Di-(2-ethylhexyl)-phthalate disrupts mouse placental growth by regulating the cell cycle of mouse placental trophoblasts through the Trim38-p53 signaling axis

Abstract

Di-(2-ethylhexyl)-phthalate (DEHP) is a common endocrine disruptor that causes very serious environmental pollution. Recent studies have described that DEHP exerts detrimental effects on key processes of placental development, including implantation, differentiation, invasion, and angiogenesis. However, its effects on the proliferation of placental trophoblasts and related regulatory mechanisms remain elusive. This study demonstrated that maternal DEHP exposure significantly disrupted placental growth. Similarly, transcriptomic and proteomic analyses of DEHP-treated placental tissues revealed that DEHP may disrupt placental growth by affecting the cell cycle of placental trophoblasts. Further analyses validated that DEHP inhibited the growth of mouse placental trophoblasts by significantly upregulating the expression of the p53 protein, which arrests the cell cycle. Mechanistically, Tripartite motif protein 38 (Trim38) was identified as a target protein of MEHP, with Trim38 binding to p53 and downregulating p53 expression by promoting its ubiquitination-proteasomal degradation. Interestingly, MEHP could inhibit the Trim38-regulated ubiquitination degradation of p53 and up-regulate p53 protein expression, which in turn inhibited the cell cycle and, ultimately, mouse placental trophoblast growth. In conclusion, DEHP disrupted mouse placental growth by inhibiting the cell cycle of mouse placental trophoblasts via the Trim38-p53 signaling axis. Overall, this study provides a theoretical reference for elucidating the mechanism underlying DEHP-induced placental toxicity.