title: From the Cover: Tributyltin Alters the Bone Marrow Microenvironment and Suppresses B Cell Development.
abstract: Organotins are industrial chemicals and agricultural pesticides, and they contaminate both outdoor and indoor environments. Organotins are detectable in human sera at biologically active concentrations and are immuno-and neuro-toxicants. Triphenyltin, tributyltin (TBT) and dibutyltin activate peroxisome proliferator-activated receptor γ in bone marrow multipotent mesenchymal stromal cells and promote adipogenesis. TBT also has been shown to suppress osteogenesis; osteoblasts not only support bone homeostasis but also support B lymphopoiesis. In addition, developing B cells are highly sensitive to exogenous insults. Thus, we hypothesized that bone marrow B cells may be negatively affected by TBT exposure both directly, through activation of apoptosis, and indirectly, through alterations of the bone marrow microenvironment. TBT activated apoptosis in developing B cells at environmentally relevant concentrations (as low as 80 nM) in vitro, via a mechanism that is distinct from that induced by high dose (μM) TBT and that requires p53. TBT suppressed the proliferation of hematopoietic cells in an ex vivo bone marrow model. Concurrent treatment of stromal cells and B cells or pretreatment of stromal cells with TBT induced adipogenesis in the stromal cells and reduced the progression of B cells from the early pro B (Hardy fraction B) to the pre B stage (Hardy fraction D). In vivo, TBT induced adipogenesis in bone marrow, reduced "aging-sensitive" AA4+CD19+ B cells in bone marrow, and reduced splenic B cell numbers. Immunosenescence and osteoporosis are adverse health effects of aging, we postulate that TBT exposure may mimic, and possibly intensify, these pathologies.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Amelia H
authors.initials: AH
authors.lastname: Baker
authors.affiliation: Lady Davis Institute for Medical Research, Department of Oncology, McGill University, Montréal, Québec, Canada.
authors.forename: Ting Hua
authors.initials: TH
authors.lastname: Wu
authors.affiliation: Lady Davis Institute for Medical Research, Department of Oncology, McGill University, Montréal, Québec, Canada.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Bolt
authors.affiliation: Department of Orthopaedic Surgery, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Louis C
authors.initials: LC
authors.lastname: Gerstenfeld
authors.affiliation: Lady Davis Institute for Medical Research, Department of Oncology, McGill University, Montréal, Québec, Canada.
authors.forename: Koren K
authors.initials: KK
authors.lastname: Mann
authors.affiliation: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Schlezinger
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D001853:Bone Marrow / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D014220:Trialkyltin Compounds / Q000633:toxicity*
chemical_list: D014220:Trialkyltin Compounds; C011559:tributyltin
keywords: B cell; adipocyte; apoptosis; bone marrow microenvironment; organotin