Plasticizer di(2-ethylhexyl)phthalate interferes with osteoblastogenesis and adipogenesis in a mouse model
Journal
Journal of Orthopaedic Research
Journal Volume
36
Journal Issue
4
Pages
1124-1134
Date Issued
2018
Author(s)
Chiu C.-Y.
Sun S.-C.
Chen H.-J.
Abstract
Plasticizer di(2-ethylhexyl)phthalate (DEHP) can leach from medical devices such as blood storage bags and the tubing. Recently, epidemiological studies showed that phthalate metabolites levels in the urine are associated with low bone mineral density (BMD) in older women. The detailed effect and mechanism of DEHP on osteoblastogenesis and adipogenesis, and bone loss remain to be clarified. Here, we investigated the effect and mechanism of DEHP and its active metabolite mono(2-ethylhexyl)phthalate (MEHP) on osteoblastogenesis and adipogenesis. The in vitro study showed that osteoblast differentiation of bone marrow stromal cells (BMSCs) was significantly and dose-dependently decreased by DEHP and MEHP (10–100 ?M) without cytotoxicity to BMSCs. The mRNA expressions of alkaline phosphatase, Runx2, osteocalcin (OCN), Wnt1, and β-catenin were significantly decreased in DEHP- and MEHP-treated BMSCs during differentiation. MEHP, but not DEHP, significantly increased the adipocyte differentiation of BMSCs and PPARγ mRNA expression. Both DEHP and MEHP significantly increased the ratios of phosphorylated β-catenin/β-catenin and inhibited osteoblastogenesis, which could be reversed by Wnt activator lithium chloride and PPARγ inhibitor T0070907. Moreover, exposure of mice to DEHP (1, 10, and 100 mg/kg) for 8 weeks altered BMD and microstructure. In BMSCs isolated from DEHP-treated mice, osteoblastogenesis and Runx2, Wnt1, and β-catenin expression were decreased, but adipogenesis and PPARγ expression were increased. These findings suggest that DEHP and its metabolite MEHP exposure may inhibit osteoblastogenesis and promote adipogenesis of BMSCs through the Wnt/β-catenin-regulated and thus triggering bone loss. PPARγ signaling may play an important role in MEHP- and DEHP-induced suppression of osteogenesis. ? 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1124–1134, 2018. ? 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
SDGs
Other Subjects
2 chloro 5 nitro n (4 pyridyl)benzamide; alkaline phosphatase bone isoenzyme; beta actin; beta catenin; estrogen receptor alpha; glyceraldehyde 3 phosphate dehydrogenase; lithium chloride; messenger RNA; osteocalcin; peroxisome proliferator activated receptor gamma; phthalic acid 2 ethylhexyl monoester; phthalic acid bis(2 ethylhexyl) ester; transcription factor RUNX2; Wnt1 protein; mono-(2-ethylhexyl)phthalate; peroxisome proliferator activated receptor gamma; phthalic acid bis(2 ethylhexyl) ester; plasticizer; adipocyte; adipogenesis; adult; animal cell; animal experiment; animal tissue; Article; bone atrophy; bone characteristics and functions; bone density; bone marrow stroma cell; bone mineralization; bone structure; cell differentiation; controlled study; cytotoxicity; enzyme activity; in vitro study; male; mouse; mRNA expression level; nonhuman; osteoblast; osteoblastogenesis; priority journal; protein phosphorylation; signal transduction; adipogenesis; analogs and derivatives; animal; bone development; cell survival; drug effect; gene expression; Institute for Cancer Research mouse; mesenchymal stem cell; metabolism; Wnt signaling; Adipogenesis; Animals; Cell Survival; Diethylhexyl Phthalate; Gene Expression; Male; Mesenchymal Stem Cells; Mice, Inbred ICR; Osteoblasts; Osteogenesis; Plasticizers; PPAR gamma; Wnt Signaling Pathway
Publisher
John Wiley and Sons Inc.
Type
journal article