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.

The effects of pubertal exposure to bisphenol-A on social behavior in male mice.

Puberty is a crucial developmental period for structural modifications of brain and activation of the neural circuits underlying sex differences in social behavior. It is possible that pubertal exposure to bisphenol-A (BPA), a common EED with a weak estrogenic activity, influences social behavior. After being exposed to BPA at 0.04, 0.4, 4 mg kg-1 for 18 days, the 7-week-old male mice were tested with social play and three-chamber. The results showed that pubertal BPA exposure decreased social play between adolescent males and sociability of adolescent males. Further, pubertal BPA exposure reduced sociability and inhibited social novel preferences of adult males. BPA inhibited social interactions with opposite sex but improved socio-sexual exploration and the low-intensity mating behavior (mounting) with same sex in adult males. In residential-intruder test, BPA-exposed adult males showed a decrease in aggressiveness and an enhancement in prosocial behavior with intruder. Western blot analysis showed that BPA (especially at 4 mg/kg/d) down-regulated the levels of AR in the amygdala and the striatum but up-regulated the levels of DR1 and DAT proteins in the striatum of adult males. BPA at 4 mg kg-1 decreased the levels of T in the serum and the brain. These results suggest that pubertal BPA exposure affects social play and sociability of adolescent males and even results in long-term effects on social behavior of adult males. BPA-induced down-regulations of the levels of AR in the amygdala and the striatum and up-regulation of the levels of DR1 and DAT in the striatum may be involved.

Bisphenol-A antagonizes the rapidly modulating effect of DHT on spinogenesis and long-term potentiation of hippocampal neurons.

Bisphenol A (BPA), a common environmental endocrine disruptor, modulates estrogenic, antiestrogenic, and antiandrogenic effects throughout the lifespan. Recent studies found more obvious adverse effect of BPA on some neurobehavior in males than that in females. In this study, BPA at 10-100 nM rapidly increased the densities of the dendrite spine and synapse in cultured hippocampal neurons of rats in vitro within 1 h. Co-treatment of BPA (100 nM) with dihydrotestosterone (DHT, 10 nM) or with 17ß-E2 (10 nM) completely eliminated the promotion of DHT or 17ß-E2 in the densities of the dendritic spine and synapse. Pretreatment of estrogen receptors (ERs) antagonist ICI182,780 but not of androgen receptors (ARs) antagonist flutamide (Flu) for 30min completely blocked BPA-enhanced densities of the dendritic spine and synapse. Pretreatment of flutamide for 30min before BPA and DHT completely rescued BPA-enhanced densities of the dendritic spine and synapse. Furthermore, pretreatment of ERK1/2 inhibitor U0126 or p38 inhibitor SB203580 entirely eliminated BPA-induced increases in the densities of the dendritic spine and synapse. Meanwhile, BPA (100 nM) enhanced long-term potentiation (LTP) induction of dentate gyrus in hippocampal slices of younger male rats, which was not blocked by co-incubation of flutamide but was inhibited by pretreatment of an P38 inhibitor SB203580. Co-application of BPA with DHT inhibited DHT-suppressed LTP. These results are the first demonstrating the antagonism of BPA to the rapid modification of DHT in synaptic plasticity. However, BPA alone rapidly promotes spinogenesis and synaptic activity through ER instead of AR, and both ERKs and p38 signaling pathways are involved in these processes.

[Effects on secretory function of rat gonad by Erxian decoction and its disassembled prescriptions].

OBJECTIVE: To explain functions, differences and coordination of three divided combinations of the "Erxian decoction", the famous traditional Chinese formula, on the effective sites of gonad gland at the cell level. METHOD: The effects of Erxian decoction and its main disassembled prescriptions, "Kidney Warming", "Yin Nourishing" and "Chong-ren Adjusting", on the level of testosterone (T) progesterone (P) estradiol (E2), respectively secreted by the primary culture Leydig cell, luteal cell and granulosa cell, were measured by radioimmunoassay. RESULT: (1) Erxian decoction could stimulate the T secretion while its three main disassembled prescriptions would seem no individual promoting effect on the secretion of T. (2) Erxian decoction and the "Kidney Warming" had the stimulating effect on P secretion, and the action of the whole formula being better than that of the "Kidney Warming". (3) Erxian decoction and its main disassembled prescriptions had the stimulating effect on E2 secretion, especially the whole formula. CONCLUSION: Erxian decoction can stimulate the secretion of T of the Leydig cell, P of luteal cell and E2 of granulosa cell. It can be seen that the effect of the whole formula is better than that of its main disassembled prescriptions.