Study On The Molecular Mechanism Of Decreased Learning And Memory In Male Offspring Rats Induced By Embryonic Exposed To Bisphenol A

[Objective] Bisphenol A (BPA), as a xenoestrogen, is one of the most common endocrine-disrupting chemicals (EDC) and used as the monomer material to manufacture polycarbonate plastics and epoxy resins. In recent years, BPA 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. Epigenetics, signaling pathways and synaptic plasticity were evaluated in the present study, to discuss the molecular mechanism of embryonic BPA exposure on learning and memory in male offspring rats, for further consummating rationale of BPA neurotoxicity and providing scientific basis of diagnosis and target drug designation.[Method] Pregnant Sprague-Dawley rats were either orally exposed to BPA dissolved in corn oil (0.05, 0.5,5 or 50 mg/kg·BW per day) or given only corn oil as a vehicle control at 0.2 mL/kg per day from embryonic day 9 (E 9) to E 20. Using the open field, object recognition test and radial arm maze, we examined the effects of embryonic exposure to BPA on spontaneous behavior, learning and memory in male offspring on postnatal day(PND) 21; applied diverse methods as HE staining, transmission electron microscope, Real-time PCR and Western blotting, this study observed the changes of hippocampus morphological structure, synapse ultrastructure, mRNA of epigenetic enzymes (DNMTs and HDACs), protein expression of ERK signaling pathway, mRNA and protein expression of synaptic markers (synaptophysin, postsynaptic density-95 (PSD-95), spinophilin), glutamate receptors (GluR1 and NMDAR1), in order to explore the mechanism of effects of embryonic BPA exposure on learing and memory during the postnatal developing stage.[Result] (1) Embryonic BPA exposure affected the physiological and biochemical index in male offspring during the postnatal developing stage. The results showed that BPA treatment significantly increased the body weight of male offspring on PND 9, PND14 and PND21. Relative brain, hippocampus and testis weight was significantly lower in the BPA group than in the control. All BPA groups showed higher levels of serum testosterone than controls; in BPA-treated groups significant decrease in estradiol levels were found when compare with control group. Embryonic BPA exposure induced hippocampus pathological changes. Hippocampus pathology slices showed, in comparison with control group, the neuron structures in BPA groups revealed some degree alteration. The volume of pyramidal cells and granule cells were smaller in the hippocampus; the number of neuron was reduced; the cell gap was enlarged and cell edge was unclear.. Many neurons were shrunken, pyknotic.(2) There was a significant negative effect of embryonic BPA exposure on the open field behavior test in male offspring on PND21, including motor activity, exploratory habits, and emotional behavior. The results of object recognition test showed that BPA impaired the short term memory and long term memory. BPA exposure increased reference and especially working memory errors in the radial arm maze.(3) There were significant effects on the levels of epigenetic enzymes in the hippocampus in the male offspring. According to the results of real-time PCR, BPA exposure reduced the expression levels of DNMT1 mRNA and HDAC1 mRNA, increased HDAC2 mRNA expression.(4) There were significant effects of embryonic BPA exposure on ERK signaling pathway associated protein levels. Compared with the control, the protein expression level of Akt, P-Akt, ERKl/2, P-ERKl/ 2, P-CREB, and BDNF was obviously decreased.(5) Embryonic 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, embryonic BPA exposure decreased the mRNA and protein expressions of synaptophysin, PSD-95, spinophilin, G1uRl and NMDAR1 in the hippocampus of male offspring on PND 21.[Conclusion] The present results revealed that embryonic BPA exposure has a side effect on learning and memory in male offspring during the postnatal developing stage. The molecular mechanism involved in epigenetics, ERK signaling pathway and synaptic plasticity, indicating the complexity of embryonic BPA exposure on central nervous system and behavioral development.