title: Dibutyl Phthalate Inhibits the Effects of Follicle-Stimulating Hormone on Rat Granulosa Cells Through Down-Regulation of Follicle-Stimulating Hormone Receptor.
abstract: Dibutyl phthalate (DBP) is used worldwide in solvents and plasticizers. The cytotoxicity and potential tumorigenic effect of DBP have been reported. DBP has also been shown to impact reproductive function. In this study, to further evaluate the effects of DBP on granulosa cells (GCs), we treated rat GCs in vitro with DBP before evaluation of the biological alterations of these GCs. We found that DBP did not induce significant GC death at the tested concentrations. However, follicle-stimulating hormone (FSH)-induced KIT ligand (KITLG) expression in GCs was significantly reduced at both mRNA and protein levels by DBP treatment in a dose-dependent manner. The down-regulation of KITLG was due to the down-regulation of expression of FSH receptor (FSHR) in GCs. Down-regulation of FSHR impaired FSH-induced intracellular signaling in GCs, demonstrated by decreased phosphorylation of AKT and mechanistic target of rapamycin (mTOR). Furthermore, DBP treatment also reduced FSH-induced expression of hypoxia-inducible factor 1-alpha (HIF1A), which is an important signaling component for KITLG expression. Other FSH-induced biological effects, such as production of estradiol and progesterone, as well as GC proliferation, were also suppressed by DBP. Therefore, our study discovered a unique mechanism underlying the toxicity of DBP on GCs. These findings may initiate the development of novel therapeutic interventions for DBP-induced damage to GCs.
authors.affiliation: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China.
authors.forename: Xue-Jin
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Liver Disease Center of Xiamen Traditional Hospital affiliated to Fujian University of Traditional Chinese Medicine, Xiamen, Fujian Province, China.
authors.forename: Gong-Peng
authors.initials: GP
authors.lastname: Xiong
authors.affiliation: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China xiangminluo126@126.com.
authors.forename: Xiang-Min
authors.initials: XM
authors.lastname: Luo
authors.affiliation: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China.
authors.forename: Su-Zhen
authors.initials: SZ
authors.lastname: Huang
authors.affiliation: Public Health Institute of Fujian Medical University, Fuzhou, Fujian Province, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China.
authors.forename: Xiao-Lan
authors.initials: XL
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China.
authors.forename: Yuan-Zhi
authors.initials: YZ
authors.lastname: Xie
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China okoklwp@126.com.
authors.forename: Wen-Ping
authors.initials: WP
authors.lastname: Lin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003993:Dibutyl Phthalate / Q000633:toxicity*; D015536:Down-Regulation; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D006107:Granulosa Cells / Q000187:drug effects* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D010968:Plasticizers / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D011962:Receptors, FSH / Q000378:metabolism*; D019089:Stem Cell Factor / Q000378:metabolism
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010968:Plasticizers; D011962:Receptors, FSH; D019089:Stem Cell Factor; D003993:Dibutyl Phthalate; D005640:Follicle Stimulating Hormone
keywords: Kit ligand; dibutyl phthalate; follicle-stimulating hormone (FSH/FSH receptor); granulosa cells; hypoxia-inducible factor 1-alpha