Tributyltin Engages Multiple Nuclear Receptor Pathways and Suppresses Osteogenesis in Bone Marrow Multipotent Stromal Cells

Baker, Amelia H.; Watt, James; Huang, Cassie; Gerstenfeld, Louis C.; Schlezinger, Jennifer J.

doi:10.1021/tx500433r

Cited by 49 publications

(56 citation statements)

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“…The organotin tributyltin (TBT), which inspired the coining of the term environmental obesogen, is an environmental PPARγ ligand (Grün et al 2006; Kanayama et al 2005). TBT is a highly potent PPARγ ligand, which induces differentiation of bone marrow and adipose-derived multipotent stromal cells (MSCs) into adipocytes and suppresses bone formation (Baker et al 2015; Grün et al 2006; Li et al 2011; Watt and Schlezinger 2015; Yanik et al 2011). Prenatal TBT exposure in mice leads to epigenetic changes in mesenchymal stem cells that favor adipogenesis at the expense of osteogenesis (Chamorro-García et al 2013), reduced ossification of the skeleton (Tsukamoto et al 2004), and increased adiposity in adulthood (Grün et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models

Kim

Monti

et al. 2018

Arch Toxicol

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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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Section: Introductionmentioning

confidence: 99%

Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models

Kim

Monti

et al. 2018

Arch Toxicol

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“…Baker et al 2015). To determine the potential nuclear receptor pathways235 involved, BM-MSC cultures were stimulated to undergo osteogenic differentiation and treated236 with Vh or TBT (80 nM).…”

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confidence: 99%

Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models

Kim

Monti

et al. 2018

Preprint

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31 Tributyltin (TBT), a peroxisome proliferator-activated receptor γ (PPARγ)/retinoid X receptor 32 (RXR) ligand and founding member of the environmental obesogen chemical class, induces 33 adipocyte differentiation and suppresses bone formation. A growing number of environmental 34 PPARγ ligands are being identified. However, the potential for environmental PPARγ ligands to 35 induce adverse metabolic effects has been questioned because PPARγ is a therapeutic target in 36 treatment of type II diabetes. We evaluated the molecular consequences of TBT exposure during 37 bone marrow multipotent mesenchymal stromal cell (BM-MSC) differentiation in comparison to 38 rosiglitazone, a therapeutic PPARγ ligand, and LG100268, a synthetic RXR ligand. Mouse 39 primary BM-MSCs (female, C57BL/6J) undergoing bone differentiation were exposed to 40 maximally efficacious and human relevant concentrations of rosiglitazone (100 nM), LG100268 41 (100 nM) or TBT (80 nM) for 4 days. Gene expression was assessed using microarrays, and in 42 silico functional annotation was performed using pathway enrichment analysis approaches. 43 Pathways related to osteogenesis were downregulated by all three ligands, while pathways 44 related to adipogenesis were upregulated by rosiglitazone and TBT. However, pathways related 45 to mitochondrial biogenesis and brown-in-white (brite) adipocyte differentiation were more 46 significantly upregulated in rosiglitazone-treated than TBT-treated cells. The lack of induction of 47 genes involved in adipocyte energy dissipation by TBT was confirmed by an independent gene 48 expression analysis in BM-MSCs undergoing adipocyte differentiation and by analysis of a 49 publically available 3T3 L1 data set. Furthermore, rosiglitazone, but not TBT, induced 50 mitochondrial biogenesis. This study is the first to show that an environmental PPARγ ligand has 51 a limited capacity to induce health promoting activities of PPARγ. 52 highly potent PPARγ ligand, which induces differentiation of bone marrow and adipose-derived 76 multipotent stromal cells (MSCs) into adipocytes and suppresses bone formation (Baker et al. 77

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“…Organotins include tributyltin (TBT) and triphenyltin, substances with strong antibacterial and fungicidal properties that were historically used as marine anti-fouling additives in paint. Baker et al[38] showed that in BM-MSCs, TBT activated adipogenesis and reduced osteogenesis. This finding was also supported in primary BM-MSCs for both TBT and tryphenyltin[39].…”

Section: Heavy Metalsmentioning

confidence: 99%

Effects of environmental stressors on stem cells

Worley

Parker

2019

WJSC

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Environmental toxicants are ubiquitous, and many are known to cause harmful health effects. However, much of what we know or think we know concerning the targets and long-term effects of exposure to environmental stressors is sadly lacking. Toxicant exposure may have health effects that are currently mischaracterized or at least mechanistically incompletely understood. While much of the recent excitement about stem cells (SCs) focuses on their potential as therapeutic agents, they also offer a valuable resource to give us insight into the mechanisms and risks of toxicant effects. Not only as a response to the increasing ethical pressure to reduce animal testing, SC studies allow us valuable insight into the true effects of human exposure to environmental stressors under controlled conditions. We present a review of the history of publications on the effects of environmental stressors on SCs, followed by a consolidation of the literature over the past five years on a subset of key environmental stressors of importance to human health and their effects on both embryonic and tissue SCs. The review will make constructive suggestions as to areas of toxicant research where further studies are needed, as well as making indications of the potential utility for advancing knowledge and directing research on environmental toxicology.

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Tributyltin Engages Multiple Nuclear Receptor Pathways and Suppresses Osteogenesis in Bone Marrow Multipotent Stromal Cells

Cited by 49 publications

References 67 publications

Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models

Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models

Tributyltin induces a transcriptional response without a brite adipocyte signature in adipocyte models

Effects of environmental stressors on stem cells

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