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.
Highlights
Influence gene expression during cell differentiation[6]
Upson K et al finding that urinary concentration of the butyl benzyl phthalate (BBP) metabolite MBzP may be associated with increased risk of endometriosis[14]
Reddy et al has demonstrated the relationship between exposure to polyethylenes such as BBP and the occurrence of endometriosis in infertile women[15]
Summary
Influence gene expression during cell differentiation[6]. How environmental factors affect cell differentiation through gene expression regulation is unclear. The pollutant butyl benzyl phthalate (BBP) is ubiquitously present in the environment. Upson K et al finding that urinary concentration of the BBP metabolite MBzP (mono-n-benzyl phthalate) may be associated with increased risk of endometriosis[14]. Emerging evidence indicates that miRNAs have a critical role in the self-renewal and differentiation of MSCs17. In addition to the contribution of genetic background, increasing evidence indicates that EDCs may affect MSC differentiation[18, 19]. The aim of the present study was to evaluate the effect of BBP on the differentiation of EN-MSCs and to investigate the relationship between BBP and epigenetic-modulated gene expression
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