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.
Sci Rep. 2017 Mar 15;7(1):186. doi: 10.1038/s41598-017-00286-6.
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.
邻苯二甲酸酯是一种环境毒素，被认为是一种内分泌干扰化学物质。越来越多的证据表明，内分泌干扰化学物质与组织发育和生殖生理学之间存在联系，但环境因素对细胞分化的基因表达调控机制尚不清楚。在此，我们研究了丁基苄基邻苯二甲酸酯（BBP）对人子宫内膜间充质干细胞/基质细胞（EN-MSC）分化的影响，并确定了一条新的信号通路。BBP 处理后，子宫内膜间充质干细胞的分化减少。我们使用 cDNA 微阵列和 Ingenuity Pathway Analysis 软件分析了 BBP 对 EN-MSC 基因表达的调控，以鉴定受影响的靶基因及其生物学功能。PITX2 作为针对骨骼和肌肉疾病、细胞形态和组织发育的独立筛选的共同基因靶点出现。BBP 降低了 PITX2 的转录，并上调了其上游负调控因子 microRNA miR-137 的表达。这些数据表明，BBP 通过 miR-137 靶向 PITX2 mRNA 的 3'非翻译区来影响 PITX2 的表达。PITX2 的下调也降低了 EN-MSC 中的 MyoD 转录水平。我们的结果表明，BBP 通过上调 miR-137 降低了 EN-MSC 的成肌分化，有助于我们理解 EN-MSC 的分化，并强调了环境激素的潜在危害。
