Abstract
Tributyltin (TBT), a peroxisome proliferator-activated receptor γ (PPARγ)/retinoid X receptor (RXR) ligand and founding member of the environmental obesogen chemical class, induces adipocyte differentiation and suppresses bone formation. A growing number of environmental PPARγ ligands are being identified. However, the potential for environmental PPARγ ligands to induce adverse metabolic effects has been questioned because PPARγ is a therapeutic target in treatment of type II diabetes. We evaluated the molecular consequences of TBT exposure during bone marrow multipotent mesenchymal stromal cell (BM-MSC) differentiation in comparison to rosiglitazone, a therapeutic PPARγ ligand, and LG100268, a synthetic RXR ligand. Mouse primary BM-MSCs (female, C57BL/6J) undergoing bone differentiation were exposed to maximally efficacious and human relevant concentrations of rosiglitazone (100 nM), LG100268 (100 nM) or TBT (80 nM) for 4 days. Gene expression was assessed using microarrays, and in silico functional annotation was performed using pathway enrichment analysis approaches. Pathways related to osteogenesis were downregulated by all three ligands, while pathways related to adipogenesis were upregulated by rosiglitazone and TBT. However, pathways related to mitochondrial biogenesis and brown-in-white (brite) adipocyte differentiation were more significantly upregulated in rosiglitazone-treated than TBT-treated cells. The lack of induction of genes involved in adipocyte energy dissipation by TBT was confirmed by an independent gene expression analysis in BM-MSCs undergoing adipocyte differentiation and by analysis of a publically available 3T3 L1 data set. Furthermore, rosiglitazone, but not TBT, induced mitochondrial biogenesis and respiration. This study is the first to show that an environmental PPARγ ligand has a limited capacity to induce health-promoting activities of PPARγ.
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Acknowledgements
The authors would like to thank Ms. Cassie Huang for her superb technical assistance. Analytical assistance was provided by the Bioinformatics and Molecular Modeling Core of the Boston University Superfund Program. This work was supported by a Superfund Research Program grant P42ES007381 (J.J.S, S.M.), and a “Seed the Scientist” award from the Find the Cause Breast Cancer Foundation (A.L., S.M.).
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Animal studies were reviewed and approved by the Institutional Animal Care and Use Committee at Boston University and performed in an American Association for the Accreditation of Laboratory Animal Care accredited facility (Animal Welfare Assurance number: A3316-01). All animals were treated humanely and with regard for alleviation of suffering.
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Kim, S., Li, A., Monti, S. et al. Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models. Arch Toxicol 92, 2859–2874 (2018). https://doi.org/10.1007/s00204-018-2268-y
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DOI: https://doi.org/10.1007/s00204-018-2268-y