De Novo Synthesized Estradiol Protects against Methylmercury-Induced Neurotoxicity in Cultured Rat Hippocampal Slices

Takeshi Yamazaki, Megumi Yamamoto, Yasuhiro Ishihara, Shota Komatsu, Eiji Munetsuna, Masahiro Onizaki, Atsuhiko Ishida, Suguru Kawato, Takao Mukuda

Research output: Contribution to journalArticle

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Abstract

Background: Estrogen, a class of female sex steroids, is neuroprotective. Estrogen is synthesized in specific areas of the brain. There is a possibility that the de novo synthesized estrogen exerts protective effect in brain, although direct evidence for the neuroprotective function of brain-synthesized estrogen has not been clearly demonstrated. Methylmercury (MeHg) is a neurotoxin that induces neuronal degeneration in the central nervous system. The neurotoxicity of MeHg is region-specific, and the molecular mechanisms for the selective neurotoxicity are not well defined. In this study, the protective effect of de novo synthesized 17β-estradiol on MeHg-induced neurotoxicity in rat hippocampus was examined. Methodology/Principal Findings: Neurotoxic effect of MeHg on hippocampal organotypic slice culture was quantified by propidium iodide fluorescence imaging. Twenty-four-hour treatment of the slices with MeHg caused cell death in a dose-dependent manner. The toxicity of MeHg was attenuated by pre-treatment with exogenously added estradiol. The slices de novo synthesized estradiol. The estradiol synthesis was not affected by treatment with 1 μM MeHg. The toxicity of MeHg was enhanced by inhibition of de novo estradiol synthesis, and the enhancement of toxicity was recovered by the addition of exogenous estradiol. The neuroprotective effect of estradiol was inhibited by an estrogen receptor (ER) antagonist, and mimicked by pre-treatment of the slices with agonists for ERα and ERβ, indicating the neuroprotective effect was mediated by ERs. Conclusions/Significance: Hippocampus de novo synthesized estradiol protected hippocampal cells from MeHg-induced neurotoxicity via ERα- and ERβ-mediated pathways. The self-protective function of de novo synthesized estradiol might be one of the possible mechanisms for the selective sensitivity of the brain to MeHg toxicity.

Original languageEnglish
Article numbere55559
JournalPloS one
Volume8
Issue number2
DOIs
Publication statusPublished - 06-02-2013

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methylmercury compounds
neurotoxicity
estradiol
Rats
Estradiol
rats
Estrogens
estrogens
Toxicity
Brain
Estrogen Receptors
toxicity
brain
neuroprotective effect
Neuroprotective Agents
protective effect
Hippocampus
pretreatment
synthesis
neurotoxins

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Yamazaki, Takeshi ; Yamamoto, Megumi ; Ishihara, Yasuhiro ; Komatsu, Shota ; Munetsuna, Eiji ; Onizaki, Masahiro ; Ishida, Atsuhiko ; Kawato, Suguru ; Mukuda, Takao. / De Novo Synthesized Estradiol Protects against Methylmercury-Induced Neurotoxicity in Cultured Rat Hippocampal Slices. In: PloS one. 2013 ; Vol. 8, No. 2.
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abstract = "Background: Estrogen, a class of female sex steroids, is neuroprotective. Estrogen is synthesized in specific areas of the brain. There is a possibility that the de novo synthesized estrogen exerts protective effect in brain, although direct evidence for the neuroprotective function of brain-synthesized estrogen has not been clearly demonstrated. Methylmercury (MeHg) is a neurotoxin that induces neuronal degeneration in the central nervous system. The neurotoxicity of MeHg is region-specific, and the molecular mechanisms for the selective neurotoxicity are not well defined. In this study, the protective effect of de novo synthesized 17β-estradiol on MeHg-induced neurotoxicity in rat hippocampus was examined. Methodology/Principal Findings: Neurotoxic effect of MeHg on hippocampal organotypic slice culture was quantified by propidium iodide fluorescence imaging. Twenty-four-hour treatment of the slices with MeHg caused cell death in a dose-dependent manner. The toxicity of MeHg was attenuated by pre-treatment with exogenously added estradiol. The slices de novo synthesized estradiol. The estradiol synthesis was not affected by treatment with 1 μM MeHg. The toxicity of MeHg was enhanced by inhibition of de novo estradiol synthesis, and the enhancement of toxicity was recovered by the addition of exogenous estradiol. The neuroprotective effect of estradiol was inhibited by an estrogen receptor (ER) antagonist, and mimicked by pre-treatment of the slices with agonists for ERα and ERβ, indicating the neuroprotective effect was mediated by ERs. Conclusions/Significance: Hippocampus de novo synthesized estradiol protected hippocampal cells from MeHg-induced neurotoxicity via ERα- and ERβ-mediated pathways. The self-protective function of de novo synthesized estradiol might be one of the possible mechanisms for the selective sensitivity of the brain to MeHg toxicity.",
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Yamazaki, T, Yamamoto, M, Ishihara, Y, Komatsu, S, Munetsuna, E, Onizaki, M, Ishida, A, Kawato, S & Mukuda, T 2013, 'De Novo Synthesized Estradiol Protects against Methylmercury-Induced Neurotoxicity in Cultured Rat Hippocampal Slices', PloS one, vol. 8, no. 2, e55559. https://doi.org/10.1371/journal.pone.0055559

De Novo Synthesized Estradiol Protects against Methylmercury-Induced Neurotoxicity in Cultured Rat Hippocampal Slices. / Yamazaki, Takeshi; Yamamoto, Megumi; Ishihara, Yasuhiro; Komatsu, Shota; Munetsuna, Eiji; Onizaki, Masahiro; Ishida, Atsuhiko; Kawato, Suguru; Mukuda, Takao.

In: PloS one, Vol. 8, No. 2, e55559, 06.02.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - De Novo Synthesized Estradiol Protects against Methylmercury-Induced Neurotoxicity in Cultured Rat Hippocampal Slices

AU - Yamazaki, Takeshi

AU - Yamamoto, Megumi

AU - Ishihara, Yasuhiro

AU - Komatsu, Shota

AU - Munetsuna, Eiji

AU - Onizaki, Masahiro

AU - Ishida, Atsuhiko

AU - Kawato, Suguru

AU - Mukuda, Takao

PY - 2013/2/6

Y1 - 2013/2/6

N2 - Background: Estrogen, a class of female sex steroids, is neuroprotective. Estrogen is synthesized in specific areas of the brain. There is a possibility that the de novo synthesized estrogen exerts protective effect in brain, although direct evidence for the neuroprotective function of brain-synthesized estrogen has not been clearly demonstrated. Methylmercury (MeHg) is a neurotoxin that induces neuronal degeneration in the central nervous system. The neurotoxicity of MeHg is region-specific, and the molecular mechanisms for the selective neurotoxicity are not well defined. In this study, the protective effect of de novo synthesized 17β-estradiol on MeHg-induced neurotoxicity in rat hippocampus was examined. Methodology/Principal Findings: Neurotoxic effect of MeHg on hippocampal organotypic slice culture was quantified by propidium iodide fluorescence imaging. Twenty-four-hour treatment of the slices with MeHg caused cell death in a dose-dependent manner. The toxicity of MeHg was attenuated by pre-treatment with exogenously added estradiol. The slices de novo synthesized estradiol. The estradiol synthesis was not affected by treatment with 1 μM MeHg. The toxicity of MeHg was enhanced by inhibition of de novo estradiol synthesis, and the enhancement of toxicity was recovered by the addition of exogenous estradiol. The neuroprotective effect of estradiol was inhibited by an estrogen receptor (ER) antagonist, and mimicked by pre-treatment of the slices with agonists for ERα and ERβ, indicating the neuroprotective effect was mediated by ERs. Conclusions/Significance: Hippocampus de novo synthesized estradiol protected hippocampal cells from MeHg-induced neurotoxicity via ERα- and ERβ-mediated pathways. The self-protective function of de novo synthesized estradiol might be one of the possible mechanisms for the selective sensitivity of the brain to MeHg toxicity.

AB - Background: Estrogen, a class of female sex steroids, is neuroprotective. Estrogen is synthesized in specific areas of the brain. There is a possibility that the de novo synthesized estrogen exerts protective effect in brain, although direct evidence for the neuroprotective function of brain-synthesized estrogen has not been clearly demonstrated. Methylmercury (MeHg) is a neurotoxin that induces neuronal degeneration in the central nervous system. The neurotoxicity of MeHg is region-specific, and the molecular mechanisms for the selective neurotoxicity are not well defined. In this study, the protective effect of de novo synthesized 17β-estradiol on MeHg-induced neurotoxicity in rat hippocampus was examined. Methodology/Principal Findings: Neurotoxic effect of MeHg on hippocampal organotypic slice culture was quantified by propidium iodide fluorescence imaging. Twenty-four-hour treatment of the slices with MeHg caused cell death in a dose-dependent manner. The toxicity of MeHg was attenuated by pre-treatment with exogenously added estradiol. The slices de novo synthesized estradiol. The estradiol synthesis was not affected by treatment with 1 μM MeHg. The toxicity of MeHg was enhanced by inhibition of de novo estradiol synthesis, and the enhancement of toxicity was recovered by the addition of exogenous estradiol. The neuroprotective effect of estradiol was inhibited by an estrogen receptor (ER) antagonist, and mimicked by pre-treatment of the slices with agonists for ERα and ERβ, indicating the neuroprotective effect was mediated by ERs. Conclusions/Significance: Hippocampus de novo synthesized estradiol protected hippocampal cells from MeHg-induced neurotoxicity via ERα- and ERβ-mediated pathways. The self-protective function of de novo synthesized estradiol might be one of the possible mechanisms for the selective sensitivity of the brain to MeHg toxicity.

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