Franssen Delphine, Gérard Arlette, Hennuy Benoit, Donneau Anne-Françoise, Bourguignon Jean-Pierre, Parent Anne-Simone
Neuroendocrinology Unit (D.F., A.G., J.-P.B., A.-S.P.), Interdisciplinary Cluster for Applied Genoproteomics Neurosciences; Interdisciplinary Cluster for Applied Genoproteomics Transcriptomic Platform (B.H.); and Department of Public Health (A.-F.D.), Biostatistics Unit, University of Liège, Sart-Tilman, B-4000 Liège, Belgium; and Department of Pediatrics (A.G., J.-P.B., A.-S.P.), Centre Hospitalier Universitaire de Liège, B-4032 Chênée, Belgium.
Endocrinology. 2016 May;157(5):1740-50. doi: 10.1210/en.2015-1937. Epub 2016 Mar 7.
Rat sexual maturation is preceded by a reduction of the interpulse interval (IPI) of GnRH neurosecretion. This work aims at studying disruption of that neuroendocrine event in females after early exposure to a very low dose of bisphenol A (BPA), a ubiquitous endocrine disrupting chemical. Female rats were exposed to vehicle or BPA 25 ng/kg·d, 25 μg/kg·d, or 5 mg/kg·d from postnatal day (PND)1 to PND5 or PND15. Exposure to 25 ng/kg·d of BPA for 5 or 15 days was followed by a delay in developmental reduction of GnRH IPI studied ex vivo on PND20. After 15 days of exposure to that low dose of BPA, vaginal opening tended to be delayed. In contrast, exposure to BPA 5 mg/kg·d for 15 days resulted in a premature reduction in GnRH IPI and a trend toward early vaginal opening. RNA sequencing analysis on PND20 indicated that exposure to BPA resulted in opposing dose effects on the mRNA expression of hypothalamic genes involved in gamma aminobutyric acid A (GABAA) neurotransmission. The study of GnRH secretion in vitro in the presence of GABAA receptor agonist/antagonist confirmed an increased or a reduced GABAergic tone after in vivo exposure to the very low or the high dose of BPA, respectively. Overall, we show for the first time that neonatal exposure to BPA leads to opposing dose-dependent effects on the neuroendocrine control of puberty in the female rat. A very low and environmentally relevant dose of BPA delays neuroendocrine maturation related to puberty through increased inhibitory GABAergic neurotransmission.
大鼠性成熟之前，促性腺激素释放激素（GnRH）神经分泌的脉冲间期（IPI）会缩短。本研究旨在探究雌性大鼠在早期暴露于极低剂量双酚A（BPA，一种普遍存在的内分泌干扰化学物质）后，该神经内分泌事件的破坏情况。从出生后第（PND）1天至PND5或PND15，将雌性大鼠暴露于赋形剂或25 ng/kg·d、25 μg/kg·d或5 mg/kg·d的双酚A中。在PND20对离体研究的GnRH IPI发育性缩短进行观察，结果显示，暴露于25 ng/kg·d双酚A 5天或15天后，该指标出现延迟。暴露于该低剂量双酚A 15天后，阴道开口有延迟倾向。相比之下，暴露于5 mg/kg·d双酚A 15天导致GnRH IPI过早缩短，并有阴道开口提前的趋势。对PND20进行的RNA测序分析表明，暴露于双酚A会对参与γ-氨基丁酸A（GABAA）神经传递的下丘脑基因的mRNA表达产生相反的剂量效应。在GABAA受体激动剂/拮抗剂存在的情况下进行的体外GnRH分泌研究证实，体内暴露于极低剂量或高剂量双酚A后，GABA能张力分别增加或降低。总体而言，我们首次表明，新生期暴露于双酚A会对雌性大鼠青春期的神经内分泌控制产生相反的剂量依赖性影响。极低且与环境相关剂量的双酚A通过增加抑制性GABA能神经传递，延迟与青春期相关的神经内分泌成熟。
