Di (2-ethyl-hexyl) phthalate (DEHP) is a widely used plasticizer. Maternal DEHP exposure inhibits cell proliferation and reduces placentas size, which associates with fetal growth restriction and adulthood diseases. However, the mechanism of placental cell proliferation inhibition by DEHP remains elusive. This study investigated the effect of DEHP on placental cell proliferation from cell cycle arrest. Utilizing in vitro and in vivo experiments, we investigated cell cycle arrest, DNA double-strand break (DSB) repair, genotoxic stress response, and micronuclei formation. Most DEHP metabolizes to mono (2-Ethylhexyl) phthalate (MEHP) and distributes to organs quickly, so MEHP and DEHP were used in cultured cell and animal experiments, respectively. Here, a double blocking mode for the proliferation inhibition of the placental cell was revealed. One is that the classical DSB repair pathways were suppressed, which arrested the cell cycle at the G2/M phase. The other is that DEHP stimulated an elevated level of progesterone, which blocked the cell cycle at metaphase by disrupting chromosome arrangement. These two sets of events facilitated micronuclei formation and resulted in cell proliferation inhibition. This findings provide a novel mechanistic understanding for DEHP to inhibit placental cell proliferation.

邻苯二甲酸二（2-乙基-己基）酯（DEHP）是一种广泛使用的增塑剂。母亲接触 DEHP 会抑制细胞增殖并减小胎盘大小，这与胎儿生长受限和成年期疾病有关。然而，DEHP 抑制胎盘细胞增殖的机制仍然难以捉摸。本研究调查了 DEHP 对细胞周期停滞引起的胎盘细胞增殖的影响。在体外和体内利用在实验中，我们研究了细胞周期停滞、DNA 双链断裂 (DSB) 修复、基因毒性应激反应和微核形成。大多数DEHP代谢为邻苯二甲酸单（2-乙基己基）酯（MEHP）并迅速分布到器官，因此MEHP和DEHP分别用于培养细胞和动物实验。在这里，揭示了胎盘细胞增殖抑制的双重阻断模式。一是经典的 DSB 修复途径被抑制，从而在 G2/M 期阻止细胞周期。另一个是 DEHP 刺激了孕酮水平升高，从而通过破坏染色体排列在中期阻止细胞周期。这两组事件促进了微核形成并导致细胞增殖抑制。