title: 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.
abstract: 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 (CREB1) as top upstream regulators. Consistently, a MAPPER promoter database analysis showed that all top dysregulated genes had CREM and/or CREB1 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.
authors.affiliation: Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address: fyuivy@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Jijing
authors.initials: J
authors.lastname: Tian
authors.affiliation: XCellAssay, LLC, San Francisco, CA, 94107, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Krylova
authors.affiliation: Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Tuan
authors.initials: T
authors.lastname: Xu
authors.affiliation: Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors.forename: Heidi Qunhui
authors.initials: HQ
authors.lastname: Xie
authors.affiliation: Department of Veterinary Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7382, USA.
authors.forename: Tai L
authors.initials: TL
authors.lastname: Guo
authors.affiliation: Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address: binzhao@rcees.ac.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002940:Circadian Rhythm / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects / Q000235:genetics; D007136:Immunoglobulins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D013154:Spleen / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D007136:Immunoglobulins; D015850:Interleukin-6; D007378:Interleukins; D000072317:Polychlorinated Dibenzodioxins; D000097043:Interleukin-22
keywords: B cell; Chronic; EphA2; TCDD; cAMP; transcriptome