Effect Of Subchronic Exposure To Arsenic On Retinoid X Receptor Expression In Brain Tissue In Mice

Backgroud: Arsenic （Arsenic, As） is a toxic metalloid elements which werewidely distributed in soil, rock and water environment.As was mainly existed by theform of compounds in nature and can cause many health hazards and also can causeabnormal changes in the morphology and function of multiple organs and systems.Tothe nervous system, As is mainly manifested as headache, lethargy, irritability,memory loss, disorientation, convulsions and even coma and other sub-clinical nerveinjury. For children were stay in the physiological developmental stage, so they weremore sensitive to the cytotoxicity of exogenous compounds.A large number ofepidemiological investigations, animal experiments show that the children exposed Ashave the central nervous system damage which are mainly to the damage in learningand memory, however, but the molecular mechanisms of arsenic caused the damageto learning and memory abilities yetunclear, so this issue has been widely arousedgreat concern.Our previous study found that arsenic exposure could significantlyinhibit the brain tissue calcium/calmodulin-dependent protein kinase IV （Camk4）,c-Fos, JunB and other learning and memory-related genes, protein expression and alsocan destruction of brain tissue in long-term memory （LTM） formation.According tothe literature,the Camk4transcription and translation dependent on the presence oftwo nuclear receptors, thyroid hormone receptor （TR） and retinoid X receptor （RXR）in brain. Our preliminary studies have found that TRβ which is one of the TR receptorsubtypes expressed lowly in the cerebellum of mice exposed of As, but arsenic alsoaffect the RXR gene expression have no relevant reports in the world.Objective: To observe the RXR gene and protein expression in the brain tissueof mice exposed arsenic and to clarify the mechanism of neurotoxicity induced byarsenic. Methods:40SPF mice were randomly divided into five groups by weight:the control group、1ppm As₂O₃、2ppm As₂O₃、4ppm As₂O₃、both of4ppm As₂O₃and150mg/kg taurine. The mice by drinking the water containing differentconcentrations of As₂O₃, the protective agent were treated by intragastricadministration and tissue of brain was obtained after60days of continuousexposure.The critical gene expression profiles related to retinoid X receptor in braintissue were analyzed by GeneChip and PCR method. Western blotting andimmunohistochemistry were used to detect RXR protein expression and tissuedistribution. Data analysis by SPSS11.5, Statistical analysis of both single factor usedto compared the significant difference between the arsenic group and control group,the comprison analysis between the two groups use LSD and the ratio less than0.05expressed significant difference.Results: Our results showed that RXR was up-regulated in brain tissue of miceexposed to As using Real Time PCR method, confirming the result of GeneChip,especially4ppm group raised significantly （p <0.05） between the groups. Meantime,We further analyzed the influence of As on cerebrum RXR expression using Westernblot method. The quantity of RXR band in the group exposed to4ppm As₂O₃significantly rised compared to the control group and expressed does-relationship,agreeing well with the gene microarray result. Immunohistochemistry showed highexpression of RXR in the cerebrum of mice in4ppm group. Furthermore, theintervening experiment showed that the coadministered antioxidants taurinescavenging ROS in vivo partly antagonize RXR expression.Conclusion: The sub-chronic arsenic exposure may increase the RXR geneexpression levels in the cerebrum of mice, but in the cerebellum, the RXR geneexpression level did not significantly change.The taurine can antagonize RXR geneexpression levels. It indicats that sub-chronic arsenic exposure by As may induce theRXR gene abnorm expression probably via a oxidation-independent way.