title: Benzyl butyl phthalate induces epigenetic stress to enhance adipogenesis in mesenchymal stem cells.
abstract: Endocrine disruptors, phthalates, may have contributed to recent global obesity health crisis. Our study investigated the potential of benzyl butyl phthalate (BBP) to regulate the mesenchymal stem cell epigenome to drive adipogenesis. BBP exposure enhanced lipid accumulation and adipogenesis in a dose-dependent manner compared to control (P < 0.001). Adipogenesis markers, PPARγ (P < 0.001), C/EBPα (P < 0.01), and aP2 (P < 0.001) were significantly upregulated by increasing concentrations of BBP when compared to DMSO. BBP enhanced H3K9 acetylation while decreasing H3K9 dimethylation. Fifty μM BBP increased histone acetyltransferases, p300 (P < 0.05) and GCN5 (P < 0.01) gene expression. Furthermore, histone deacetylases (HDACs), HDAC3 (P < 0.01) and HDAC10 (P < 0.01, 10 μM BBP; P < 0.001, 50 μM BBP) and histone methyltransferases, SETDB1 (P < 0.01) and G9a (P < 0.01), were significantly downregulated by BBP exposure. BBP acts, in part, through PPARγ, as PPARγ knockdown led to decreased H3K9ac and rescued H3K9me2 during BBP exposure. In conclusion, BBP regulated MSCs towards adipogenesis by tipping the epigenomic balance.
authors.affiliation: Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, MS131, 1010 West Ave B, COP 309, Kingsville, TX 78363 USA. Electronic address: sonkar@pharmacy.tamhsc.edu.
authors.forename: Ravi
authors.initials: R
authors.lastname: Sonkar
authors.affiliation: Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, MS131, 1010 West Ave B, COP 309, Kingsville, TX 78363 USA. Electronic address: powell@pharmacy.tamhsc.edu.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Powell
authors.affiliation: Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, MS131, 1010 West Ave B, COP 309, Kingsville, TX 78363 USA. Electronic address: mchoudhury@pharmacy.tamhsc.edu.
authors.forename: Mahua
authors.initials: M
authors.lastname: Choudhury
mesh_terms: D000107:Acetylation / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002460:Cell Line; D052244:Endocrine Disruptors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D057890:Epigenomics / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D010795:Phthalic Acids / Q000494:pharmacology*
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D052244:Endocrine Disruptors; D047495:PPAR gamma; D010795:Phthalic Acids; C032279:phthalic acid; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C027561:butylbenzyl phthalate
keywords: Adipogenesis; Benzyl butyl phthalate; Epigenetics; Histone acetylation; Histone methylation; Mesenchymal stem cell