Di (2-ethylhexyl) phthalate exposure during pregnancy disturbs temporal sex determination regulation in mice offspring

• DOI: 10.1016/j.tox.2015.07.009
• Publication Date: 2015-07-26T14:55:23Z
• Authors: Yongan Wang; Wei Liu; Qing Yang; Mingxi Yu; Zhou Zhang
• Keywords: Forkhead Box Protein L2; Male; 0301 basic medicine; Mice, Inbred ICR; Dose-Response Relationship, Drug; Gene Expression Regulation, Developmental; Forkhead Transcription Factors; Sex Determination Processes; Real-Time Polymerase Chain Reaction; Sex-Determining Region Y Protein; Mice; 03 medical and health sciences; Pregnancy; Diethylhexyl Phthalate; Prenatal Exposure Delayed Effects; Animals; Female; In Situ Hybridization

Animal researches and clinical studies have supported the relevance between phthalates exposure and testicular dysgenesis syndrome (TDS). These disorders may comprise common origin in fetal life, especially during sex determination and differentiation, where the mechanism remains unclear. The present study evaluated the disturbances in gene regulatory networks of sex determination in fetal mouse by in utero Di (2-ethylhexyl) phthalate (DEHP) exposure. Temporal expression of key sex determination genes were examined during the critical narrow time window, using whole-mount in situ hybridization and quantitative-PCR. DEHP exposure resulted in significant reduction in mRNA of Sry during sex determination from gestation day (GD) 11.0 to 11.5 in male fetal mice, and the increasing of Sry expression to threshold level on GD 11.5 was delayed. Meanwhile, Gadd45g and Gata4, the upstream genes of Sry, and downstream gene Sox9 were also significantly downregulated in expression. In fetal females, the expression of Wnt4 and beta-catenin were up-regulated by DEHP exposure. Taken together, the results suggest that the potential mechanism of gonadal development disorder by DEHP may origin from repression of important male sex determination signaling pathway, involving Gadd45g → Gata4 → Sry → Sox9. The results would promote a better understanding of the association between phthalate esters (PAEs) exposure and the reductive disorder.