DEHP and its metabolite MEHP exposure impairs endometrial decidualization during early pregnancy via up-regulation of Mtmr6

DEHP is a pervasive endocrine disrupting chemical with multiple adverse effects on the female reproductive system. However, its impact on endometrial decidualization, the foundation for embryo implantation and successful pregnancy, remains poorly defined, and the underlying regulatory mechanisms have been rarely explored. In present study, we utilized several assays with DEHP-exposed mouse decidual tissues to clarify whether DEHP exposure confers adverse effects on decidualization. The results showed that 1000 mg/kg/d DEHP exposure led to a significant reduction in the weight and area of the uterine deciduoma, accompanied by a significant decrease in the expression of decidualization markers on GD6, GD8 of pregnancy, and PD8 of pseudopregnancy in mice. Moreover, the in vitro findings revealed that exposure to 12.5 μM MEHP, the primary and active metabolite of DEHP, disturbed the cytoskeletal remodeling and downregulated the marker molecules during endometrial stromal cell decidualization. Meanwhile, we detected that Mtmr6 as identified by proteomics analysis, was up-regulated after DEHP and MEHP exposure in vivo and in vitro. Knockdown of Mtmr6 alleviated the deficiencies in stromal cell decidualization induced by DEHP’ metabolite MEHP. Furthermore, we also found that the active-site residue ALA-131 of Mtmr6 may be the direct binding site for MEHP by performing molecular docking. This study uncovered the adverse effects of DEHP on endometrial decidualization and revealed the possible mechanisms, providing potential strategies for minimizing their toxicological effects on female reproductive health.