Jang Hyewon, Song Gwonhwa, Lim Whasun, Park Sunwoo
Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
Toxicol Appl Pharmacol. 2025 Feb;495:117186. doi: 10.1016/j.taap.2024.117186. Epub 2024 Dec 6.
Dibutyl phthalate is a chemical commonly used as a plasticizer in the production of daily necessaries, such as cosmetics and toys. Although several toxic effects of dibutyl phthalate have been confirmed, those related to pregnancy are unknown. Trophoblasts are critical for fetal and placental development, and trophoblast damage may cause preeclampsia. This study aimed to confirm the toxic effect of dibutyl phthalate on trophoblasts. We used the human trophoblast cell line HTR-8/SVneo and human choriocarcinoma JEG-3 cells as a placental trophoblast model to investigate the toxic effects of dibutyl phthalate. Both cell lines were treated with dibutyl phthalate (0-20 μg/mL) to verify the mechanisms regulating trophoblast function. Dibutyl phthalate treatment significantly reduced trophoblast viability, reduced invasion ability, and induced mitochondrial depolarization. Ultimately, dibutyl phthalate regulated the PI3K and MAPK signaling pathways and the expression of autophagy-related proteins ATG5, LC3B, and SQSTM1/p62. We concluded that dibutyl phthalate induced autophagy and effectively weakened trophoblast function. Additionally, we conducted experiments to assess the potential effects of monobutyl phthalate, a metabolite of dibutyl phthalate, on cellular mobility, penetration, and autophagy induction. Our results demonstrated that monobutyl phthalate impaired these functions and weakened the trophoblast barrier, after dibutyl phthalate metabolized. Thus, exposure to dibutyl phthalate and its metabolite monobutyl phthalate can damage trophoblast function, highlighting their potential as hazardous substances that impair trophoblast barrier integrity.
邻苯二甲酸二丁酯是一种常用于日用品生产（如化妆品和玩具）中的增塑剂。尽管邻苯二甲酸二丁酯的几种毒性作用已得到证实，但其与妊娠相关的毒性作用尚不清楚。滋养层细胞对胎儿和胎盘发育至关重要，滋养层细胞损伤可能导致子痫前期。本研究旨在证实邻苯二甲酸二丁酯对滋养层细胞的毒性作用。我们使用人滋养层细胞系HTR-8/SVneo和人绒毛膜癌JEG-3细胞作为胎盘滋养层模型，研究邻苯二甲酸二丁酯的毒性作用。两种细胞系均用邻苯二甲酸二丁酯（0-20μg/mL）处理，以验证调节滋养层细胞功能的机制。邻苯二甲酸二丁酯处理显著降低了滋养层细胞的活力，降低了侵袭能力，并诱导线粒体去极化。最终，邻苯二甲酸二丁酯调节了PI3K和MAPK信号通路以及自噬相关蛋白ATG5、LC3B和SQSTM1/p62的表达。我们得出结论，邻苯二甲酸二丁酯诱导自噬并有效削弱滋养层细胞功能。此外，我们进行了实验，以评估邻苯二甲酸二丁酯的代谢产物邻苯二甲酸单丁酯对细胞迁移、穿透和自噬诱导的潜在影响。我们的结果表明，邻苯二甲酸二丁酯代谢后，邻苯二甲酸单丁酯损害了这些功能并削弱了滋养层屏障。因此，接触邻苯二甲酸二丁酯及其代谢产物邻苯二甲酸单丁酯会损害滋养层细胞功能，突出了它们作为损害滋养层屏障完整性的有害物质的潜力。
