Abstract
BackgroundEstrogen, 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 FindingsNeurotoxic 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/SignificanceHippocampus 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.
Highlights
Estrogen, a type of female sex steroid, is an important factor in the brain, where it has non-reproductive functions such as memory enhancement, neurotrophic action, and neuroprotection, as well as a role in reproductive behavior [1]
We examined the protective action of de novo synthesized estradiol against MeHg-induced cell death
The protective effects of hippocampal de novo synthesized estradiol against MeHg-induced tissue cell death were demonstrated by the following results: (1) exogenously added estradiol protected rat hippocampal slices from the toxic effect of MeHg (Fig. 3), (2) the slices synthesized estradiol (Fig. 4), (3) de novo estradiol synthesis was not affected by 1 mM MeHg, and (4) letrozole inhibited de novo estradiol synthesis and increased the neurotoxicity of MeHg (Fig. 4, 5A)
Summary
A type of female sex steroid, is an important factor in the brain, where it has non-reproductive functions such as memory enhancement, neurotrophic action, and neuroprotection, as well as a role in reproductive behavior [1]. Brain estrogen can be derived from peripheral steroidogenic organs via the blood stream, and from de novo synthesis at specific brain regions from steroid precursors or cholesterol [12]. Neurosteroids are synthesized from cholesterol in the central and peripheral nervous systems through mechanisms that are independent of peripheral steroidogenic organs, which include gonads and adrenal glands [12]. Estradiol concentrations were the same or higher in the newborn rat brain after removing the gonads and adrenals compared with sham-operated rats, indicating contribution of de novo estradiol synthesis as a neurosteroid [13]. There is a possibility that the de novo synthesized estrogen exerts protective effect in brain, direct evidence for the neuroprotective function of brain-synthesized estrogen has not been clearly demonstrated. The protective effect of de novo synthesized 17b-estradiol on MeHg-induced neurotoxicity in rat hippocampus was examined
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