Chronic TCDD exposure results in the dysregulation of gene expression in splenic B-lymphocytes and in the impairments in T-cell and B-cell differentiation in mouse model

2,3,7,8-Tetrachlorodibenzo-p-dioxin（TCDD） exposure in humans is associated with marked immune suppressions and increased incidence of lymphoblastic diseases.To elucidate mechanisms of impairments in humoral immune responses,we used a murine model.Following a 20-week administration of low doses of TCDD,we observed severely reduced antibody titers,dramatically decreased number of splenic Th1 and Th2 cells and an increase in CD19^＋ B cells.Transcriptional profiling of CD19^＋ B cells showed that markers of pre-B cells were significantly elevated,indicating delayed B cell maturation.These changes in B cells were accompanied by decreases of T helper cell numbers and reduced IgM and IgG titers.A transcriptome analysis of splenic B cells followed by Ingenuity Pathway Analysis（IPA） revealed a set of differentially expressed genes known to play roles in tumorigenesis,cell-proliferation and cell-migration.The most up-regulated transcript gene was Eph receptor A2（EphA2）,a known oncogene,and the most down-regulated transcript was ZBTB16 that codes for a negative transcriptional regulator important in epigenetic chromatin remodeling.IPA identified cAMP-responsive element modulator（CREM） and cAMP-responsive element binding protein 1（CREBl） as top upstream regulators.Consistently,a MAPPER promoter database analysis showed that all top dysregulated genes had CREM and/or CREBl binding sites in their promoter regions.In summary,our data showed that chronic TCDD exposure in mice caused suppressed humoral immunity accompanied with profound dysregulation of gene expression in splenic B-lymphocytes,likely through cAMP-dependent pathways.This dysregulation resulted in impairments in T-cell and B-cell differentiation and activation of the tumorigenic transcription program.