Toxic effects of dibutyl phthalate on trophoblast through mitochondria mediated cellular dysfunction

Abstract

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. © 2024 Elsevier Inc.