Previous study reported that gestational Di-(2-ethylhexyl) phthalate (DEHP) exposure caused fetal intrauterine growth restriction (IUGR). We aimed to investigate the role of placental thyroid hormone receptor (THR) signaling in DEHP-induced IUGR. Dams were treated with DEHP (50 or 200 mg/kg) by gavage daily throughout pregnancy. As expected, gestational DEHP exposure dose-dependently caused fetal IUGR. The mRNA levels of placental Thrα1 and Thrβ1 were reduced and nuclear translocation of placental THRα1 and THRβ1 were suppressed in DEHP-exposed mice even though thyroid hormones in maternal and fetal sera were unaffected. Correspondingly, Vegf, Pgf, Igf1 and Igf2, several THR downstream genes essential for placental angiogenesis, were down-regulated in placenta of DEHP-exposed mice. Histopathology showed that vascular space in the labyrinthine region was shrunken in placenta of DEHP-treated mice. The microvessel density in labyrinthine region was reduced in DEHP-treated mice. A nested case-control study based on MABC suggested that microvessel density was decreased in placenta of SGA cases. Moreover, protein abundance of placental THRα1 and THRβ1 were lower in SGA cases. In conclusion, gestational DEHP exposure increases fetal IUGR incidence through disturbing placental THR signaling. The present study, at least partially, elucidate the underlying mechanism of DEHP-induced fetal IUGR.

中文翻译：

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妊娠期邻苯二甲酸二（2-乙基己基）酯暴露通过干扰胎盘甲状腺激素受体信号传导导致胎儿宫内生长受限

先前的研究报告称，妊娠期邻苯二甲酸二(2-乙基己基)酯 (DEHP) 暴露会导致胎儿宫内生长受限 (IUGR)。我们旨在研究胎盘甲状腺激素受体 (THR) 信号在 DEHP 诱导的 IUGR 中的作用。在整个怀孕期间，每天通过强饲法用 DEHP（50 或 200 毫克/千克）处理水坝。正如预期的那样，妊娠期 DEHP 暴露剂量依赖性地导致胎儿 IUGR。尽管母体和胎儿血清中的甲状腺激素未受影响，但在暴露于 DEHP 的小鼠中，胎盘 Thrα1 和 Thrβ1 的 mRNA 水平降低，胎盘 THRα1 和 THRβ1 的核转位受到抑制。相应地，胎盘血管生成所必需的几个 THR 下游基因 Vegf、Pgf、Igf1 和 Igf2 在暴露于 DEHP 的小鼠胎盘中被下调。组织病理学显示，在 DEHP 处理的小鼠胎盘中，迷宫区域的血管空间缩小。在 DEHP 治疗的小鼠中，迷宫区域的微血管密度降低。基于 MABC 的巢式病例对照研究表明 SGA 病例胎盘中的微血管密度降低。此外，SGA病例中胎盘THRα1和THRβ1的蛋白质丰度较低。总之，妊娠期 DEHP 暴露会通过干扰胎盘 THR 信号增加胎儿 IUGR 发生率。本研究至少部分阐明了 DEHP 诱导胎儿 IUGR 的潜在机制。此外，SGA病例中胎盘THRα1和THRβ1的蛋白质丰度较低。总之，妊娠期 DEHP 暴露会通过干扰胎盘 THR 信号增加胎儿 IUGR 发生率。本研究至少部分阐明了 DEHP 诱导胎儿 IUGR 的潜在机制。此外，SGA病例中胎盘THRα1和THRβ1的蛋白质丰度较低。总之，妊娠期 DEHP 暴露会通过干扰胎盘 THR 信号增加胎儿 IUGR 发生率。本研究至少部分阐明了 DEHP 诱导胎儿 IUGR 的潜在机制。