Adolescent exposure to bisphenol-a antagonizes androgen regulation of social behavior in male mice.

Social behavior is sexually dimorphic, which is regulated by gonadal hormones in the brain. Our recent study found that exposure to low doses of bisphenol-A (BPA) during adolescence, permanently alters social behavior in adult male mice, but the underlying mechanisms remain unclear. Using adolescent gonadectomy (GDX) male mice with testosterone propionate (TP, 0.5 mg/kg) supplement (TP-GDX), this study showed that BPA antagonized promoting effects of TP on social interaction, sexual behavior, and aggression in GDX mice. BPA eliminated the reversal effects of TP on GDX-induced decrease in the number of immunoreactive to arginine vasopressin (AVP-ir) neurons in the medial amygdala (MeA) and the levels of AVP receptor 1a (V1aR) in the MeA and the nucleus accumbens (NAc). In addition, BPA removed down-regulation in the levels of dopamine (DA) transporter (DAT) and DA receptor 1 (DR1) in the NAc of TP-GDX mice. BPA exposure reduced testosterone (T) levels in the brain and serum and the expression of androgen receptor (AR) protein in the amygdala and striatum of sham-operated and TP-GDX males. These results suggest that adolescent exposure to BPA inhibits regulation of androgen in AVP and DA systems of the brain regions associated with social behavior, and thus alters social behaviors of adult male mice.

Zhong X ，Li J ，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 ... -  《-》

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 ... -  《-》

Pubertal exposure to bisphenol-A affects social recognition and arginine vasopressin in the brain of male mice.

Social recognition is an ability of animals to identify and distinguish conspecifics, which is essential for nearly all social species to establish social relationships. Social recognition provides the basis for a variety of social behaviors. Because of modulated by gonadal hormones, it is possible that social cognition is affected by environmental endocrine disruptors (EEDs). In the present study, after being pubertal exposed to bisphenol A (BPA, 0.04, 0.4, and 4 mg/kg) for 18 days, adult male mice did not show significant dishabituation to a novel female stimulus in habituation-dishabituation task. The capacity for discriminating the odors between familiar and novel female urine or between male and female urine was suppressed in BPA-exposed male. In addition, BPA (0.4, 4 mg/kg) decreased the number of immunoreaction of AVP (AVP-ir) neurons in both the bed nucleus of the stria terminalis (BNST) and the medial amygdala (MeA), and BPA (0.04, 0.4, 4 mg/kg) reduced the level of V1αR in the lateral septum (LS) of adult male. Further, BPA decreased the levels of testosterone (T) in the brain and androgens receptor (AR) in the LS, the amygdala, and BNST, as well the levels of estrogen receptor α and β (ERα/β) in the amygdala and BNST. These results indicate that pubertal exposure to BPA affected the actions of both androgens and estrogens in the brain and inhibited AVP system of social circuits, and these alterations may be associated with impaired social recognition of adult male mice.

Wang J ，Jin S ，Fu W ，Liang Y ，Yang Y ，Xu X ... -  《-》

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.

Gao T ，Yin Z ，Wang M ，Fang Z ，Zhong X ，Li J ，Hu Y ，Wu D ，Jiang K ，Xu X ... -  《-》