title: DEHP exposure in utero disturbs sex determination and is potentially linked with precocious puberty in female mice.
abstract: Human's ubiquitous exposure to di (2-ethylhexyl) phthalate (DEHP) is thought to be associated with female reproductive toxicity. Previous studies found that DEHP inhibited follicle growth and decreased estradiol levels in adult female mice. However, limited information is available on the link between in utero DEHP exposure and ovarian development in female mouse offspring. The present study evaluates the disturbances in regulatory genes involved in female sex determination and the ovarian outcomes in fetal and postnatal female mice treated with in utero DEHP exposure. Pregnant mice were exposed to DEHP by gavage, with the dosage regime beginning at human relevant exposure levels. After in utero DEHP exposure, increased follicular atresia was observed in the female pups at postnatal days (PND) 21. Foxl2 expression was significantly upregulated, and Fst was significantly downregulated by DEHP above 2mg/kg/d at PND 1 and 21. This suggests that lesion of granulosa cell differentiation and disturbance of follicle development in postnatal female mice. The expression of Cyp11a1 and Star were significantly downregulated by in utero DEHP exposure, indicating effects on estradiol biosynthesis. The female sex determination pathway was disturbed in fetus by DEHP at 2mg/kg/d and above during the critical time window of sex determination causing significant upregulation of Foxl2, Wnt4, β-catenin and Fst. Furthermore, the increased expression of Wnt4 was supported by whole-mount in situ hybridization (WISH). These results suggest a possible association between in utero DEHP exposure and precocious puberty in the postnatal life of mice offspring, where disturbance of the sex determination regulating pathway acted as an important mechanism.
authors: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors: Yongan
authors: Y
authors: Wang
authors: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors: Qing
authors: Q
authors: Yang
authors: 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: Wei
authors: W
authors: Liu
authors: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors: Mingxi
authors: M
authors: Yu
authors: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors: Zhou
authors: Z
authors: Zhang
authors: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
authors: Xiaoyu
authors: X
authors: Cui
mesh_terms: D000818:Animals; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D005260:Female; D038681:Follistatin / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics; D008431:Maternal-Fetal Exchange; D008813:Mice, Inbred ICR; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics; D010968:Plasticizers / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011629:Puberty, Precocious / Q000139:chemically induced* / Q000378:metabolism; D019849:Sex Determination Processes / Q000187:drug effects*; D060528:Wnt4 Protein / Q000235:genetics; D051176:beta Catenin / Q000235:genetics; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C495267:CTNNB1 protein, mouse; D038681:Follistatin; D051858:Forkhead Transcription Factors; C585346:Foxi3 protein, mouse; D010750:Phosphoproteins; D010968:Plasticizers; D060528:Wnt4 Protein; D051176:beta Catenin; D000098682:Steroidogenic Acute Regulatory Protein; D004051:Diethylhexyl Phthalate; D002786:Cholesterol Side-Chain Cleavage Enzyme
keywords: DEHP; Follicular atresia; Gonadal development; Granulosa cells; In utero exposure; Sex determination