Anti-androgenic effects of bisphenol-A on spatial memory and synaptic plasticity of the hippocampus in mice
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).
References (50)
- et al.
ERK and p38 inhibitors attenuate memory deficits and increase CREB phosphorylation and PGC-1α levels in Aβ-injected rats
Behav. Brain Res.
(2012) Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmaco l
Science
(2009)- et al.
An alternate pathway for androgen regulation of brain function: activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5alpha-androstane-3beta,17beta-diol
Horm Behav.
(2008) - et al.
Androgen rapidly increases dendritic thorns of CA3 neurons in male rat hippocampus
Biochem. Biophys. Res. Commun.
(2009) - et al.
Testosterone modulates spatial recognition memory in male rats
Horm. Behav.
(2013) - et al.
Crosstalk between ERK and PKA is required for Ca2 + stimulation of CREB-dependent transcription and ERK nuclear translocation
Neuron
(1998) - et al.
High dose bisphenol A impairs hippocampal neurogenesis in female mice across generations
Toxicology
(2012) Thinking with your gonads: testosterone and cognition
Trends Cogn. Sci.
(2006)- et al.
Changes in estrogen receptors α and β expression in the brain of mice exposed prenatally to bisphenol A
Regul. Toxicol. Pharmacol.
(2007) - et al.
Exposure to bisphenol-A appears to impair hippocampal neurogenesis and spatial learning and memory
Food Chem. Toxicol.
(2011)
Effects of testosterone on hippocampal CA1 spine synaptic density in the male rat are inhibited by fimbria/fornix transection
Neuroscience
Androgen modulation of hippocampal synaptic plasticity
Neuroscience
The role of synaptic morphology in neural plasticity: structural interactions underlying synaptic power
Brain Res. Rev.
The role of testicular hormones and luteinizing hormone in spatial memory in adult male rats
Horm. Behav.
Bisphenol A may cause testosterone reduction by adversely affecting both testis and pituitary systems similar to estradiol
Toxicol. Lett.
Effects of perinatal exposure to bisphenol A on the behavior of offspring in F344 rats
Environ. Toxicol. Pharmacol.
Study on anti-androgenic effects of bisphenol A diglycidyl ether (BADGE), bisphenol F diglycidyl ether(BFDGE) and their derivatives using cells stably transfected with human androgen receptor, AR-EcoScreen
Food Chem. Toxicol.
How synapsin I may cluster synaptic vesicles
Semin. Cell Dev. Biol.
Effect of bisphenol A, tetrachloro bisphenol A and pentachlorophenol on the transcriptional activities of androgen receptor-mediated reporter gene
Food Chem. Toxicol.
Mitogen-activated protein kinases in synaptic plasticity and memory
Curr. Opin. Neurobiol.
Estrogen-mediated structural and functional synaptic plasticity in the female rat hippocampus
Horm. Behav.
Evaluation of androgen receptor transcriptional activities of bisphenol A, octylphenol and nonylphenol in vitro
Toxicology
Bisphenol-A rapidly promotes dynamic changes in hippocampal dendritic morphology through estrogen receptor-mediated pathway by concomitant phosphorylation of NMDA receptor subunit NR2B
Toxicol. Appl. Pharmacol.
Perinatal exposure to bisphenol-A impairs learning-memory by concomitant down-regulation of N-methyl- D-aspartate receptors of hippocampus in male offspring mice
Horm. Behav.
Sex-specific influence of exposure to bisphenol-A between adolescence and young adulthood on mouse behaviors
Neuropharmacology
Cited by (22)
Role of miR-219a-5p in regulating NMDAR in nonylphenol-induced synaptic plasticity damage
2023, Ecotoxicology and Environmental SafetyPubertal exposure to bisphenol-A affects social recognition and arginine vasopressin in the brain of male mice
2021, Ecotoxicology and Environmental SafetyDevelopmental exposure of bisphenol A induces spatial memory deficits by weakening the excitatory neural circuits of CA3-CA1 and EC-CA1 in mice
2021, Toxicology and Applied PharmacologyCitation Excerpt :However, the exact BPA limit for total intake has not yet been established in China (Huang et al., 2012). Thus, our experimental mice were exposed to 0.5 mg/kg/day BPA, a dosage that was also adopted in previous studies, including our lab (Liu et al., 2015; Wang et al., 2016; Fang et al., 2017). The MWM and the Barnes maze are the classical behavioral test of spatial memory for rodents (Vorhees and Williams, 2006; Pitts, 2018).
PSA mimetic 5-nonyloxytryptamine protects cerebellar neurons against glutamate induced excitotoxicity: An in vitro perspective
2021, NeuroToxicologyCitation Excerpt :5-NOT treatment restored the NR2A, Erk and CREB expression in glutamate challenged neurons (Fig. 5 a, c, d). Glutamate-induced downregulation in pNMDAR2A expression was also associated with decrease in levels of presynaptic protein pSynapsin I and these observations are also supported by recent literature reports (Fang et al., 2017; Marsh et al., 2017; Shi et al., 2017). pSynapsin I plays a pivotal role in promoting the synapse formation, transmission and synaptic plasticity (Roshal et al., 1993, Ji et al., 2015).
- 1
Zhaoqing Fang and Qingjie Zhu contributed equally to this work.