High dose bisphenol A impairs hippocampal neurogenesis in female mice across generations.

Bisphenol A (BPA) is used as a monomer during the manufacture of polycarbonate plastics and epoxy resins. However, BPA adversely affects reproductive organ growth and development, and it has been proposed that the detrimental effects of BPA could extend to future generations. The present study was conducted to evaluate the transgenerational effects of BPA on hippocampal neurogenesis and neurocognitive function. Pregnant female C57BL/6 mice (F0) were exposed to BPA (0.1-10 mg/kg) from gestation day 6 to 17, and female offspring (F2) from F1 generation mice were prepared. It was found that exposure of F0 mice to BPA at 10 mg/kg decreased the number of newly generated cells in the hippocampi of F2 female mice. Passive avoidance testing revealed that high-doses BPA (1 mg/kg and 10 mg/kg) decreased cross-over latency time in F2 mice, suggesting a BPA-mediated neurocognitive deficit in terms of memory retention. Furthermore, it was found that levels of phospho-ERK, brain-derived neurotrophic factor (BDNF), and phospho-CREB in hippocampi were significantly lower in F2 mice. Interestingly, the effects of BPA on hippocampal neurogenesis were found to be correlated with altered DNA methylation. In particular, high-dose BPA exposure increased DNA methylation of the CREB regulated transcription coactivator 1 (Crtc1) generated in F2 mice. These findings suggest that BPA exposure of pregnant mothers could adversely affect hippocampal neurogenesis and cognitive function in future generations by modulating the ERK and BDNF-CREB signaling cascades.

Jang YJ ，Park HR ，Kim TH ，Yang WJ ，Lee JJ ，Choi SY ，Oh SB ，Lee E ，Park JH ，Kim HP ，Kim HS ，Lee J ... -  《-》

Exposure to bisphenol A appears to impair hippocampal neurogenesis and spatial learning and memory.

Bisphenol A (BPA) is widely used in the manufacture of plastics and epoxy resins, and is known to affect reproductive organ growth and development. However, the effects of BPA on hippocampal neurogenesis are unclear in young adult mice. Therefore, the present study was conducted to examine the effects of BPA on hippocampal neurogenesis and learning as well as memory performance in young adult mice. BPA (1, 5, and 20 mg/kg/day) was administered orally to mice for 2 weeks. It was found that high-dose BPA (20 mg/kg/day) decreased the number of newly generated cells in hippocampus, but that low-dose BPA (1 mg/kg) increased the survival of newly generated cells in hippocampi of young mice. Furthermore, high-dose BPA (20mg/kg/day) was found to impair learning and memory performance significantly. However, no significant differences were observed between high- and low-dose treated mice in terms of levels of brain-derived neurotrophic factor (BDNF) or reactive oxygen species production in hippocampus. In addition, BPA treatment did not induce neuronal loss or damage or astrocyte activation. These data suggest that exposure to BPA causes fluctuations in hippocampal neurogenesis in young adult mice that result in spatial learning and memory impairment via a BDNF-independent pathway.

Kim ME ，Park HR ，Gong EJ ，Choi SY ，Kim HS ，Lee J ... -  《-》

Impairment of object recognition memory by maternal bisphenol A exposure is associated with inhibition of Akt and ERK/CREB/BDNF pathway in the male offspring hippocampus.

Bisphenol A (BPA) is a commonly used endocrine-disrupting chemical used as a component of polycarbonates plastics that has potential adverse effects on human health. Exposure to BPA during development has been implicated in memory deficits, but the mechanism of action underlying the effect is not fully understood. In this study, we investigated the effect of maternal exposure to BPA on object recognition memory and the expressions of proteins important for memory, especially focusing on the ERK/CREB/BDNF pathway. Pregnant Sprague-Dawley female rats were orally treated with either vehicle or BPA (0.05, 0.5, 5 or 50 mg/kg BW/day) during days 9-20 of gestation. Male offspring were tested on postnatal day 21 with the object recognition task. Recognition memory was assessed using the object recognition index (index=the time spent exploring the novel object/(the time spent exploring the novel object+the time spent exploring the familiar object)). In the test session performed 90 min after the training session, BPA-exposed male offspring not only spent more time in exploring the familiar object at the highest dose than the control, but also displayed a significantly decreased the object recognition index at the doses of 0.5, 5 and 50 mg/kg BW/day. During the test session performed 24h after the training session, BPA-treated males did not change the time spent exploring the familiar object, but had a decreased object recognition index at 5 and 50 mg/kg BW/day, when compared to control group. These findings indicate that object recognition memory was susceptible to maternal BPA exposure. Western blot analysis of hippocampi from BPA-treated male offspring revealed a decrease in Akt, phospho-Akt, p44/42 MAPK and phospho-p44/42 MAPK protein levels, compared to controls. In addition, BPA significantly inhibited the levels of phosphorylation of CREB and BDNF in the hippocampus. Our results show that maternal BPA exposure may full impair object recognition memory, and that impairment may be related to a decrease in Akt activation and an inhibition of the ERK/CREB/BDNF pathway in the hippocampus. This study also adds new evidence that suggests BPA has an antagonistic effect on the action of estrogen in the brain.

Wang C ，Li Z ，Han H ，Luo G ，Zhou B ，Wang S ，Wang J ... -  《-》

Potencies of bisphenol A on the neuronal differentiation and hippocampal neurogenesis.

Kim K ，Son TG ，Park HR ，Kim SJ ，Kim HS ，Kim HS ，Kim TS ，Jung KK ，Han SY ，Lee J ... -  《journal of toxicology and environmental health》

Corticosterone-regulated actions in the rat brain are affected by perinatal exposure to low dose of bisphenol A.

The estrogen-mimicking endocrine disrupter bisphenol A (BPA) which is used in the manufacture of plastic and epoxy resins, is one of the world's most heavily produced synthetic chemicals. BPA is detected in animal tissues, and its bio-accumulation has shown to be higher in the fetus than the mother. Exposure to doses below the daily safe limit has been reported to affect the sexual differentiation of the brain and modify the behavior of the exposed rodent offspring. The aim of the present study was to investigate in the rat the possible organizational effects of low BPA exposure on glucocorticoid-regulated responses. Female breeders were exposed to 40 microg/kg b.w. BPA daily throughout pregnancy and lactation. Plasma corticosterone levels and the two types of hippocampal corticosteroid receptors (GR and MR) were determined in mid-adolescent offspring under basal conditions and following a Y-maze task. BPA treated females had higher corticosterone levels than control females and BPA males and lower GR levels than BPA males, under basal conditions. Following the mildly stressful experience of Y-maze, corticosterone levels were increased in BPA-treated animals of both sexes, compared to the controls. GR levels were also increased in BPA-treated females compared to males. No effect of BPA was observed on MR levels, whereas the Y-maze experience significantly decreased receptors' levels in both female groups. The animals' performance in the task was also evaluated. BPA exposure significantly impaired the spatial recognition memory in both sexes, and modified the behavioural coping in a sex-dependent manner. Female BPA-treated offspring exhibited increased "anxiety-like" behaviour and dramatic loss of exploration attitude during the task, in comparison to males. This study provides for the first time evidence that corticosterone and its actions in the brain are sensitive to the programming effects of BPA at a dose below the currently acceptable daily intake.

Poimenova A ，Markaki E ，Rahiotis C ，Kitraki E ... -  《-》