Nanomolar dose of bisphenol A rapidly modulates spinogenesis in adult hippocampal neurons
Highlights
► The elevation of BPA level to 10 nM induced rapid increase in the density of middle-head spines. ► ERRγ was a high affinity receptor of BPA, mediating the modulation of spinogenesis. ► ICI, antagonist of ERα/ERβ, did not suppress the BPA-induced enhancement of spinogenesis.
Introduction
Low dose exposure to bisphenol A (BPA) may induce hormone-like effects on wildlife and humans. BPA is a widely used synthetic material included in polycarbonate resin used in water pipe sealant, dental prostheses, compact discs and baby bottles. Toxic effects of high dose BPA (mg/kg weight/day) have been investigated in relation to the development and functions of the reproduction systems (Fisher et al., 1999, Al-Hiyasat et al., 2002, Grote et al., 2004, Halldin et al., 2005). However, the low dose exposure to BPA (μg/kg/day or nanomolar doses) shows rather weak toxic effects on reproductive or endocrine functions in the peripheral tissues, probably due to the efficient detoxification of BPA by the liver. On the other hand, low dose exposure to BPA may significantly affect the brain function, because the detoxification of BPA in the brain is probably very weak, due to the extremely low expression of drug-metabolizing enzymes in the brain (Miksys and Tyndale, 2002, Kishimoto et al., 2004, Chinta et al., 2005).
The low dose exposure to BPA during fetal/neonatal stages has been extensively investigated. For example, fetal or neonatal exposure to BPA inhibits sexual differentiation of nonreproductive behaviors of adult animals, including maze learning behavior (Carr et al., 2003, Kubo et al., 2003, Fujimoto et al., 2006), at doses as low as 1/1000 of those required for the stimulation of uterine growth (Ashby, 2001). On the other hand, inadequate information is available for the low dose exposure to BPA in the adult stage, except some pioneer works in vivo (MacLusky et al., 2005, Leranth et al., 2008, Hajszan and Leranth, 2010).
The high affinity functional receptor for BPA has not been identified yet. Although ERα is one candidate of BPA receptor, the affinity of ERα for BPA is very low, in the order of 1/100–1/1000 of that for 17β-estradiol (E2) (Kuiper et al., 1997, Morohoshi et al., 2005). On the other hand, estrogen-related receptor gamma (ERRγ) is a high affinity binding protein for BPA (Takayanagi et al., 2006). However, ERRγ has not been recognized as a BPA receptor, because ERRγ shows constitutive transcriptional activity even without any ligand (Coward et al., 2001).
We here performed the investigation on the rapid modulation by nanomolar doses of BPA on the density and morphology of dendritic spines in the adult hippocampal slices, including investigations of BPA receptors. In order to observe the direct effects of BPA on hippocampal neurons, we used isolated ‘acute’ hippocampal slices which do not have projections of cholinergic or serotonergic neurons from outside of the hippocampus.
Section snippets
Chemicals
BPA, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), cycloheximide, nicardipine, N-methyl-d-aspartate (NMDA), PD98059, ICI 182,780 (ICI), MK-801 and Lucifer Yellow were purchased from Sigma (USA). 4-hydroxy-tamoxifen (OH-Tam) was from Calbiochem (Germany). Other chemicals used were of highest purity commercially available. Polyclonal anti-ERRγ antibody (against C-terminal of ligand binding site) was prepared by Dr. Shimohigashi at Kyushu Univ. (Tokunaga et al., 2006).
Animals
Adult male Wistar rats (12
Rapid effect of BPA on spinogenesis
We analyzed the effect of BPA on the modulation of the density and head diameter of spines in the CA1 region. To do this, single spine imaging was performed for Lucifer Yellow-injected neurons in hippocampal slices from adult male rats. We analyzed secondary branches of the apical dendrites located 100–200 μm distant from the pyramidal cell body around the middle of the stratum radiatum of CA1 region.
Discussion
Current investigations of the rapid effects of BPA on spinogenesis in isolated hippocampal slices lead to the finding of ERRγ-mediated BPA action at synapses of pyramidal neurons.
Acknowledgments
We thank Prof. J.A. Rose (Ritsumeikan University) and Dr. Anna Barron (Univ. of Tokyo) for critical reading of the manuscript. Drs. S. Homma and M. Okuyama (Aska Pharma Medical) are acknowledged for technical assistance of mass-spectrometric analysis.
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Rapid effect of bisphenol A on glutamate-induced Ca <sup>2+</sup> influx in hippocampal neurons of rats
2019, Molecular and Cellular EndocrinologyCitation Excerpt :BPA was found to have a very low affinity with ERs (about 1/100–1/1000 for 17β-E2), but have a high affinity with ERRγ (Takayanagi et al., 2006). Further pre-treatment of Tam, an antagonist of both ERs and ERRγ, completely suppressed the promotion of BPA to glutamate-elevated [Ca2+]i. Tanabe et al. (2012) recently found that BPA-induced enhancement of the spine density in CA1 neurons of adult hippocampal slices was blocked by Tam rather than ICI at 1 μM. Therefore, ERRγ is deduced to mediate BPA modulating glutamate-elevated [Ca2+]i in the hippocampal neurons.
Bisphenol-A antagonizes the rapidly modulating effect of DHT on spinogenesis and long-term potentiation of hippocampal neurons
2018, ChemosphereCitation Excerpt :Our previous and present studies in hippocampal neurons in vitro showed that BPA alone enhanced the densities of dendritic filopodium, spine, and synapse but inhibited 17β-E2- or DHT-induced increases in the densities of dendritic spine and synapse (Xu et al., 2010, 2014). Using hippocampal slices of adult rat, Tanabe et al. demonstrated the rapidly enhancement of 10 nM BPA in spinogenesis within 2 h, in particular, the density of middlehead spine (Tanabe et al., 2012). BPA was also rapidly enhance LTP and LTD in DG or CA1 of hippocampus slice in vitro of adolescence or adult male rats (Chen et al., 2017; Ogiue-Ikeda et al., 2008; Tanabe et al., 2005) but inhibited the 17β-E2-promotion in LTP when it was co-treatment with 17β-E2 (Chen et al., 2017).
Developmental Neurotoxicity of Endocrine Disruptor Chemicals: A Challenge for Behavioral Toxicology
2018, Advances in NeurotoxicologyCitation Excerpt :However the in vivo findings showed that the effects of BPA can be detected even for exposure at very low doses, and a growing body of data point to several mechanisms implicated, including both genomic and nongenomic actions of estrogens, interaction with the ERγ estrogen receptors, with androgen receptors, disruption of thyroid hormone signaling and inhibition of key enzymes involved in steroidogenesis (reviewed in Gore et al., 2015). In the brain BPA is able to modulate rapidly synaptic plasticity in cultured hippocampal neurons and spinogenesis in hippocampal slices (Tanabe et al., 2012). BPA acts as agonist of the membrane associated estrogen receptors and activate the extracellular signal regulated kinase (ERK) pathway (Chen et al., 2017).
Bisphenol A and congenital developmental defects in humans
2015, Mutation Research - Fundamental and Molecular Mechanisms of MutagenesisCitation Excerpt :The adverse effects induced by a “low dose” of BPA include neuronal and behavioral alterations: documented effects of prenatal exposure to BPA are abnormal development of the neocortex in terms of differentiation and neuronal migration [19,38], aberrant positions and connections between thalamus and cortex [39], inhibition of the proliferation of neural progenitor cells [21], loss of sexual dimorphism in terms of brain structure and behavior [24], increased anxiety and cognitive deficits [45,54]. Part of these results are justified by the strong affinity of BPA to the dopamine receptor, the estrogen-like receptor-β type [8] and the estrogen-like receptor-γ type present in hippocampal neurons [51]. In all these hypotheses the normal synaptic communication was altered.
Perinatal exposure to bisphenol-A inhibits synaptogenesis and affects the synaptic morphological development in offspring male mice
2013, ChemosphereCitation Excerpt :Our previous study also found that BPA attenuated E2-induced enhancement on the dendritic filopodia outgrowth in vitro (Xu et al., 2010b). In contrast, BPA was reported to enhance spinogenesis of adult rat hippocampal slice following a 2 h treatment (Tanabe et al., 2012) and to rapidly enhance the motility and the density of dendritic filopodia in the cultured hippocampal neurons within 30 min (Xu et al., 2010b). In this study, a synaptogenesis inhibition was evidenced by perinatal exposure to BPA.
Prenatal exposure to bisphenol A impacts midbrain dopamine neurons and hippocampal spine synapses in non-human primates
2013, NeuroToxicologyCitation Excerpt :Many studies on BPA have attributed its biological properties to an agonist interaction with estrogen receptors. For example in vitro studies with hippocampal neurons have shown that BPA, like estradiol, enhances synapse and spine formation (Tanabe et al., 2012; Xu et al., 2010). However, the current data with fetal exposure to BPA, and our previous studies involving treatment of adult monkeys with BPA (Hajszan and Leranth, 2010), have demonstrated a that an anti-estrogen-like, rather than an estrogen-like, property of BPA being responsible for loss of synapses.
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These authors contributed equally.