Alteration of the Neuroendocrine Control of Puberty after Postnatal Exposure to Bisphenol a and Involvement of GPR151, a Potential New Regulator of the GnRH Network
Presentation Number: OR19-5
Date of Presentation: April 4th, 2017
Delphine Franssen*1, Nadine Dupuis2, David Lopez Rodriguez1, Arlette Gerard1, Julien Hanson2, Jean-Pierre J Bourguignon1 and Anne Simone Parent1
1Developmental Neuroendocrinology Unit, GIGA Neurosciences, University of Liège, Liège, Belgium, 2University of Liège, Liege, Belgium
Bisphenol A (BPA) is a ubiquitous endocrine disrupting chemical that has been shown to alter pubertal timing. The endocrine disrupting effects of low BPA doses, in the ng and µg ranges, are a matter of controversy, while these doses correspond to human environmental exposure. Last year, we demonstrated that an early postnatal exposure (PND 1 – 15) to a very low dose of BPA disturbed the neuroendocrine sexual maturation in female rat through altered GABAergic neurotransmission. A dose of 25 ng/kg/d induced a delay of maturation of GnRH secretion associated with an increased GABAergic tone at PND 20. We observed opposite effects, acceleration of GnRH secretion and decrease of GABAergic tone, after a higher dose of 5 mg/kg/d at PND20 (Franssen et al, 2016). At the same age, RNAsequencing analysis of mediobasal hypothalamus mRNAs revealed that several genes were affected by these two doses of BPA. We showed that GPR151 was the gene most affected in opposite direction by the 2 doses of BPA. Levels of mRNA coding for GPR151 increased after the low dose of BPA (1.78 ± 0.21 vs 1.00 ± 0.24; P < 0.05 ; n = 8 per group) and decreased after the high dose (0.28 ± 0.17 vs 1.00 ± 0.24 ; P < 0.05 ; n = 8 per group). We described for the first time that this orphan GPCR sharing sequence homology with GPR54 was expressed in the fibers of GnRH neurons in the median eminence of pubertal and adult female rats. In this region, GPR151 mRNA expression increased throughout postnatal development, with significant differences between PND 15 (1.00 ± 0.51) versus PND 25 (3.94 ± 0.49; P < 0.01) and PND 80 (5.32 ± 0.80; P < 0.001). Because β-arrestin is responsible for GPCR internalization after GPCR activation by a ligand, we analysed the capacity of several neuropeptides (kisspeptin, galanin and RFRP3) to activate the receptor and induce the recruitment of β-arrestin 2 using a β-arrestin recruitment assay. None of these peptides induced this recruitment but we identified a high constitutive activity for GPR151. To test the potential involvement of GPR151 in GnRH release, we overexpressed GPR151 in an immortalized GnRH cell line (GnV3 cells) and observed that it leaded to a significant increase of GnRH release from these cells (3.30 ± 0.06 pg/ml vs 2.00 ± 0.05 pg/ml; P < 0.01; n = 10 per group). In conclusion, early postnatal exposure to very low dose of BPA altered the onset of puberty in female rats through disruption of the GnRH release. This effect could involve changes in expression of a potential new regulator of the GnRH network, GPR151.
Nothing to Disclose: DF, ND, DL, AG, JH, JPJB, ASP