Abstract: OBJECTIVE To study the effect of Astragalus polysaccharide(APS) on the whole genome methylation level of bone marrow stem cells(BMSCs) induced by multiple X-ray ionizing radiation(IR).METHODS APS was used to act on BMSCs irradiated 5 times with 2 Gy X-rays per time, and BMSCs were divided into control group, APS group, IR group and APS+IR group. Cytokinesis blocking method was used to determine the rate of micronucleus formation; cell chromosome karyotype analysis was used to detect nuclear damage; EPIGENTEK kit was used to detect the degree of methylation of the whole genome of BMSCs in each group; Western blotting was used to detect the expression levels of BMSCs methyltransferase DNMT3a, DNMT3b, methyl-Cp G-binding protein 2(MeCP2), methyl-Cp G-binding domain protein 2(MBD2), oncogenes c-Myc, H-ras, and tumor suppressor genes P53 and P16 of BMSCs in each group.RESULTS Compared with the control group, the number of micronuclei and chromosome aberrations in IR group increased significantly(P<0.01), the degree of methylation of the whole genome of BMSCs in the IR group was significantly decreased(P<0.01); compared with IR group, the number of micronuclei and chromosome aberrations in the APS+IR group decreased(P<0.05), the degree of methylation of the whole genome of BMSCs in APS+IR group increased(P<0.01). In terms of protein characterization, compared with the control group, DNMT3a and MeCP2 in IR group were significantly decreased(P<0.01), the expressions of c-Myc and H-ras were significantly increased, and the expressions of P53 and P16 were significantly decreased(P<0.01). Compared with IR group, DNMT3a and MeCP2 in the APS+IR group were significantly increased(P<0.01 or P<0.05), the expressions of c-Myc and H-ras were decreased(P<0.01), and the expressions of P53 and P16 were significantly increased(P<0.01).CONCLUSION APS can prevent and control the methylation level of the whole genome of BMSCs induced by multiple X-ray radiation, and reduce the risk of deterioration of BMSCs.