title: Di(2-Ethylhexyl) Phthalate Exposure In Utero Damages Sertoli Cell Differentiation Via Disturbance of Sex Determination Pathway in Fetal and Postnatal Mice.
abstract: Mice may share similar mechanism with human underlying reproductive toxicity induced by di(2-ethylhexyl) phthalate (DEHP), which is not supposed to be associated with decreased testicular testosterone. Pregnant mice were exposed to DEHP by gavage, with the dosage regime beginning at human relevant exposure level. After in utero DEHP exposure, loss of Sertoli cells and germ cells were observed in the male pups at postnatal days 21. And SRY-related HMG box 9 (SOX9), Fibroblast growth factor-9 (FGF9), and Double-sex and Mab-3 related transcripttion factor 1 (DMRT1) proteins were significantly downregulated by DEHP at 2 mg/kg/d and above, suggesting the depression of Sertoli cell differentiation. The repression of Sox9 genes expression was supported by whole-mount in situ hybridization and real-time real-time-quantitative PCR. The expressions of Cyp11α1 and Star were not significantly affected by in utero DEHP exposure, indicating the absence of effects on testosterone biosynthesis. Furthermore, the testosterone-independent pathway regulating Sertoli cells differentiation was disturbed in fetus by DEHP at 2 mg/kg/d and above during the critical time window of sex determination, involving Gadd45g → Gata4/Fog2 → Sry → Sox9 → Fgf9 The results suggest that in utero DEHP exposure damaged Sertoli cells in the postnatal life of mice offspring via disturbance of the differentiation regulating pathway, potentially inducing declines in spermatogenesis.
authors.affiliation: *Key Laboratory of Industrial Ecology and Environmental Engineering (MOE).
authors.forename: Yongan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Environmental Science and Technology;
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: *Key Laboratory of Industrial Ecology and Environmental Engineering (MOE) liu_wei@dlut.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: *Key Laboratory of Industrial Ecology and Environmental Engineering (MOE).
authors.forename: Mingxi
authors.initials: M
authors.lastname: Yu
authors.affiliation: *Key Laboratory of Industrial Ecology and Environmental Engineering (MOE).
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: *Key Laboratory of Industrial Ecology and Environmental Engineering (MOE).
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Cui
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000235:genetics / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D018811:Maternal Exposure; D008813:Mice, Inbred ICR; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012708:Sertoli Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019849:Sex Determination Processes / Q000187:drug effects*; D013091:Spermatogenesis / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein; D000097642:GADD45 Proteins
chemical_list: D002352:Carrier Proteins; D002786:Cholesterol Side-Chain Cleavage Enzyme; D004051:Diethylhexyl Phthalate; D051525:Fibroblast Growth Factor 9; D050991:GATA4 Transcription Factor; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D055758:SOX9 Transcription Factor; D014157:Transcription Factors; D000098682:Steroidogenic Acute Regulatory Protein; C110547:DMRT1 protein; C496460:Fgf9 protein, mouse; C121373:Gadd45g protein, mouse; D000097642:GADD45 Proteins; C484171:Gata4 protein, mouse; C527933:Sox9 protein, mouse
keywords: DEHP; Sertoli cells; differentiation; spermatogenesis