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Cited by 24Effects and risks of endocrine disrupting chemicalsNeuroscience and Neuropharmacology ResearchMemory and Neural Mechanisms

The Rapid Effect of Bisphenol-A on Long-Term Potentiation in Hippocampus Involves Estrogen Receptors and ERK Activation

Open access
Chen, Xiaowei, Wang, Yu, Xu, Fang, Wei, Xiaofei, Zhang, Junfang, Wang, Chuang, Wei, Hua, Xu, Shujun +5 more·2017·Neural Plasticity
DOI 10.1155/2017/5196958PMC PMC5307006
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Abstract

Bisphenol-A (BPA), a widely used synthetic compound in plastics, disrupts endocrine function and interferes with physiological actions of endogenous gonadal hormones. Chronic effects of BPA on reproductive function, learning and memory, brain structure, and social behavior have been intensively investigated. However, less is known about the influence of BPA on long-term potentiation (LTP), one of the major cellular mechanisms that underlie learning and memory. In the present study, for the first time we investigated the effect of different doses of BPA on hippocampal LTP in rat brain slices. We found a biphasic effect of BPA on LTP in the dentate gyrus: exposure to BPA at a low dose (100 nM) enhanced LTP and exposure to BPA at a high dose (1000 nM) inhibited LTP compared with vehicle controls. The rapid facilitatory effect of low-dose BPA on hippocampal LTP required membrane-associated estrogen receptor (ER) and involved activation of the extracellular signal-regulated kinase (ERK) signaling pathway. Coadministration of 17 β-estradiol (E 2, the primary estrogen hormone) and BPA (100 nM) abolished both the BPA-induced enhancement of LTP and the E 2-induced enhancement of baseline fEPSP, suggesting a complex interaction between BPA- and E 2-mediated signaling pathways. Our investigation implies that even nanomolar levels of endocrine disrupters (e.g., BPA) can induce significant effects on hippocampal LTP.

AI snapshot

Written from the paper’s full text.

TL;DR

In rat hippocampal slices, bisphenol-A (BPA) had a biphasic effect on dentate gyrus long-term potentiation (LTP): 100 nM enhanced LTP, while 1000 nM inhibited it. The low-dose facilitation required estrogen receptor activation and ERK signaling, and coapplication of BPA with 17β-estradiol (E2) abolished both BPA-induced LTP enhancement and E2-induced baseline fEPSP enhancement.

Key findings

  • BPA at 100 nM increased LTP to 193.1 ± 8.3% of baseline versus vehicle controls at 143.7 ± 7.6% (n = 8, p < 0.001); 10 nM BPA had no effect (140.8 ± 5.2%, n = 8), while 1000 nM BPA inhibited LTP to 121.1 ± 4.0% of baseline (n = 8, p < 0.05).
  • The ER antagonist ICI 182,780 blocked BPA-enhanced LTP (123.4 ± 6.2% of baseline, n = 8, p < 0.001), indicating the facilitatory effect requires ER activation.
  • The MEK/ERK inhibitor U0126 inhibited LTP (103.1 ± 3.5% of baseline, n = 8, p < 0.001) and completely blocked BPA-enhanced LTP when applied before BPA (102.8 ± 6.1% of baseline, n = 8, p < 0.001); when BPA was applied before U0126, inhibition was partial (151.0 ± 4.7% of baseline, n = 8, p < 0.001).
  • E2 (10 nM) increased baseline fEPSP by ~20–30% but did not enhance LTP; coapplication of BPA (100 nM) and E2 reversed the E2-induced baseline fEPSP increase and blocked BPA-induced LTP enhancement.

Methods

  • Experiments used male Wistar rats (120–140 g, 5–6 weeks) and transverse hippocampal slices (350 μm thick); fEPSPs were recorded from the dentate gyrus molecular layer after medial perforant path stimulation, with LTP induced by high-frequency stimulation (two trains at 100 Hz for 1 s, 15 s intertrain interval).
  • Drugs were bath-applied: BPA (10, 100, 1000 nM), ICI 182,780 (100 nM), U0126 (100 nM), and 17β-E2 (10 nM); all solutions contained 100 μM picrotoxin, and vehicle was 0.05% DMSO.
  • Data were analyzed with pCLAMP 10.3; values are means ± SEM for n slices, with slices from different animals; two-tailed Student’s t-test and one-way ANOVA were used, with p < 0.05 considered significant.

Limitations

  • The paper states that it is unclear which ER subtype mediates the BPA effect because ICI 182,780 blocks both nuclear and membrane ERs, and that the mechanism underlying the BPA–E2 interaction remains unclear and requires further exploration.
  • Evident from the text: the study is acute in vitro slice electrophysiology in male rats only, so it cannot establish in vivo behavioral effects, sex differences, or chronic exposure outcomes.
  • Evident from the text: E2 alone did not enhance LTP in this preparation, which limits direct comparison with prior studies reporting E2-induced LTP enhancement.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1155/2017/5196958

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

5 of 25 cited sources checked · 4 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Pre- and perinatal exposures to BPA at or below the TDI (≤50 μg/kg/day) have resulted in adverse effects on memory processes in rodents.

    “In rodents, pre- and perinatal exposures to BPA at or below the TDI (tolerable daily intake; ⩽50 μg/kg/day) have resulted in adverse effects on memory processes [4–9].”
    Quote in the paperNot a substantial claim2 of 6 sources checked
    • cites [4] Xu X.-H. Zhang J. Wang Y.-M. Ye Y.-P. Luo Q.-Q. Perinatal exposure to bisphenol-A impairs learning-memory by concomitant down-regulation of N-methyl-d-aspartate receptors of hippocampus in male offspring mice Hormones and Behavior 2010 58 2 326 333 10.1016/j.yhbeh.2010.02.012 2-s2.0-77953363306 20206181 source
    • cites [5] Diaz Weinstein S. Villafane J. J. Juliano N. Bowman R. E. Adolescent exposure to Bisphenol-A increases anxiety and sucrose preference but impairs spatial memory in rats independent of sex Brain Research 2013 1529 56 65 10.1016/j.brainres.2013.07.018 2-s2.0-84882602522 23872220 source
    • cites [6] Kumar D. Kumar Thakur M. Perinatal exposure to bisphenol-A impairs spatial memory through upregulation of neurexin1 and neuroligin3 expression in male mouse brain PLoS ONE 2014 9 10 e110482 10.1371/journal.pone.0110482 2-s2.0-84908133393 PMC4201550 25330104 source
    • cites [7] Sadowski R. N. Wise L. M. Park P. Y. Schantz S. L. Juraska J. M. Early exposure to bisphenol A alters neuron and glia number in the rat prefrontal cortex of adult males, but not females Neuroscience 2014 279 122 131 10.1016/j.neuroscience.2014.08.038 2-s2.0-84907549528 25193849 PMC4197082 source

      The Discussion (page not provided) says there were no significant changes in reference or working memory in any BPA-exposed group. That includes the 4 and 40 μg/kg/day groups, both below the stated 50 μg/kg/day threshold. This paper therefore reports the opposite of the memory effect attributed to it. (LLM, conf=0.92)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [8] Wang C. Niu R. Zhu Y. Changes in memory and synaptic plasticity induced in male rats after maternal exposure to bisphenol A Toxicology 2014 322 51 60 10.1016/j.tox.2014.05.001 2-s2.0-84901617609 24820113 source
    • cites [9] Zhang Q. Xu X. Li T. Exposure to bisphenol-A affects fear memory and histone acetylation of the hippocampus in adult mice Hormones and Behavior 2014 65 2 106 113 10.1016/j.yhbeh.2013.12.004 2-s2.0-84892152837 24333847 source
  • Premisecitation

    The E2-induced increase in synapse density is inhibited by simultaneous application of BPA (40 ug/kg) and E2 (60 ug/kg) in ovariectomized rats for 30 min.

    “Our findings are consistent with a previous in vivo study showing that the E2-induced increase in synapse density is inhibited by the simultaneous application of BPA (40 ug/kg) and E2 (60 ug/kg) in ovariectomized rats for 30 min [37].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] MacLusky N. J. Hajszan T. Leranth C. The environmental estrogen bisphenol A inhibits estradiol-induced hippocampal synaptogenesis Environmental Health Perspectives 2005 113 6 675 679 10.1289/ehp.7633 2-s2.0-20844456812 15929888 PMC1257590 source
  • Findingown data

    ICI 182,780 alone does not affect LTP in rat dentate gyrus.

    “Application of ICI 182,780 had no effect on LTP (120.6 ± 3.7% of baseline, n = 8, controls: 140.8 ± 5.2% of baseline, n = 8. p > 0.05, Figure 2(b))”
    Quote in the paperSubstantial claim
  • Findingown data

    BPA at 100 nM increases LTP in rat dentate gyrus compared with vehicle controls.

    “However, 100 nM BPA increased LTP (193.1 ± 8.3% of baseline, n = 8) compared to control (143.7 ± 7.6% of baseline, n = 8, p < 0.001, Figures 1(a) and 1(b)).”
    Quote in the paperSubstantial claim
  • Findingown data

    BPA at 10 nM does not affect LTP in rat dentate gyrus compared with vehicle controls.

    “We found that application of 10 nM BPA did not have any effect on LTP (140.8 ± 5.2% of baseline, n = 8) compared with vehicle controls (143.7 ± 7.6% of baseline, n = 8, p > 0.05, Figures 1(a) and 1(b)).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 6
  • May combine two claims. 3

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    E2 influences hippocampal memory.

    “Mounting articles demonstrate that E2 influences hippocampal memory [31, 32].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [31] Luine V. N. Estradiol and cognitive function: past, present and future Hormones and Behavior 2014 66 4 602 618 10.1016/j.yhbeh.2014.08.011 2-s2.0-84907737483 25205317 PMC4318702 source
    • cites [32] Korol D. L. Pisani S. L. Estrogens and cognition: friends or foes?. An evaluation of the opposing effects of estrogens on learning and memory Hormones and Behavior 2015 74 105 115 10.1016/j.yhbeh.2015.06.017 2-s2.0-84941741051 26149525 PMC4573330 source

  • May combine two claims.

    Findingown data

    BPA has a biphasic effect on hippocampal LTP in rat dentate gyrus: low dose (100 nM) enhances LTP and high dose (1000 nM) inhibits LTP.

    “We found a biphasic effect of BPA on LTP in the dentate gyrus: exposure to BPA at a low dose (100 nM) enhanced LTP and exposure to BPA at a high dose (1000 nM) inhibited LTP compared with vehicle controls.”
    • Also stated in: § 3.1. The Facilitatory Effect of Low-Dose BPA on LTP in the Dentate Gyrus · hedged
      “indicating a biphasic effect of low-dose (100 nM) and high-dose (1000 nM) BPA on hippocampal LTP.”
    • Also stated in: § 5. Conclusions · boosted
      “we demonstrated biphasic effects of BPA on LTP in DG region of rat hippocampus: exposure to BPA at a low dose (100 nM) enhances LTP while to a high dose BPA (1000 nM) inhibits LTP.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The electrophysiological techniques were applied according to previous reports.

    “The electrophysiological techniques were applied according to our previous reports [24, 25].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Klyubin I. Wang Q. Reed M. N. Protection against Aβ-mediated rapid disruption of synaptic plasticity and memory by memantine Neurobiology of Aging 2011 32 4 614 623 10.1016/j.neurobiolaging.2009.04.005 2-s2.0-79953061290 19446369 source
    • cites [25] Chen X. Lin R. Chang L. Enhancement of long-term depression by soluble amyloid β protein in rat hippocampus is mediated by metabotropic glutamate receptor and involves activation of p38MAPK, STEP and caspase-3 Neuroscience 2013 253 435 443 10.1016/j.neuroscience.2013.08.054 2-s2.0-84885197799 24012839 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Exposure to BPA at low concentrations (10-100 nM) rapidly suppressed LTD in the dentate gyrus of hippocampus.

    “Interestingly, it has been reported that exposure to BPA at low concentrations (10–100 nM) rapidly enhanced LTD in CA1 and CA3 but suppressed LTD in the dentate gyrus of the hippocampus [20, 21].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Ogiue-Ikeda M. Tanabe N. Mukai H. Rapid modulation of synaptic plasticity by estrogens as well as endocrine disrupters in hippocampal neurons Brain Research Reviews 2008 57 2 363 375 10.1016/j.brainresrev.2007.06.010 2-s2.0-40749110603 17822775 source
    • cites [21] Hasegawa Y. Ogiue-Ikeda M. Tanabe N. Bisphenol a significantly modulates long-term depression in the hippocampus as observed by multi-electrode system Neuroendocrinology Letters 2013 34 2 129 134 2-s2.0-84878220732 23645310

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All brain slices in the same group were from different animals.

    “All brain slices in the same group were from different animals.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Control levels of LTP were measured on slices perfused with vehicle (DMSO) alone.

    “Control levels of LTP were measured on slices perfused with vehicle (DMSO) alone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    BPA can bind to estrogen receptors at low concentration and affects normal hormonal regulation and endocrine function.

    “BPA can bind to estrogen receptors (ERs) at low concentration and thus affects normal hormonal regulation and endocrine function [1].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Richter C. A. Birnbaum L. S. Farabollini F. In vivo effects of bisphenol A in laboratory rodent studies Reproductive Toxicology 2007 24 2 199 224 10.1016/j.reprotox.2007.06.004 2-s2.0-34548529042 17683900 PMC2151845 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Exposure to BPA at low concentrations (10-100 nM) rapidly enhanced LTD in CA1 and CA3 of hippocampus.

    “Interestingly, it has been reported that exposure to BPA at low concentrations (10–100 nM) rapidly enhanced LTD in CA1 and CA3 but suppressed LTD in the dentate gyrus of the hippocampus [20, 21].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Ogiue-Ikeda M. Tanabe N. Mukai H. Rapid modulation of synaptic plasticity by estrogens as well as endocrine disrupters in hippocampal neurons Brain Research Reviews 2008 57 2 363 375 10.1016/j.brainresrev.2007.06.010 2-s2.0-40749110603 17822775 source
    • cites [21] Hasegawa Y. Ogiue-Ikeda M. Tanabe N. Bisphenol a significantly modulates long-term depression in the hippocampus as observed by multi-electrode system Neuroendocrinology Letters 2013 34 2 129 134 2-s2.0-84878220732 23645310

  • May combine two claims.

    Premisenone given

    No studies have assessed the potential of BPA to influence LTP, and the underlying mechanisms are largely unknown.

    “However, no studies have assessed the potential of BPA to influence LTP, and the underlying mechanisms are yet largely unknown.”
    Quote in the paperSubstantial claim
9 of 9

  • The paper relies on this without support.

    U0126 at 100 nM specifically inhibits MEK1/2/ERK signaling without affecting other pathways.

    “Application of 100 nM U0126 (a MEK1/2 or ERK inhibitor) 60 min before HFS did not alter the baseline fEPSP but inhibited the hippocampus LTP in rat dentate gyrus compared with vehicle controls (103.1 ± 3.5% of baseline, n = 8, p < 0.001, Figures 3(a) and 3(c)).”

  • The paper relies on this without support.

    ICI 182,780 at 100 nM acts as a high-affinity nonselective estrogen receptor antagonist without other effects.

    “we add a high-affinity nonselective ER antagonist ICI 182,780 (100 nM) into bath solution 30 min before BPA application.”

  • The paper relies on this without support.

    The effects of BPA on LTP in hippocampal slices reflect effects on hippocampal LTP in vivo.

    “Our investigation implies that even nanomolar levels of endocrine disrupters (e.g., BPA) can induce significant effects on hippocampal LTP.”
3 of 3

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • E2 is said both to enhance and not enhance LTP

    Minor

    The discussion says E2 alone enhances LTP, whereas the results state that E2 treatment did not enhance LTP.

  • Membrane estrogen receptor requirement is stated despite receptor type being unresolved

    Minor

    The abstract says the BPA effect required a membrane-associated estrogen receptor, but the discussion says the experiment cannot establish which type of estrogen receptor is involved.

2 of 2

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1371/journal.pone.0110482

    Info

    The cited work was retracted on 2019-07-18 (notice 10.1371/journal.pone.0220212), not before this paper was published (2017).

    Cited work 10.1371/journal.pone.0110482 · retracted 2019-07-18 · notice 10.1371/journal.pone.0220212 · this paper published 2017

1 of 1

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 3

  1. 2006, Neuroendocrinology Letters, 27, 97
  2. 2013, Neuroendocrinology Letters, 34, 129
  3. 2004, Environmental sciences : an international journal of environmental physiology and toxicology, 11, 1

Cited by

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Related

Authors
Chen, X., Wang, Y., Xu, F., Wei, X., Zhang, J., Wang, C., Wei, H., Xu, S., Yan, P., Zhou, W., Mody, I., Xu, X., & Wang, Q.
Affiliations
  • Ningbo University (CN)
  • Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo 315211, China
  • Zhejiang Normal University (CN)
Corresponding author
  • Xu, Xiaohong
  • Wang, Qinwen
ORCID
Venue
Neural Plasticity
Publisher
Wiley
Published
2017
Volume
2017
Pages
1-9
ISSN
  • 1687-5443 (ISSN-L)
  • 2090-5904
DOI
10.1155/2017/5196958
PMC
PMC5307006
OpenAlex
W2584977985
Cited by
24
References
39
Citations by year
2024: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 7 · 2019: 4 · 2018: 5 · 2017: 1
FWCI
2.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Neural Plasticity (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Natural Science Foundation of China (U1503223, 81671089, 81472935, 81172627, LY15H090011, LY14H090004, Z2090955, 2016A610086, 2015C110026)
  • Zhejiang Provincial Natural Science Foundation of China (U1503223, 81671089, 81472935, 81172627, LY15H090011, LY14H090004, Z2090955, 2016A610086, 2015C110026)
  • Ningbo Natural Science Foundation (U1503223, 81671089, 81472935, 81172627, LY15H090011, LY14H090004, Z2090955, 2016A610086, 2015C110026)
  • Ningbo municipal innovation team of life science and health (U1503223, 81671089, 81472935, 81172627, LY15H090011, LY14H090004, Z2090955, 2016A610086, 2015C110026)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
bisphenol A, endocrine disruptors, long-term potentiation, hippocampus, dentate gyrus, estrogen receptor, ERK signaling, estradiol, learning and memory, synaptic plasticity
MeSH terms
Fulvestrant, Bisphenol A Compounds, Animals, Benzhydryl Compounds, Dose-Response Relationship, Drug, Estradiol, Hippocampus, Male, Phenols, Receptors, Estrogen, Rats, Wistar, Long-Term Potentiation, Dentate Gyrus, Excitatory Postsynaptic Potentials, MAP Kinase Signaling System, Rats, Estrogen Receptor Antagonists

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