Mono-(2-ethylhexyl) Phthalate Induces Trophoblast Hypoxia and Mitochondrial Dysfunction Through HIF-1α-miR-210-3p Axis in HTR-8/SVneo Cell Line

Sunitha Meruvu,Zehuan Ding,Mahua Choudhury

Current Research in Toxicology（2024）

Department of Pharmaceutical Sciences

Cited 0|Views2

Abstract

The exposure to the ubiquitous phthalate metabolite mono-(2-ethylhexyl) phthalate (MEHP) is connected to dysregulated trophoblast function and placenta health; however, the underlying mechanisms preluding this scenario remain to be elucidated. In this study, we explored the hypoxemic effects of MEHP on a human placental first-trimester trophoblast cell line (HTR-8/Svneo). MEHP-treated trophoblast cells displayed significantly increased levels of oxidative stress and hypoxia-inducible factor-1 alpha (HIF-1α) attributed by the induction of hypoxia. Further, HIF-1α exhibited higher DNA binding activity and upregulated gene expression of its downstream target vascular endothelial growth factor A (VEGFA). The hypoxia-induced microRNA miR-210-3p was also significantly increased upon MEHP treatment followed by disrupted mitochondrial ATP generation and membrane potential. This was identified to possibly be facilitated by lowered mitochondrial DNA copy number and inhibited expression of electron transport chain subunits, such as mitochondrial complex-IV. These results suggest potential adverse effects of MEHP exposure in a trophoblast cell line mediated by HIF-1α and the epigenetic modulator miR-210-3p. Chronic placental hypoxia and oxidative stress have long been implicated in the pathogenesis of pregnancy complications such as preeclampsia. As we’ve revealed genetic and epigenetic factors underscoring a potential mechanism induced by MEHP, this brings to light another significant implication of phthalate exposure on maternal and fetal health.

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Key words

Mono-(2-ethylhexyl) phthalate,Hypoxia,Mitochondrial dysfunction,HIF-1α,miR-210-3p,First-trimester trophoblast cells

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【要点】：该论文揭示了MEHP通过HIF-1α-miR-210-3p轴诱导滋养层细胞缺氧和线粒体功能障碍的分子机制，为理解其影响母儿健康的潜在作用提供了新见解。

【方法】：研究采用HTR-8/SVneo细胞系，通过处理MEHP来观察细胞内的氧化应激水平、HIF-1α的表达及其下游VEGFA的变化，同时检测了线粒体功能相关指标。

【实验】：实验在HTR-8/SVneo细胞系中进行MEHP处理，使用实时定量PCR、Western blot、线粒体膜电位检测试剂盒等方法，数据集未明确提及，但结果显示MEHP处理显著增加了氧化应激和HIF-1α水平，上调VEGFA表达，并引起miR-210-3p表达增加及线粒体功能紊乱。