Viswanathan Mangala Priya, Mullainadhan Vigneswari, Karundevi Balasubramanian
Department of Endocrinology, Dr. A.L.M Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai, India.
Int J Toxicol. 2025 Mar-Apr;44(2):170-180. doi: 10.1177/10915818241305090. Epub 2024 Dec 10.
Endocrine-disrupting chemicals (EDCs) play an important role in the incidence of type-2 diabetes. Di-2-ethyl hexyl Phthalate (DEHP) is one of the endocrine-disrupting chemicals used as a plasticizer to impart flexibility and softness to plastic-containing materials. Mono-2-ethylhexyl Phthalate (MEHP), a DEHP's primary metabolite, is preferentially absorbed once metabolized. A previous study from our laboratory showed that DEHP and MEHP altered the key proteins such as insulin receptor (INSR) and glucose transporter-4 (GLUT4) in L6 myotubes. In a sequel to the previous study, the present study hypothesized that DEHP and its metabolite MEHP may alter the and gene expression in L6 myotubes. Therefore, to find out the molecular mechanism behind the decreased INSR and GLUT4 protein levels in the previous study, the direct effect of DEHP and its metabolite MEHP in regulating and gene transcription in L6 myotubes was studied. The L6 myotubes were exposed to 50 and 100 μM DEHP and MEHP for 24 h, followed by insulin stimulation for 20 min. We observed decreased and mRNA levels in DEHP and MEHP-treated groups. Western blot data showed decreased protein levels of MEF2A and MyoD in treated groups. ChIP assay detected a decreased association of MEF2A and MyoD to the gene promoter and HMGA1 to the gene promoter. The study revealed that DEHP and MEHP diminished the and gene expression through weakened interaction of their transcription factors on the respective promoter.
内分泌干扰化学物质（EDCs）在2型糖尿病的发病中起重要作用。邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种内分泌干扰化学物质，用作增塑剂，使含塑料材料具有柔韧性和柔软性。邻苯二甲酸单（2-乙基己基）酯（MEHP）是DEHP的主要代谢产物，代谢后优先被吸收。我们实验室之前的一项研究表明，DEHP和MEHP改变了L6肌管中的关键蛋白，如胰岛素受体（INSR）和葡萄糖转运蛋白4（GLUT4）。作为之前研究的后续，本研究假设DEHP及其代谢产物MEHP可能会改变L6肌管中[此处原文缺失相关基因名称]和[此处原文缺失相关基因名称]的基因表达。因此，为了找出之前研究中INSR和GLUT4蛋白水平降低背后的分子机制，研究了DEHP及其代谢产物MEHP对L6肌管中[此处原文缺失相关基因名称]和[此处原文缺失相关基因名称]基因转录的直接影响。将L6肌管暴露于50和100μM的DEHP和MEHP中24小时，随后进行20分钟的胰岛素刺激。我们观察到DEHP和MEHP处理组中[此处原文缺失相关基因名称]和[此处原文缺失相关基因名称]的mRNA水平降低。蛋白质印迹数据显示处理组中MEF2A和MyoD的蛋白水平降低。染色质免疫沉淀分析检测到MEF2A和MyoD与[此处原文缺失相关基因名称]基因启动子的结合减少，以及HMGA1与[此处原文缺失相关基因名称]基因启动子的结合减少。该研究表明，DEHP和MEHP通过削弱其转录因子在各自启动子上的相互作用，减少了[此处原文缺失相关基因名称]和[此处原文缺失相关基因名称]的基因表达。
