title: The plasticizer BBP selectively inhibits epigenetic regulator sirtuin during differentiation of C3H10T1/2 stem cell line.
abstract: Exposure to environmental chemicals can perturb an individual's metabolic set point, especially during critical periods of development, and as a result increase his or her propensity towards obesity that is manifested later in life and possibly in successive generations. We hypothesized that benzyl butyl phthalate (BBP), a widespread endocrine disruptor, may impair one important epigenetic regulator, sirtuin, in mesenchymal stem cells and induce adipogenesis. Our results showed that gene expression of two well-known adipogenic markers, aP2 and PPARγ, were significantly increased from day 2 to day 8 under 50μM BBP exposure when compared to control in C3H10T1/2 stem cells (p<0.05) and induced adipogenesis. Sirt1 gene expression was also significantly decreased at day 2, 4, 6, and 8 (p<0.05). However, Sirt7 gene expression was decreased only at day 2 and 8 (p<0.05) while other sirtuin transcriptional levels remained unaltered throughout. Furthermore, Sirt1 and Sirt3 protein expression was decreased (p<0.05) and overall protein hyperacetylation was observed at day 8. Furthermore, FOXO1 and β-catenin, Sirt1 targets and adipogenesis regulators, were hyperacetylated at day 8. PGC1α, NRF1, NRF2, and Tfam, were also significantly decreased (p<0.05). In conclusion, our study suggests for the first time that BBP, a potential epigenetic disruptor, can lead to increased adipogenesis and metabolic dysregulation by impairing vital epigenetic regulators.
authors.affiliation: Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, TX, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, TX, USA. Electronic address: mchoudhury@pharmacy.tamhsc.edu.
authors.forename: Mahua
authors.initials: M
authors.lastname: Choudhury
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D044127:Epigenesis, Genetic; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006609:High Mobility Group Proteins / Q000235:genetics; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics; D010795:Phthalic Acids / Q000633:toxicity*; D010968:Plasticizers / Q000633:toxicity*; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D006609:High Mobility Group Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010795:Phthalic Acids; D010968:Plasticizers; C485290:Ppargc1a protein, mouse; C081930:Tfam protein, mouse; D051176:beta Catenin; D037761:Sirtuins; C027561:butylbenzyl phthalate
keywords: Adipogenesis; Benzyl butyl phthalate (BBP); Endocrine disruptor; Hyperacetylation; Mesenchymal stem cell; Sirtuins