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.