Abstract: Bisphenol A (BPA), one of the most common environmental endocrine disrupters, can bind to estrogen receptors (ERs) to interfere with the regulation of endogenous estrogen on the central nervous system. The aim of the present study was to investigate the effects of long-term exposure to BPA on the learning and memory behavior. The adult mice at age of 10 weeks were exposed to BPA (0.4, 4, and 40 mg/kg/day) or sesame oil for 12 weeks. In open field test, BPA increased the frequencies of rearing and grooming of the males, but reduced the frequency of rearing in the females. Exposure to BPA (0.4 or 40 mg/kg/day) extended the escape pathlength to find the hidden platform in Morris water maze and shortened the step-down latency 24 h after footshock of the males, but no changes were found in the females. Meanwhile, BPA induced a reduced numeric synaptic density and a negative effect on the synaptic structural modification, including the enlarged synaptic cleft and the reduced length of active zone and PSD thickness in the hippocampus of the males. Western blot analyses further indicated that BPA down-regulated the expressions of synaptic proteins (synapsin I and PSD-95) and NMDA receptor subunit NR1 in the hippocampus of the males. These results suggest that long-term exposure to the low levels of BPA in adulthood sex-specifically impaired spatial and passive avoidance memory of mice. These effects may be associated with the higher susceptibility of hippocampal synaptic plasticity processes, such as remodeling of spinal synapses and the expressions of synaptic proteins and NMDA receptor, to BPA in the adult males. After acclimatization for one week, adult male and female ICR mice were orally exposed to BPA dissolved in peanut oil (40, 4,0.4 mg/kg/day) or only peanut oil as a vehicle control from 10 weeks of age throughout 22 weeks. At 22 weeks of age, open field, elevated plus-maze, Morris water maze, and step-down were respectively used to test spontaneous activity and exploratory behavior, anxiety, spatial learning and memory, and passive avoidance memory in mice. After the behavior detection, using Western blot method detecting NMDA and AMPA receptor NR1、GluR1、Synapsin I and PSD 95. At the same time, take animals which were not used in Behavioral experiments for electron microscope observation of microscopic structure change. Test results show that the opening behavior BPA (0.4, 4, 40 mg/kg/day) increase the stand number and frequency of grooming male, BPA (4 mg/kg/day) was significantly decrease the number of stand for females. Water maze and passive avoidance behavior model test showed that BPA main damage male rats of passive avoidance and spatial learning memory. Ultrathin slice through the preparation of hippocampus CA1 area, electron microscope observation found that BPA (0.4, 40 mg/kg/day) exposed to lower the synaptic number density in the male rat hippocampal CA1 zone, shorten the males presynaptic active zone length, reducing male mice postsynaptic density (PSD) thickness, increase male mice width of synaptic cleft. Further using Western blot method to detect the synapse the iconic Synapsin I protein before and after and PSD95 and excitatory amino acids GluR1 NMDA receptor NR1 and and AMPA receptor subunit proteins expression, and found that BPA exposure to male mice of Synapsin I cut, PSD95, NR1 protein expression level. And BPA memory for female behavior, synaptic proteins and receptors, synaptic form are not obvious. Adulthood long-term exposure to low doses of BPA can gender selective damage of male rats learning and memory behavior and negative change in synaptic plasticity of hippocampal neurons, synaptic proteins and NMDA receptor expression levels may participate in the above process.

Key words: Bisphenol A, learning and memory, synaptic morphology, Synapsin I, PSD-95, NMDA receptor