RESUMEN
Humans are routinely exposed to low levels of bisphenol A (BPA), an environmental endocrine disruptor, which is widely used in the production of polycarbonate plastics. The effects of perinatal exposure to BPA have been shown to affect various aspects of social behaviors such as anxiety and depression in adult offspring. Because sex hormones play a critical role in neurobehavior in adulthood, it is possible that long-term exposure to BPA has widespread effects on these emotional behaviors in adulthood. In the present study, adult mice were exposed to BPA at dosages of 0.04, 0.4, 4, 40 mg kg(-1)d(-1) for 12 weeks. A behavioral assay was performed using the open field test (OFT), mirrored maze, the elevated plus maze (EPM), and the forced swim task. The results showed that, after exposure to BPA at 0.4-40 mg kg(-1)d(-1), the number of open arm entries and the time spent in them in the elevated plus maze task were reduced in males but increased in females, and thus eliminating or reversing sex differences in these behaviors. BPA at 0.04-40 mg kg(-1)d(-1) increased the immobility of male mice in the forced swimming test. Furthermore, BPA (0.4-40 mg kg(-1)d(-1)) significantly decreased brain level of testosterone in males, but no significant influence was found in serum and the brain levels of estradiol in females. Western blot analysis further indicated that BPA at 0.4, 4, or 40 mg kg(-1)d(-1) significantly down-regulated the protein level of estrogen receptor ß (ERß) in the hippocampus of the adult males but not females, and inhibited the protein level of GABA(A)α2 receptor in hippocampus of males but promoted that of females. These results suggest that long-term exposure to BPA sex specifically affects anxiety- and depression-like behaviors in adult mice. Changes in the levels of GABA(A)α2 receptor and ERß proteins of hippocampus might be associated with BPA-induced changes in these emotional behaviors.
Asunto(s)
Ansiedad/inducido químicamente , Compuestos de Bencidrilo/toxicidad , Depresión/inducido químicamente , Disruptores Endocrinos/toxicidad , Fenoles/toxicidad , Animales , Receptor beta de Estrógeno/metabolismo , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Receptores de GABA-A/metabolismo , Factores SexualesRESUMEN
Bisphenol-A (BPA), an environmental endocrine disruptor, has been reported to possess weak estrogenic, anti-estrogenic, and anti-androgen properties. Previous evidence indicates that perinatal exposure to low levels of BPA affects anxiety-like and cognitive behaviors in adult rodents. The present study aims to investigate the effect of BPA on emotional memory using the contextual fear conditioning of male mice in adulthood exposed to BPA for 90days. The results indicated that exposure to BPA increased the freezing time 1h and 24h after fear conditioning training. Furthermore, western blot analyses showed that BPA exposure decreased the level of N-methyl-d-aspartic acid (NMDA) receptor subunit NR1 and increased the expression of histone deacetylase 2 (HDAC2) before fear conditioning training in the hippocampus of male mice. One and twenty-four hours after fear conditioning training, BPA enhanced the changes of the expressions of NR1, phosphorylated extracellular regulated protein kinases (ERK1/2), and histone acetylation induced by contextual fear conditioning in the hippocampus. These results suggest that long term exposure to BPA enhanced fear memory by the concomitant increased level of NMDA receptor and/or the enhanced histone acetylation in the hippocampus, which may be associated with activation of ERK1/2 signaling pathway.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Estrógenos no Esteroides/farmacología , Miedo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Histonas/metabolismo , Memoria/efectos de los fármacos , Fenoles/farmacología , Acetilación/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Reacción Cataléptica de Congelación/efectos de los fármacos , Hipocampo/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , FosforilaciónRESUMEN
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.