Delayed Neuroendocrine Sexual Maturation in Female Rats After a Very Low Dose of Bisphenol A Through Altered GABAergic Neurotransmission and Opposing Effects of a High Dose
Delayed Neuroendocrine Sexual Maturation in Female Rats After a Very Low Dose of Bisphenol A Through Altered GABAergic Neurotransmission and Opposing Effects of a High Dose
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DOI：
10.1210/en.2015-1937
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发表时间：
2016-05-01
期刊：
影响因子：
4.8
通讯作者：
Parent, Anne-Simone
中科院分区：
文献类型：
--
作者：
Franssen, Delphine;Gerard, Arlette;Parent, Anne-Simone
大鼠性成熟之前，GnRH神经分泌的脉冲间隔（IPI）的减少。这项工作的目的是研究早期暴露于非常低剂量的双酚A（BPA），一种普遍存在的内分泌干扰化学物质后，女性神经内分泌事件的中断。雌性大鼠从出生后第1天（PND）至PND 5或PND 15暴露于溶剂或BPA 25 ng/kg.d、25 μ g/kg.d或5 mg/kg.d。暴露于25 ng/kg.d BPA 5或15天后，在PND 20离体研究GnRHIPI发育减少延迟。在暴露于低剂量BPA 15天后，阴道开放倾向于延迟。相反，暴露于BPA 5 mg/kg.d 15天导致GnRH IPI过早降低和阴道早期开放的趋势。PND 20的RNA测序分析表明，BPA暴露对下丘脑参与γ-氨基丁酸A（GABA（A））神经传递的基因的mRNA表达产生相反的剂量效应。在GABA（A）受体激动剂/拮抗剂存在下的体外GnRH分泌研究证实，分别在体内暴露于极低或高剂量BPA后，GABA能张力增加或减少。总体而言，我们首次表明，新生儿暴露于双酚A导致相反的剂量依赖性影响的神经内分泌控制的青春期雌性大鼠。一个非常低的和环境相关剂量的BPA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。
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 mu g/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 GnRHIPI 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 (GABA(A)) neurotransmission. The study of GnRH secretion in vitro in the presence of GABA(A) 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.