Effect Of Early Exposure To Bisphenol A On Estrogen Receptor Signaling In Hippocampus Of Male Rats

Bisphenol A (BPA) is an environmental endocrine disruptor which is widely usedin the manufacturing of plastic and epoxy resin productions. There is increasingexperimental evidence showing that continuous exposure to low level of BPA duringperinatal period impairs brain development, resulting in the aberrant behavior in adults.The available information regarding the molecular mechanisms underlying thebiological function of BPA has emphasized its ability to competitively bind theestrogen receptor (ER) in brain neurons, leading to the altered expression of ER intarget neurons and the disruption of normal ER signaling. However, virtually little isknown whether BPA affects the phosphorylation and nuclear translocation of ER, twoprocesses important for ER to execute its action. Here, we used the SD rats toinvestigate whether, and if yes, how BPA modulate the phosphorylation and nucleartranslocation of ER in hippocampus neurons. We found that during the developmentfrom postnatal day7(P7) to P21, the ER mRNA and protein expression experiencedconsiderable decline in hippocampus. Early BPA exposure resulted in bidirectional,development-dependent effects on ER mRNA and protein expression. It decreasedER mRNA and protein expression at P7and P21but increase it at P11, which wasreadily prevented by coadministration of low dose of ER antagonist, ICI182780. SinceICI itself had little effect on ER mRNA and protein expression, the above findingssuggest that ER is critically involved in the modulation of ER expression by BPA. Inspite of the contrasting effects of BPA on ER protein expression at P7and P11, itmarkedly reduced the level of ER protein in the nucleus at both time points withnegligible effect at P21. Further analysis revealed that BPA decreased the ratio betweenthe levels of nuclear and total ER at P7and P11, indicating that BPA impairs thenuclear translocation of ER. We also observed that the expression of phosphorylatedER in hippocampus experienced slight but significant decline from P7to P21andearly BPA exposure conspicuously downregualted its expression at P7and P11but notP21. These effects could also be blocked by ICI, highlighting an indispensable role ofER. We also examined the possible long lasting effect of early BPA exposure on hippocampus-related behavior in adult rats and found that relative to control rats, thosesubjected to BPA exposure displayed aberrant locomotor and exploratory behavior andexhibited impaired spatial learning. ICI treatment readily rescued the behavioraldeficits in BPA-exposed rats. To summarize, our current study demonstrated that BPAdisrupted the normal ER signaling in developing hippocampus, which may lead to theabnormal hippocampus development and result in the functional abnormality in adults.