In vitro exposure to xenoestrogens induces growth hormone transcription and release via estrogen receptor-dependent pathways in rat pituitary GH3 cells.
In this study, we employed an in vitro model to examine the effects of endocrine disruptors (EDs) in the regulation of growth hormone (GH) gene, an important hormone in growth, development and body composition. The rat pituitary cells, GH3, were treated with alkyl-phenols (APs), i.e., 4-tert-octyl-phenol (OP), p-nonyl-phenol (NP) or bisphenol A (BPA) for 24h in a dose-dependent manner (10(-5), 10(-6) and 10(-7)M) and in a time-dependent fashion (1, 3, 6, 12 and 24h) at a high concentration (10(-5)M). An anti-estrogen, ICI 182,780, was used to examine the potential involvement of estrogen receptor (ER) in the induction of GH by EDs through an ER-mediated pathway. Treatment with OP, NP and BPA induced a significant increase in GH gene expression at high and medium doses at 24h. ED-exposure induced a marked increase in GH gene transcription as early as 6h and peaked at 12h. Co-treatment with ICI 182,780 significantly attenuated ED-induced GH expression in GH3 cells. Interestingly, the level of in vitro GH release was significantly increased at 24h in response to OP, NP or BPA, whereas co-treatment with ICI 182,780 significantly reversed ED-induced GH secretion, indicating that ER may take part in both GH gene transcription and its release in these cells. In addition, the activation of extracellular signal-regulated kinases (ERKs), protein kinases B (Akt) or G protein in response to OP, NP or BPA at 24h was observed in this study. Exposure to these APs resulted in a rapid and significant activation of ERK phosphorylation, reflecting that EDs-induced response may involve both genomic and non-genomic pathways in these cells. Taken together, these results may provide new insight into the mode of ED-induced action in GH gene regulation as well as the biological pathway underlying these molecular events.
Dang
Vu Hoang
VH
Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
Nguyen
Thi Hoa
TH
Lee
Geun-Shik
GS
Choi
Kyung-Chul
KC
Jeung
Eui-Bae
EB
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D000077267:Fulvestrant; D005786:Gene Expression Regulation / Q000187:drug effects; D013006:Growth Hormone / Q000235:genetics*; D010636:Phenols / Q000494:pharmacology*; D010902:Pituitary Gland / Q000166:cytology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*
D052244:Endocrine Disruptors; D010636:Phenols; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; D013006:Growth Hormone