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

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, 0.5mg/kg), TP and BPA (0.4 and 4mg/kg), or vehicle for 45days. 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 (4mg/kg/day) and TP-treated GDX mice (0.4mg/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 (4mg/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.

Fang Z ，Zhu Q ，Gu T ，Shen X ，Yang Y ，Liang Y ，Zhang Z ，Xu X ... -  《-》

Bisphenol-A inhibits improvement of testosterone in anxiety- and depression-like behaviors in gonadectomied male mice.

Bisphenol-A (BPA) is a well-known environmental endocrine disruptor. Developmental exposure to BPA affected a variety of behaviors in multiple model organisms. Our recent study found that exposure to BPA during adulthood aggravated anxiety- and depression-like states in male mice but not in females. In this study, 11-w-old gonadectomied (GDX) male mice daily received subcutaneous injections of testosterone propionate (TP, 0.5 mg/kg), TP and BPA (0.04, 0.4, or 4 mg/kg), or vehicle for 45 days. BPA (0.4 or 4 mg/kg) did not affect the elevated plus maze task of GDX mice but shortened the time on open arms and decreased the frequency of head dips of sham and TP-GDX mice. In forced swim task, BPA prolonged the total time of immobility of both sham and TP-GDX mice but not GDX mice. In addition, BPA reduced the levels of T in the serum and the brain of sham and TP-GDX mice. Western blot analysis further showed that BPA reduced the levels of androgen receptor (AR) and GABA(A)α2 receptor of the hippocampus and the amygdala in sham and inhibited the rescue of TP in these proteins levels of GDX mice. Meanwhile, BPA decreased the level of phospho-ERK1/2 in these two brain regions of sham and TP-GDX mice. These results suggest that long-term exposure to BPA inhibited TP-improved anxiety- and depression-like behaviors in GDX male mice. The down-regulated levels of GABA(A)α2 receptor and AR and an inhibited activity of ERK1/2 pathway in the hippocampus and the amygdala may be involved in these process.

Liang Y ，Li J ，Jin T ，Gu T ，Zhu Q ，Hu Y ，Yang Y ，Li J ，Wu D ，Jiang K ，Xu X ... -  《-》

Sex-specific effects of bisphenol-A on memory and synaptic structural modification in hippocampus of adult mice.

Humans are routinely exposed to low levels of bisphenol A (BPA), a synthetic xenoestrogen widely used in the production of polycarbonate plastics. The effects of long-term exposure to BPA on memory and modification of synaptic structure in hippocampus of adult mice were investigated in the present study. The adult mice were exposed to BPA (0.4, 4, and 40 mg/kg/day) or arachis oil for 12 weeks. In open field test, BPA at 0.4, 4, or 40 mg/kg/day increased the frequency of rearing and time in the central area of the males, while BPA at 0.4 mg/kg/day reduced the frequency of rearing in the females. Exposure to BPA (0.4 or 40 mg/kg/day) extended the average escape pathlength to the hidden platform in Morris water maze task and shortened the step-down latency 24 h after footshock of the males, but no changes were found in the females for these measures. Meanwhile, BPA induced a reduced numeric synaptic density and a negative effect on the structural parameters of synaptic interface, including an enlarged synaptic cleft and the reduced length of active zone and PSD thickness, in the hippocampus of the male mice. Western blot analyses further indicated that BPA down-regulated expressions of synaptic proteins (synapsin I and PSD-95) and synaptic NMDA receptor subunit NR1 and AMPA receptor subunit GluR1 in the hippocampus of the males. These results suggest that long-term exposure to 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 the hippocampal synaptic plasticity processes, such as remodeling of spinal synapses and the expressions of synaptic proteins (e.g. synapsin I and PSD-95) and NMDA and AMPA receptors, to BPA in the adult male mice.

Xu X ，Liu X ，Zhang Q ，Zhang G ，Lu Y ，Ruan Q ，Dong F ，Yang Y ... -  《-》

Different effects of bisphenol-A on memory behavior and synaptic modification in intact and estrogen-deprived female mice.

Bisphenol-A (BPA) has the capability of interfering with the effects of estrogens on modulating brain function. The purpose of this study was to investigate the effects of BPA on memory and synaptic modification in the hippocampus of female mice under different levels of cycling estrogen. BPA exposure (40, 400 μg/kg/day) for 8 weeks did not affect spatial memory and passive avoidance task of gonadally intact mice but improved ovariectomy (Ovx)-induced memory impairment, whereas co-exposure of BPA with estradiol benzoate (EB) diminished the rescue effect of EB on memory behavior of Ovx mice. The results of morphometric measurement showed that BPA positively modified the synaptic interface structure and increased the synaptic density of CA1 pyramidal cell in the hippocampus of Ovx females, but inhibited the enhancement of EB on synaptic modification and synaptogenesis of Ovx mice. Furthermore, BPA up-regulated synaptic proteins synapsin I and PSD-95 and NMDA receptor NR2B but inhibited EB-induced increase in PSD-95 and NR2B in the hippocampus of Ovx mice. These results suggest that BPA interfered with normal hormonal regulation in synaptic plasticity and memory of female mice as a potent estrogen mimetic and as a disruptor of estrogen under various concentrations of cycling estrogen.

Xu X ，Gu T ，Shen Q 《-》

Perinatal exposure to bisphenol-A inhibits synaptogenesis and affects the synaptic morphological development in offspring male mice.

Our previous study indicated that perinatal exposure to low-dose BPA, one of the most common environmental endocrine disrupters, alters behavioral development in offspring mice. Given that synaptic structure of the hippocampus is closely related to behaviors, in the present study, we examined the effects of perinatal exposure to BPA (0.04, 0.4, and 4.0 mg kg(-1) day(-1)) on the synaptic density and the synaptic structural modification of pyramidal cells in hippocampus region CA1 and the expressions of synaptic proteins such as synapsin I and PSD-95 and glutamate NMDA and AMPA receptors in male offspring mice on postnatal day (PND) 14, 21, and 56. The results of electron microscope measurement showed that BPA significantly reduced the numeric synaptic density and altered the structural modification of synaptic interface of pyramidal cells with the enlarged synaptic cleft, the shortened active zone, and the thinned postsynaptic density (PSD) on PND 14, 21, and 56 and the increased curvature of synaptic interface on PND 14 and 21. Further analyses of Western blot indicated that BPA markedly reduced the levels of synapsin I and PSD-95 on PND 14, 21, and 56 and down-regulated NMDA receptor subunit NR1 and AMPA receptor subunit GluR1 during development and young adulthood. These results suggest that perinatal exposure to low level of BPA inhibits synaptogenesis and affects synaptic structural modification after birth. The reduced expressions of synaptic proteins synapsin I and PSD-95 and glutamate NMDA and AMPA receptors may be involved in the negative changes in the synaptic plasticity.

Xu X ，Xie L ，Hong X ，Ruan Q ，Lu H ，Zhang Q ，Zhang G ，Liu X ... -  《-》