Elsevier

Hormones and Behavior

Volume 93, July 2017, Pages 151-158
Hormones and Behavior

Anti-androgenic effects of bisphenol-A on spatial memory and synaptic plasticity of the hippocampus in mice

https://doi.org/10.1016/j.yhbeh.2017.05.014Get rights and content

Highlights

  • BPA extended the latency of locating the platform of sham and TP-treated GDX mice.

  • BPA reduced the synaptic density and had an adverse effect on the synaptic interface of sham and TP-treated GDX mice.

  • BPA reduced the levels of synapsin I, PSD-95, and NMDA receptor subunit NR2B of hippocampus in sham and TP-treated GDX mice.

  • BPA reduced phospho-ERK1/2 but increased phospho-p38 of hippocampus in sham and TP-treated GDX mice.

Abstract

Bisphenol-A (BPA) is a common environmental endocrine disruptor. Our recent studies found that exposure to BPA in both adolescent and adulthood sex-specifically impaired spatial memory in male mice. In this study, 11-week-old gonadectomied (GDX) male mice daily received subcutaneous injections of testosterone propionate (TP, 0.5 mg/kg), TP and BPA (0.4 and 4 mg/kg), or vehicle for 45 days. The results of Morris water maze task showed that exposure to BPA did not affect the spatial memory of GDX mice but impaired that of sham (4 mg/kg/day) and TP-treated GDX mice (0.4 mg/kg/day). In addition, BPA reduced the level of testosterone (T) in the serum and brain of sham and TP-treated GDX mice. Exposure to BPA decreased the synaptic density and had an adverse effect on the synaptic interface of the hippocampus in sham and TP-treated GDX mice. The results of western blot analysis further showed that BPA (4 mg/kg) reduced the levels of synaptic proteins (synapsin I and PSD-95) and NMDA receptor subunit NR2B in sham and TP-treated GDX mice. BPA decreased the phosphorylation of ERK1/2 but increased the phosphorylation of p38 in sham and TP-treated GDX mice. These results suggest that impairment of spatial memory and adverse effects on synaptic remodeling of hippocampal neurons in males after long-term BPA exposure is related to the anti-androgen effect of BPA. These effects of BPA may be associated with downregulated synaptic proteins and NMDA receptor through inhibiting ERKs and promoting the p38 pathways.

Introduction

Bisphenol-A (BPA), an industrial chemical widely used in the manufacture of polycarbonate plastics and epoxy resins, is known to act as an endocrine disruptor. BPA exerts weak estrogenic properties in vitro by competing with the endogenous estrogens at their receptor level (Negishi et al., 2003). Given the widespread use of products containing BPA, exposure to BPA is unavoidable for wildlife and humans. Recent studies found that BPA sex-specifically influences the development of the brain and behavior. BPA impaired visual and spatial memory of adult male rats in object recognition and object placement tasks (Eilam-Stock et al., 2012) and spatial memory of young male mice (Kim et al., 2011). Our previous study found that exposure to BPA in both adolescent and adulthood impaired spatial memory and avoidance memory in male mice but not in female mice (Xu et al., 2011, Xu et al., 2013). However, previous studies mainly focused on the estrogenic properties of BPA (MacLusky et al., 2005, Kundakovic et al., 2013, Kawai et al., 2007). Recent experiments revealed that BPA can change testosterone (T) synthesis, mRNA expression of 17-α hydroxylase (P450c17), cholesterol side chain cleavage enzyme (P450scc), and steroidogenic acute regulatory protein in rat ovarian theca-intestinal and granulose cells (Zhou et al., 2008). BPA antagonizes androgen receptor (AR)-mediated transcriptional activities (Satoh et al., 2004, Sun et al., 2006, Xu et al., 2005). Because androgens are just as critical in the cognition in males as estrogens are in females, the potential exists that BPA also interferes with the effects of androgens on the adult male brain.

Synaptic plasticity in the hippocampus is considered to be critical for learning and memory. Gonadal steroids, both estrogens and androgens, have a high potential to regulate the remodeling of prefrontal and hippocampal spine synapses in adulthood (Leranth et al., 2008). Reduced spine synapse density in the hippocampal CA1 region of gonadectomized (GDX) male rats can be reversed by replacement with either T or the nonaromatizable androgen, dihydrotestosterone (DHT) (Leranth et al., 2003), suggesting that synaptic responses to androgen in males do not require intermediate estrogen biosynthesis. BPA exposure more significantly decreased dendritic spine density of the medial prefrontal cortex (mPFC) in male rats than that in female rats after restraint stress (Bowman et al., 2014). In addition, synaptic interface structural modification is susceptible to behavioral training and chemicals (Marrone and Petit, 2002). Our previous study found that exposure to BPA had sex-specific adverse effects on synaptic interface structural modification of the hippocampus along with impaired spatial and passive avoidance memory performance in male mice (Xu et al., 2013). Thus, the following experiments were performed to investigate whether BPA impaired spatial memory through disrupting the modulation of androgens in the remodeling of hippocampal spine synapse of adult male mice.

Section snippets

Animals and treatment

Eight-week-old male ICR mice (n = 216) were purchased from the Experimental Animal Center, Zhejiang Academy of Medical Science, and kept under standard laboratory conditions in a 12-h light, 12-h dark cycle, with free access to food and water. To minimize the background exposure to BPA beyond treatment regimen, mice were housed in white polypropylene cages with ad libitum access to BPA-free water provided in glass bottles and diet. All experiments in this study were conducted according to the

Brain hormone levels and serum hormone levels

Two-way ANOVAs showed no significant interaction of surgery × treatment in the serum level of T and in the brain, but the significant main effect of surgery or treatment on the serum level of T [F(1,63) = 27.45, p < 0.001, η2 = 0.09; F(5,63) = 23.81, p < 0.001, η2 = 0.16] and on the T level in the brain [F(1,63) = 18.20, p < 0.001, η2 = 0.07; F(5,63) = 12.57, p < 0.001, η2 = 0.12]. GDX operation markedly decreased T level in the serum (1.05 ± 0.02 ng/mL, p < 0.001, d = 2.16) and in the brain (0.70 ± 0.04 ng/g, p < 0.001, d = 2.35)

Discussion

Androgens are just as critical in the cognitive functions and synaptogenesis in males as estrogens are in females (Janowsky, 2006, MacLusky et al., 2006a). GDX impaired spatial recognition and memory in Y-maze task and in object location task, which was rescued by T supplement (Hawley et al., 2013, McConnell et al., 2012). In this study, GDX mice with markedly lower level of T in the serum and brain showed a prolonged latency in locating the platform and a reduced percentage of time spent in

Acknowledgments

This study was supported by the National Natural Science Foundation of China (Nos. 81472935, 81172627).

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    Zhaoqing Fang and Qingjie Zhu contributed equally to this work.

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