title: Structurally-diverse, PPARγ-activating environmental toxicants induce adipogenesis and suppress osteogenesis in bone marrow mesenchymal stromal cells.
abstract: Environmental obesogens are a newly recognized category of endocrine disrupting chemicals that have been implicated in contributing to the rising rates of obesity in the United States. While obesity is typically regarded as an increase in visceral fat, adipocyte accumulation in the bone has been linked to increased fracture risk, lower bone density, and osteoporosis. Exposure to environmental toxicants that activate peroxisome proliferator activated receptor γ (PPARγ), a critical regulator of the balance of differentiation between adipogenesis and osteogenesis, may contribute to the increasing prevalence of osteoporosis. However, induction of adipogenesis and suppression of osteogenesis are separable activities of PPARγ, and ligands may selectively alter these activities. It currently is unknown whether suppression of osteogenesis is a common toxic endpoint of environmental PPARγ ligands. Using a primary mouse bone marrow culture model, we tested the hypothesis that environmental toxicants acting as PPARγ agonists divert the differentiation pathway of bone marrow-derived multipotent mesenchymal stromal cells towards adipogenesis and away from osteogenesis. The toxicants tested included the organotins tributyltin and triphenyltin, a ubiquitous phthalate metabolite (mono-(2-ethylhexyl) phthalate, MEHP), and two brominated flame retardants (tetrabromobisphenol-a, TBBPA, and mono-(2-ethylhexyl) tetrabromophthalate, METBP). All of the compounds activated PPARγ1 and 2. All compounds increased adipogenesis (lipid accumulation, Fabp4 expression) and suppressed osteogenesis (alkaline phosphatase activity, Osx expression) in mouse primary bone marrow cultures, but with different potencies and efficacies. Despite structural dissimilarities, there was a strong negative correlation between efficacies to induce adipogenesis and suppress osteogenesis, with the organotins being distinct in their exceptional ability to suppress osteogenesis. As human exposure to a mixture of toxicants is likely, albeit at low doses, the fact that multiple toxicants are capable of suppressing bone formation supports the hypothesis that environmental PPARγ ligands represent an emerging threat to human bone health.
authors.affiliation: Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA.
authors.forename: James
authors.initials: J
authors.lastname: Watt
authors.affiliation: Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA. Electronic address: jschlezi@bu.edu.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Schlezinger
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000737:chemistry / Q000633:toxicity*; D004785:Environmental Pollutants / Q000737:chemistry / Q000633:toxicity*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009947:Organotin Compounds / Q000633:toxicity; D010012:Osteogenesis / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D015415:Biomarkers; D052244:Endocrine Disruptors; D004785:Environmental Pollutants; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D008024:Ligands; D009947:Organotin Compounds; D047495:PPAR gamma; D012333:RNA, Messenger; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D000469:Alkaline Phosphatase
keywords: Mono-(2-ethylhexyl) phthalate; Mono-(2-ethylhexyl) tetrabromophthalate; Organotin; Osteoblast; PPARγ; Tetrabromobisphenol-a