Hexabromocyclododecane facilitates FSH activation

Authors: Svetlana Fa Dragana Samardzija Ljubica Odzic Kristina PogrmicMajkic Sonja Kaisarevic Radmila Kovacevic Nebojsa Andric

Publish Date: 2013/09/27

Volume: 88, Issue: 2, Pages: 345-354

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Abstract

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 folliclestimulating hormone FSHdriven cell proliferation and differentiation Here we show that HBCDD affects the FSHdriven signal transduction and ovulatory competence of granulosa cells We found that HBCDD overactivates the FSHstimulated extracellularregulated 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 mitogenregulated kinase activity with U0126 completely prevented ERK1/2 activation in the FSHstimulated and HBCDDexposed granulosa cells Moreover AG1478 restored the HBCDDinduced AKT activation to the level observed in the FSHstimulated cells Western blot shows that HBCDD potentiates FSHstimulated EGFR phosphorylation in granulosa cells Realtime PCR demonstrates that HBCDD decreases the FSHinduced luteinizing hormone receptor Lhr expression Inadequate level of LHR in the HBCDDexposed 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 FSHstimulated and HBCDDexposed granulosa cells These results indicate a direct effect of HBCDD on EGFR activation resulting in overactivation of ERK1/2 and AKT signal transduction pathways in the FSHtreated cells Increased activity of the EGFRERK1/2 pathway above physiological level prevents sufficient acquisition of LHR in proliferating granulosa cells thus compromising ovulationThis work was supported by the grants from the European Commission Research Executive Agency PCIG112012321745 to NA Serbian Ministry of Education and Science and Secretariat of Autonomic Province of Vojvodina Republic of Serbia Grant Numbers 173037 and 257 respectively The authors are grateful to G D Niswender Colorado State University for the supply of estradiol and progesterone antiserum The authors wish to thank Bojana Stanic for her assistance in English language editing

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