PMID- 24071787 OWN - NLM STAT- MEDLINE DCOM- 20140930 LR - 20181203 IS - 1432-0738 (Electronic) IS - 0340-5761 (Linking) VI - 88 IP - 2 DP - 2014 Feb TI - Hexabromocyclododecane facilitates FSH activation of ERK1/2 and AKT through epidermal growth factor receptor in rat granulosa cells. PG - 345-54 LID - 10.1007/s00204-013-1133-2 [doi] AB - The toxicity of hexabromocyclododecane (HBCDD) has been extensively studied; however, the mechanism and the effects of HBCDD on female reproductive system have been less frequently reported. In this study, we exposed rat granulosa cells to HBCDD during in vitro follicle-stimulating hormone (FSH)-driven cell proliferation and differentiation. Here, we show that HBCDD affects the FSH-driven signal transduction and ovulatory competence of granulosa cells. We found that HBCDD over-activates the FSH-stimulated extracellular-regulated kinase 1/2 (ERK1/2) and protein kinase B (PKB, also known as AKT). Inactivation of the epidermal growth factor receptor (EGFR) kinase activity with AG1478 and the mitogen-regulated kinase activity with U0126 completely prevented ERK1/2 activation in the FSH-stimulated and HBCDD-exposed granulosa cells. Moreover, AG1478 restored the HBCDD-induced AKT activation to the level observed in the FSH-stimulated cells. Western blot shows that HBCDD potentiates FSH-stimulated EGFR phosphorylation in granulosa cells. Real-time PCR demonstrates that HBCDD decreases the FSH-induced luteinizing hormone receptor (Lhr) expression. Inadequate level of LHR in the HBCDD-exposed granulosa cells prevented human chorionic gonadotropin in stimulating expression of the ovulatory genes such as amphiregulin (Areg), epiregulin (Ereg), and progesterone receptor (Pgr). Addition of U0126 and AG1478 restored Lhr level in the FSH-stimulated and HBCDD-exposed granulosa cells. These results indicate a direct effect of HBCDD on EGFR activation, resulting in over-activation of ERK1/2 and AKT signal transduction pathways in the FSH-treated cells. Increased activity of the EGFR-ERK1/2 pathway above physiological level prevents sufficient acquisition of LHR in proliferating granulosa cells, thus compromising ovulation. FAU - Fa, Svetlana AU - Fa S AD - Laboratory for Ecotoxicology, Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, 2 Dositeja Obradovica Square, 21000, Novi Sad, Serbia. FAU - Samardzija, Dragana AU - Samardzija D FAU - Odzic, Ljubica AU - Odzic L FAU - Pogrmic-Majkic, Kristina AU - Pogrmic-Majkic K FAU - Kaisarevic, Sonja AU - Kaisarevic S FAU - Kovacevic, Radmila AU - Kovacevic R FAU - Andric, Nebojsa AU - Andric N LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130927 PL - Germany TA - Arch Toxicol JT - Archives of toxicology JID - 0417615 RN - 0 (Butadienes) RN - 0 (Hydrocarbons, Brominated) RN - 0 (Nitriles) RN - 0 (Quinazolines) RN - 0 (Receptors, LH) RN - 0 (Tyrphostins) RN - 0 (U 0126) RN - 170449-18-0 (RTKI cpd) RN - 5I9835JO3M (hexabromocyclododecane) RN - 9002-68-0 (Follicle Stimulating Hormone) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Butadienes/pharmacology MH - Cells, Cultured MH - ErbB Receptors/antagonists & inhibitors/*metabolism MH - Female MH - Follicle Stimulating Hormone/*pharmacology MH - Gene Expression Regulation/drug effects MH - Granulosa Cells/*drug effects/metabolism MH - Hydrocarbons, Brominated/*toxicity MH - MAP Kinase Signaling System/drug effects MH - Nitriles/pharmacology MH - Phosphorylation/drug effects MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Quinazolines MH - Rats MH - Rats, Wistar MH - Receptors, LH/genetics MH - Toxicity Tests/methods MH - Tyrphostins EDAT- 2013/09/28 06:00 MHDA- 2014/10/01 06:00 CRDT- 2013/09/28 06:00 PHST- 2013/05/28 00:00 [received] PHST- 2013/09/12 00:00 [accepted] PHST- 2013/09/28 06:00 [entrez] PHST- 2013/09/28 06:00 [pubmed] PHST- 2014/10/01 06:00 [medline] AID - 10.1007/s00204-013-1133-2 [doi] PST - ppublish SO - Arch Toxicol. 2014 Feb;88(2):345-54. doi: 10.1007/s00204-013-1133-2. Epub 2013 Sep 27.