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3350311 
Journal Article 
Dibutyl Phthalate Inhibits the Effects of Follicle-Stimulating Hormone on Rat Granulosa Cells Through Down-Regulation of Follicle-Stimulating Hormone Receptor 
Wang, XJ; Xiong, GP; Luo, XM; Huang, SZ; Liu, J; Huang, XL; Xie, YZ; Lin, WP 
2016 
Yes 
Biology of Reproduction
ISSN: 0006-3363
EISSN: 1529-7268 
Biol Reprod. 
94 
6 
144 
English 
26962121 
WOS:000379572800020 
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. 
Animals; Cells, Cultured; Dibutyl Phthalate/toxicity; Down-Regulation; Follicle Stimulating Hormone/metabolism; Granulosa Cells/drug effects/metabolism; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism; Plasticizers/toxicity; Rats, Sprague-Dawley; Receptors, FSH/metabolism; Stem Cell Factor/metabolism; Kit ligand; dibutyl phthalate; follicle-stimulating hormone (FSH/FSH receptor); granulosa cells; hypoxia-inducible factor 1-alpha; 2286E5R2KE; 9002-68-0 
IRIS
• Dibutyl Phthalate (DBP)
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