title: Benzyl butyl phthalate decreases myogenic differentiation of endometrial mesenchymal stem/stromal cells through miR-137-mediated regulation of PITX2.
abstract: Phthalate, an environmental toxin, has been considered as an endocrine-disrupting chemical. Growing evidence has demonstrated links between endocrine-disrupting chemicals, tissue development, and reproductive physiology, but the mechanisms of gene expression regulation by environmental factors that affect cell differentiation are unclear. Herein, we investigated the effects of butyl benzyl phthalate (BBP) on human endometrial mesenchymal stem/stromal cell (EN-MSC) differentiation and identified a novel signaling pathway. Differentiation of endometrial mesenchymal stem/stromal cells decreased after administration of BBP. We analyzed BBP regulation of gene expression in EN-MSC using cDNA microarrays and Ingenuity Pathway Analysis software to identify affected target genes and their biological functions. PITX2 emerged as a common gene hit from separate screens targeting skeletal and muscular disorders, cell morphology, and tissue development. BBP decreased transcription of PITX2 and elevated expression of the microRNA miR-137, the predicted upstream negative regulator of PITX2. These data indicated that BBP affects PITX2 expression through miR-137 targeting of the 3' untranslated region of PITX2 mRNA. PITX2 down-regulation also decreased MyoD transcript levels in EN-MSC. Our results demonstrate that BBP decreases EN-MSC myogenic differentiation through up-regulation of miR-137, contribute to our understanding of EN-MSC differentiation, and underline the hazardous potential of environmental hormones.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan.|Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan.
authors.forename: Hung-Sheng
authors.initials: HS
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan.
authors.forename: Yu-Chia
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan.
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Chuang
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan.
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Long
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan. pelagice@yahoo.com.tw.
authors.forename: Tsung-Hua
authors.initials: TH
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan. tsaieing@yahoo.com.|Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan. tsaieing@yahoo.com.|Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. tsaieing@yahoo.com.|Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan. tsaieing@yahoo.com.|Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan. tsaieing@yahoo.com.
authors.forename: Eing-Mei
authors.initials: EM
authors.lastname: Tsai
mesh_terms: D020413:3' Untranslated Regions; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004717:Endometrium / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D024510:Muscle Development / Q000187:drug effects*; D017570:MyoD Protein / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010795:Phthalic Acids / Q000633:toxicity*; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D020413:3' Untranslated Regions; D018398:Homeodomain Proteins; D035683:MicroRNAs; D017570:MyoD Protein; D010795:Phthalic Acids; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C545567:MIRN137 microRNA, human; C057363:MyoD1 myogenic differentiation protein; C027561:butylbenzyl phthalate