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

Abstract

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.

Keywords: Bisphenol A; Estrogen receptor α; Learning and memory; PKC/ERK/CREB pathway; Synaptic plasticity.