Changes in memory and synaptic plasticity induced in male rats after maternal exposure to bisphenol A.

Bisphenol A (BPA), a component of polycarbonate and epoxy resins, has been reported to adversely impact the central nervous system, especially with respect to learning and memory. However, the precise effect and specific mechanisms have not been fully elucidated. In the present study, pregnant Sprague-Dawley rats were orally administered with BPA at 0.05, 0.5, 5 or 50mg/kg·body weight (BW) per day from embryonic day 9 (E 9) to E 20. We examined the effects of maternal BPA exposure on memory and synaptic structure in the hippocampus of male offspring at postnatal day (PND) 21. Maternal BPA exposure significantly affected locomotor activity, exploratory habits, and emotional behavior in open field test, and increased reference and especially working memory errors in the radial arm maze during the postnatal developing stage. Maternal BPA exposure had an adverse effect on synaptic structure, including a widened synaptic cleft, a thinned postsynaptic density (PSD), unclear synaptic surface and disappeared synaptic vesicles. Furthermore, maternal BPA exposure decreased the mRNA and protein expressions of synaptophysin, PSD-95, spinophilin, GluR1 and NMDAR1 in the hippocampus of male offspring on PND 21. These results showed that fetal growth and development was more sensitive to BPA exposure. The decreased learning and memory induced by maternal exposure to BPA in this study may be involved in synaptic plasticity alteration.

Wang C ，Niu R ，Zhu Y ，Han H ，Luo G ，Zhou B ，Wang J ... -  《-》

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 《-》

Impairment of learning and memory induced by perinatal exposure to BPA is associated with ERα-mediated alterations of synaptic plasticity and PKC/ERK/CREB signaling pathway in offspring rats.

The effect of bisphenol A (BPA) on learning and memory has attracted much attention recently, but its underlying mechanism remains unclear. We aimed to investigate whether the impairment of learning and memory induced by perinatal exposure to BPA was associated with the hippocampal estrogen receptor α (ERα)-mediated synaptic plasticity and PKC/ERK/CREB signaling pathway in different sex offspring rats. Pregnant Sprague-Dawley rats were treated with BPA (1 and 10 μg/mL) through drinking water from gestational day (GD) 6 to postnatal day (PND) 21. After weaning, offspring drank BPA-free water until PND 56. Morris water maze, placement and object recognition, and step-down passive avoidance task were performed. The serum estradiol (E2) levels, histopathology of hippocampus, and the expression of learning and memory related proteins were measured. The results showed that spatial and recognition memory were impaired in BPA-exposed female and male offspring, but the impaired passive avoidance memory presented only in males, not in females. The serum E2 levels were increased in BPA-exposed females and males. BPA altered the morphology and quantity of hippocampal neurons. The levels of ERα, NMDA receptor subunit 2B (NR2B), p-NR2B, AMPA receptor 1 (GluA1), p-GluA1, PSD-95, synapsin I, PKC, p-ERK and p-CREB protein expression were decreased in BPA exposed females and males, and there were interactions of sex × BPA exposure in ERα, p-NR2B and p-ERK levels. These findings suggested that perinatal exposure to BPA has sex-specific effects on learning and memory, which is associated with ERα-mediated impairment of synaptic plasticity and down-regulation of PKC/ERK/CREB signaling pathway.

Wu D ，Wu F ，Lin R ，Meng Y ，Wei W ，Sun Q ，Jia L ... -  《-》

Developmental treatment with bisphenol A causes few alterations on measures of postweaning activity and learning.

Widespread bisphenol A (BPA) exposure necessitates increased knowledge of its potential effects for better risk assessment and regulatory guidance. Here, female Sprague-Dawley rats, reared in low exogenous estrogen environments and bred at adulthood, were gavaged on gestational days 6-21 with vehicle (VEH), 2.5 or 25.0 μg/kg/day BPA, or 5.0 or 10.0 μg/kg/day ethinyl estradiol (EE₂). Offspring were orally treated on postnatal days (PNDs) 1-21 with the same dose their dam received. A naïve control group (NC) was not gavaged. Post-weaning, one offspring/sex/litter (n=11-12/sex/group) was assessed for the typical behaviors measured in developmental neurotoxicology studies. At PND 29, novelty preference was unaffected by treatment; however, relative to the VEH group, males and females of both EE₂ groups were more active. VEH males appeared somewhat hypoactive in open field assessments at PNDs 40-42 and, as a result, males of the BPA and EE₂ groups were significantly more active. Latency to locate the Barnes maze escape box at PNDs 47-50 was increased in males and females of the 5.0 μg/kg/day EE₂ group. Relative to other male groups, VEH males exhibited an increased startle response on the first trial block at PND 54 and thus, males of both BPA groups and the 10.0 μg/kg/day EE₂ group exhibited a significantly decreased startle response. PNDs 43-44 motor coordination and PNDs 75-79 water maze performance were unaffected by treatment. These results indicate few consistent or dose-related effects resulting from developmental treatment with BPA at these doses. Few of these behaviors, however, were sexually dimorphic which may prove more sensitive.

Ferguson SA ，Law CD ，Abshire JS 《-》