title: Di (2-ethylhexyl) phthalate exposure during pregnancy disturbs temporal sex determination regulation in mice offspring.
abstract: 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.
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors.forename: Yongan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China. Electronic address: liu_wei@dlut.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China. Electronic address: qingyang@dlut.edu.cn.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors.forename: Mingxi
authors.initials: M
authors.lastname: Yu
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology*; D060888:Real-Time Polymerase Chain Reaction; D019849:Sex Determination Processes / Q000187:drug effects*; D051876:Sex-Determining Region Y Protein / Q000187:drug effects
chemical_list: D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; D051876:Sex-Determining Region Y Protein; C497746:Sry protein, mouse; D004051:Diethylhexyl Phthalate
keywords: DEHP; In utero exposure; Sex determination; Temporal expression