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 indoorenvironments. Organotins are detectable in human sera at biologically active concentrations and are immuno-and neurotoxicants.Triphenyltin, tributyltin (TBT) and dibutyltin activate peroxisome proliferator-activated receptor c in bonemarrow multipotent mesenchymal stromal cells and promote adipogenesis. TBT also has been shown to suppressosteogenesis; osteoblasts not only support bone homeostasis but also support B lymphopoiesis. In addition, developing Bcells are highly sensitive to exogenous insults. Thus, we hypothesized that bone marrow B cells may be negatively affectedby TBT exposure both directly, through activation of apoptosis, and indirectly, through alterations of the bone marrowmicroenvironment. TBT activated apoptosis in developing B cells at environmentally relevant concentrations (as low as80 nM) in vitro, via a mechanism that is distinct from that induced by high dose (μM) TBT and that requires p53. TBTsuppressed the proliferation of hematopoietic cells in an ex vivo bone marrow model. Concurrent treatment of stromal cellsand B cells or pretreatment of stromal cells with TBT induced adipogenesis in the stromal cells and reduced the progressionof B cells from the early pro B (Hardy fraction B) to the pre B stage (Hardy fraction D). In vivo, TBT induced adipogenesis inbone 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, andpossibly intensify, these pathologies.