisphenol A (BPA), as stressors. Using public datasets and network-based approach, we constructed a chemical-gene-phenotype-disease network (CGPDN) and developed a preliminary AOP of GDM using literature mining. In this AOP, estrogen antagonism was identified as the MIE, and four KEs, including decreased NMDAR expression (KE1), ERK1/2 signaling pathway inhibition (KE2), aberrant synaptic formation and plasticity (KE3), and decreased neuronal network function system (KE4), were selected to connect estrogen antagonism and ASD (AO).

The weight of evidence (WoE) of overall AOP was assessed based on the biological plausibility, empirical support, and evidence supporting essentiality of the KEs and KERs according to the OECD handbook of AOP. As a result, both the biological plausibility and evidence supporting essentiality were rated as “High”, empirical support was rated as “Moderate”, indicating “Moderate” confidence in this AOP. But we have no quantitative understanding of relationships between two key events, so, in the future, we can conduct some experiments about it.

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

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

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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

112

Antagonism, Estrogen receptor

KE	2207	inhibition, EKR1/2 signaling pathway	inhibition, EKR1/2 signaling pathway
KE	195	Inhibition, NMDARs	Inhibition, NMDARs
KE	2208	Aberrant, synaptic formation and plasticity	Aberrant, synaptic formation and plasticity
KE	386	Decrease of neuronal network function	Neuronal network function, Decreased

2209

autism-like behavior

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

Antagonism, Estrogen receptor leads to inhibition, EKR1/2 signaling pathway	adjacent	High	Not Specified
inhibition, EKR1/2 signaling pathway leads to Aberrant, synaptic formation and plasticity	adjacent	Moderate	Not Specified
Aberrant, synaptic formation and plasticity leads to Neuronal network function, Decreased	adjacent	Moderate	Not Specified
Neuronal network function, Decreased leads to autism-like behavior	adjacent	Low	Not Specified
Inhibition, NMDARs leads to Aberrant, synaptic formation and plasticity	adjacent	Moderate	Not Specified

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
During brain development	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
Homo sapiens	Homo sapiens	Moderate	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

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

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

KE essentiality assessment of the AOP that Estrogen antagonism leading to increased risk of autism-like behavior

MIE: Antagonism, estrogen

Supporting Data:

Estrogen can bind to estrogen receptors and activate the ERK signaling pathway, leading to an increase in the density of synapses and dendritic spines, inducing LTP, and promoting synaptic plasticity^{[17, 19, 38]}. Antagonizing the estrogen effect can inhibit the ERK signaling pathway^[10]，also inhibit the increase in dendritic spines, the synaptic density and the induction of LTP^{[17, 19]}. The prevalence of ASD is much higher in males than females, and multiple clinical and preclinical researches suggest that estrogen plays a role in inhibiting the development of ASD and protecting neuroprotection^[39].

Potentially Inconsistent Data: N/A

Evidence Rank: High

Reference: Yang, Y.^[17], Xu, X.^[38], Wang, C.^[10], Chen, X.^[19], Crider, A.^[39]

KE1: Decreasing, NMDAR expression

Supporting Data:

Pharmacological enhancement or inhibition of NMDAR function can improve symptoms of ASD in humans. The activation of NMDAR is crucial for inducing synaptic plasticity^[15]. Activation of NMDAR can rapidly improve synaptic plasticity inhibition caused by NGL-2 deficiency, as well as autism-like behaviors such as social interaction deficits and repetitive behaviors^[40]. NMDAR activation can also improve social behavior impairments caused by CTTNBP2 deficiency^[41]. Pharmacological enhancement of NMDAR function can improve symptoms of ASD in humans^[42].

Potentially Inconsistent Data: N/A

Evidence Rank: High

References: Citri, A.^[15], Um, S. M.^[40], Shih, P. Y.^[41], Lee, E. J^[42].

Evidence Assessment

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

KER biological plausibility assessment of AOP that Estrogen antagonism leading to increased risk of autism-like behavior
KER	Description	Reference	Evidence Rank
Antagonism, estrogen→Inhibition, ERK1/2 signaling pathway	BPA can inhibit the ERK signaling pathway by acting anti-estrogen effect^[10]. The activation of the ERK pathway by estrogen binding to estrogen receptors plays an important role in neuroprotection^[11-13].	Wang, C.^[10] Zhao, L.^[11] Yang, L. C.^[12] Lu, Y.^[13]	High
Decreased, NMDAR expression→Aberrant, synaptic formation and plasticity	NMDAR plays a critical role in forming the plasticity of the hippocampus, mice with NMDAR defects exhibit inhibited long-term potentiation of synapses^{[14, 15]}. Compared to normal mice, mice with mutations in GluN2B (a subunit that consists NMDAR) show impaired plasticity in the hippocampus^[16].	Tsien, J. Z.^[14] Citri, A.^[15] Brigman, J. L.^[16]	Moderate
Inhibition, ERK1/2 signaling pathway→Aberrant, synaptic formation and plasticity	Inhibiting the ERK pathway can inhibit the increase in dendritic spine and synaptic density caused by estrogen^{[17, 18]}. Inhibiting the ERK pathway can inhibit the induction of LTP in hippocampal neurons by estrogen^[19].	Hojo, Y.^[18] Yang, Y.^[17] Chen, X.^[19]	Moderate
Aberrant, synaptic formation and plasticity→Decrease of neuronal network function	Proper synaptic structure and formation of neuronal connections are necessary for normal brain development. Disruption of synaptic formation and plasticity in the hippocampus during development leads to structural and functional abnormalities in the hippocampus^{[20, 21]}.	Harris, K. M.^[21] Leuner, B.^[20]	Moderate
Decrease of neuronal network function→autism-like behavior	In ASD rat model, changes in hippocampal synaptic function-related proteins were found in life early phase^[22]. Autopsy findings in individuals with ASD reveal reduced dendritic branching and neuron size in the hippocampus^[23]. The hippocampus is involved in memory, spatial reasoning, and social interaction. structural and functional abnormalities in the hippocampus may lead to ASD through impairments in memory, spatial reasoning, and social interaction^[24].	Codagnone, M. G.^[22] Raymond, G. V.^[23] Banker, S. M.^[24]	Low

KER empirical support assessment of AOP that Estrogen antagonism leading to increased risk of autism-like behavior

Stressor	Administration Dose	Study Type	Administration Time	Test Time	MIE	KE1	KE2	KE3	KE4	AO	Reference
DEHP	100uM	in vitro (N2a Cell)	24h	immediately^a				√			Qiu, F.^[25]
DEHP	300mg/kg·BW/d	in vivo（rat）	GD0-PND21	PND21				√			Dong, J.^[26]
DEHP	100 kg·BW/d	in vivo（rat）	GD0-PND35	PND35					√	√	Li, Y.^[27]
DEHP	10 kg·BW/d	in vivo（rat）	GD14-GD21	GD21		√					Sun, G. C.^[28]
DEHP	50mg/kg·BW/d	in vivo（mice）	GD3-GD17	PND63				√		√	Zhang, X.^[29]
DEHP	50mg/kg·BW/d	in vivo（mice）	GD7-PND21	PND42		√					Dai, Y.^[30]
DEHP	500mg/kg·BW/d	in vivo（mice）	GD11-PND0	PND16 months					√		Barakat, R.^[31]
BPA	0.05 mg/kg·BW/d	in vivo（rat）	GD9-PND0	PND21			√				Wang, C.^[10]
BPA	0.5 mg/kg·BW/d	in vivo（rat）	GD9-PND0	PND21			√		√		Wang, C.^[10]
BPA	0.03 mg/kg·BW/d	in vivo（rat）	GD15-PND7	PND70				√			Kawato, S.^[32]
BPA	50 mg/kg·BW/d	in vivo（rat）	GD1-PND3	PND21						√	Singha, S. P.^[33]
BPA	50 mg/kg·BW/d	in vivo（rat）	Gavage (42 Days)	immediately^a			√		√		El Morsy, E. M.^[34]
BPA	1 mg/kg·BW/d	in vivo（rat）	Gavage (28 Days)	immediately^a				√			Hu, F.^[35]
BPA	4 mg/kg·BW/d	in vivo（mice）	GD7—PND14	PND14				√			Xu, X.^[36]
BPA	0.05 mg/kg·BW/d	in vivo（mice）	Oral (2 months)	immediately^a						√	Hyun, S. A.^[37]

a. “immediately” means that after “Administration Time”, researchers test the results immediately.

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

Modulating Factor (MF)	Influence or Outcome	KER(s) involved

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

None

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

[1] BAXTER A J, BRUGHA T S, ERSKINE H E, et al. The epidemiology and global burden of autism spectrum disorders [J]. Psychological medicine, 2015, 45(3): 601-13.

[2] ZEIDAN J, FOMBONNE E, SCORAH J, et al. Global prevalence of autism: A systematic review update [J]. Autism Res, 2022, 15(5): 778-90.

[3] GAUGLER T, KLEI L, SANDERS SJ, et al. Most genetic risk for autism resides with common variation [J]. Nat Genet, 2014, 46(8): 881-5.

[4] LORD C, BRUGHA T S, CHARMAN T, et al. Autism spectrum disorder [J]. Nat Rev Dis Primers, 2020, 6(1): 5.

[5] SAUER A K, STANTON J E, HANS S, et al. Autism Spectrum Disorders: Etiology and Pathology [M]//GRABRUCKER A M. Autism Spectrum Disorders. Brisbane (AU). 2021.

[6] MARí-BAUSET S, DONAT-VARGAS C, LLóPIS-GONZáLEZ A, et al. Endocrine Disruptors and Autism Spectrum Disorder in Pregnancy: A Review and Evaluation of the Quality of the Epidemiological Evidence [J]. Children (Basel, Switzerland), 2018, 5(12).

[7] KARDAS F, BAYRAM A K, DEMIRCI E, et al. Increased Serum Phthalates (MEHP, DEHP) and Bisphenol A Concentrations in Children With Autism Spectrum Disorder: The Role of Endocrine Disruptors in Autism Etiopathogenesis [J]. Journal of child neurology, 2016, 31(5): 629-35.

[8] KONDOLOT M, OZMERT E N, ASCı A, et al. Plasma phthalate and bisphenol a levels and oxidant-antioxidant status in autistic children [J]. Environ Toxicol Pharmacol, 2016, 43: 149-58.

[9] DAY D B, COLLETT B R, BARRETT E S, et al. Phthalate mixtures in pregnancy, autistic traits, and adverse childhood behavioral outcomes [J]. Environ Int, 2021, 147: 106330.

[10] WANG C, LI Z, HAN H, et al. Impairment of object recognition memory by maternal bisphenol A exposure is associated with inhibition of Akt and ERK/CREB/BDNF pathway in the male offspring hippocampus [J]. Toxicology, 2016, 341-343: 56-64.

[11] ZHAO L, BRINTON R D. Estrogen receptor alpha and beta differentially regulate intracellular Ca(2+) dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons [J]. Brain Res, 2007, 1172: 48-59.

[12] YANG L C, ZHANG Q G, ZHOU C F, et al. Extranuclear estrogen receptors mediate the neuroprotective effects of estrogen in the rat hippocampus [J]. PLoS One, 2010, 5(5): e9851.

[13] LU Y, SAREDDY G R, WANG J, et al. Neuron-Derived Estrogen Regulates Synaptic Plasticity and Memory [J]. J Neurosci, 2019, 39(15): 2792-809.

[14] TSIEN J Z, HUERTA P T, TONEGAWA S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory [J]. Cell, 1996, 87(7): 1327-38.

[15] CITRI A, MALENKA R C. Synaptic plasticity: multiple forms, functions, and mechanisms [J]. Neuropsychopharmacology, 2008, 33(1): 18-41.

[16] BRIGMAN J. L, WRIGHT T, TALANI G, et al. Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning [J]. J Neurosci, 2010, 30(13): 4590-600.

[17] YANG Y, FANG Z, DAI Y, et al. Bisphenol-A antagonizes the rapidly modulating effect of DHT on spinogenesis and long-term potentiation of hippocampal neurons [J]. Chemosphere, 2018, 195: 567-75.

[18] HOJO Y, MUNETOMO A, MUKAI H, et al. Estradiol rapidly modulates spinogenesis in hippocampal dentate gyrus: Involvement of kinase networks [J]. Hormones and behavior, 2015, 74: 149-56.

[19] CHEN X, WANG Y, XU F, et al. The Rapid Effect of Bisphenol-A on Long-Term Potentiation in Hippocampus Involves Estrogen Receptors and ERK Activation [J]. Neural Plast, 2017, 2017: 5196958.

[20] LEUNER B, GOULD E. Structural plasticity and hippocampal function [J]. Annu Rev Psychol, 2010, 61: 111-40, C1-3.

[21] HARRIS K M. Structural LTP: from synaptogenesis to regulated synapse enlargement and clustering [J]. Curr Opin Neurobiol, 2020, 63: 189-97.

[22] CODAGNONE M G, PODESTA M F, UCCELLI N A, et al. Differential Local Connectivity and Neuroinflammation Profiles in the Medial Prefrontal Cortex and Hippocampus in the Valproic Acid Rat Model of Autism [J]. Dev Neurosci, 2015, 37(3): 215-31.

[23] RAYMOND G V, BAUMAN M L, KEMPER T L. Hippocampus in autism: a Golgi analysis [J]. Acta Neuropathol, 1996, 91(1): 117-9.

[24] BANKER S M, GU X, SCHILLER D, et al. Hippocampal contributions to social and cognitive deficits in autism spectrum disorder [J]. Trends Neurosci, 2021, 44(10): 793-807.

[25] QIU F, ZHOU Y, DENG Y, et al. Knockdown of TNFAIP1 prevents di-(2-ethylhexyl) phthalate-induced neurotoxicity by activating CREB pathway [J]. Chemosphere, 2020, 241: 125114.

[26] DONG J, FU H, FU Y, et al. Maternal Exposure to Di-(2-ethylhexyl) Phthalate Impairs Hippocampal Synaptic Plasticity in Male Offspring: Involvement of Damage to Dendritic Spine Development [J]. ACS Chem Neurosci, 2021, 12(2): 311-22.

[27] LI Y, ZHAO Y, LU Y, et al. Autism spectrum disorder-like behavior induced in rat offspring by perinatal exposure to di-(2-ethylhexyl) phthalate [J]. Environmental science and pollution research international, 2022, 29(34): 52083-97.

[28] SUN G C, LEE Y J, LEE Y C, et al. Exercise prevents the impairment of learning and memory in prenatally phthalate-exposed male rats by improving the expression of plasticity-related proteins [J]. Behav Brain Res, 2021, 413: 113444.

[29] ZHANG X, HUANG J, ZHENG G, et al. Prenatal exposure to di (2-ethylhexyl) phthalate causes autism-like behavior through inducing Nischarin expression in the mouse offspring [J]. Biochemical and biophysical research communications, 2021, 585: 29-35.

[30] DAI Y, YANG Y, XU X, et al. Effects of uterine and lactational exposure to di-(2-ethylhexyl) phthalate on spatial memory and NMDA receptor of hippocampus in mice [J]. Hormones and behavior, 2015, 71: 41-8.

[31] BARAKAT R, LIN P C, PARK C J, et al. Prenatal Exposure to DEHP Induces Neuronal Degeneration and Neurobehavioral Abnormalities in Adult Male Mice [J]. Toxicol Sci, 2018, 164(2): 439-52.

[32] KAWATO S, OGIUE-IKEDA M, SOMA M, et al. Perinatal Exposure of Bisphenol A Differently Affects Dendritic Spines of Male and Female Grown-Up Adult Hippocampal Neurons [J]. Frontiers in neuroscience, 2021, 15: 712261.

[33] SINGHA S. P, MEMON S, BANO U, et al. Evaluation of p21 expression and related autism-like behavior in Bisphenol-A exposed offspring of Wistar albino rats [J]. Birth Defects Res, 2022, 114(11): 536-50.

[34] EL MORSY E M, AHMED M. Protective effects of lycopene on hippocampal neurotoxicity and memory impairment induced by bisphenol A in rats [J]. Human & experimental toxicology, 2020, 39(8): 1066-78.

[35] HU F, LI T, GONG H, et al. Bisphenol A Impairs Synaptic Plasticity by Both Pre- and Postsynaptic Mechanisms [J]. Adv Sci (Weinh), 2017, 4(8): 1600493.

[36] XU X, XIE L, HONG X, et al. Perinatal exposure to bisphenol-A inhibits synaptogenesis and affects the synaptic morphological development in offspring male mice [J]. Chemosphere, 2013, 91(8): 1073-81.

[37] HYUN S A, KO M Y, JANG S, et al. Bisphenol-A impairs synaptic formation and function by RGS4-mediated regulation of BDNF signaling in the cerebral cortex [J]. Disease models & mechanisms, 2022, 15(7).

[38] XU X, LU Y, ZHANG G, et al. Bisphenol A promotes dendritic morphogenesis of hippocampal neurons through estrogen receptor-mediated ERK1/2 signal pathway [J]. Chemosphere, 2014, 96: 129-37.

[39] CRIDER A, PILLAI A. Estrogen Signaling as a Therapeutic Target in Neurodevelopmental Disorders [J]. J Pharmacol Exp Ther, 2017, 360(1): 48-58.

[40] UM S M, HA S, LEE H, et al. NGL-2 Deletion Leads to Autistic-like Behaviors Responsive to NMDAR Modulation [J]. Cell Rep, 2018, 23(13): 3839-51.

[41] SHIH P Y, HSIEH B Y, LIN M H, et al. CTTNBP2 Controls Synaptic Expression of Zinc-Related Autism-Associated Proteins and Regulates Synapse Formation and Autism-like Behaviors [J]. Cell Rep, 2020, 31(9): 107700.

[42] LEE E. J, CHOI S Y, KIM E. NMDA receptor dysfunction in autism spectrum disorders [J]. Curr Opin Pharmacol, 2015, 20: 8-13.