Ibuprofen results in alterations of human fetal testis development.
Ibuprofen results in alterations of human fetal testis development.
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DOI：
10.1038/srep44184
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发表时间：
2017-03-10
影响因子：
4.6
通讯作者：
Jégou B
中科院分区：
文献类型：
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作者：
Ben Maamar M;Lesné L;Hennig K;Desdoits-Lethimonier C;Kilcoyne KR;Coiffec I;Rolland AD;Chevrier C;Kristensen DM;Lavoué V;Antignac JP;Le Bizec B;Dejucq-Rainsford N;Mitchell RT;Mazaud-Guittot S;Jégou B
在孕妇中，布洛芬是最常用的药物化合物之一，报告使用比例高达28%。尽管如此，布洛芬是否能像其他止痛药扑热息痛和阿司匹林那样起到内分泌干扰作用仍是个未知数。为了研究这一点，我们使用体外培养和异种移植系统，将人胎儿睾丸(7-17孕周)暴露于布洛芬。在8-9 胎龄胎儿睾丸培养过程中，布洛芬抑制了睾酮和间质细胞激素INSL3的表达，并伴随着类固醇合成酶Cyp11a1、CyP17a1和Hsd17b3以及INSL3的表达减少。在小于8 GW、大于10-12 GW的胎儿或中期妊娠(14-17 GW)的异种移植睾丸中，睾酮不受抑制。在体外，布洛芬还通过抑制AMH的产生和AMH、SOX9、DHH和COL2A1的mRNA表达而影响Sertoli细胞。布洛芬可抑制PGE2的产生，但不抑制PGD2的产生。生殖细胞转录本Pou5f1、Tfap2c、Lin28a、ALPP和KIT也被布洛芬降低。我们的结论是，在与人类接触相关的浓度下，在怀孕早期特定狭窄的敏感性窗口内，布洛芬会导致人类胎儿睾丸的直接内分泌紊乱和生殖细胞生物学的改变。
Among pregnant women ibuprofen is one of the most frequently used pharmaceutical compounds with up to 28% reporting use. Regardless of this, it remains unknown whether ibuprofen could act as an endocrine disruptor as reported for fellow analgesics paracetamol and aspirin. To investigate this, we exposed human fetal testes (7–17 gestational weeks (GW)) to ibuprofen using ex vivo culture and xenograft systems. Ibuprofen suppressed testosterone and Leydig cell hormone INSL3 during culture of 8–9 GW fetal testes with concomitant reduction in expression of the steroidogenic enzymes CYP11A1, CYP17A1 and HSD17B3, and of INSL3. Testosterone was not suppressed in testes from fetuses younger than 8 GW, older than 10–12 GW, or in second trimester xenografted testes (14–17 GW). Ex vivo, ibuprofen also affected Sertoli cell by suppressing AMH production and mRNA expression of AMH, SOX9, DHH, and COL2A1. While PGE2 production was suppressed by ibuprofen, PGD2 production was not. Germ cell transcripts POU5F1, TFAP2C, LIN28A, ALPP and KIT were also reduced by ibuprofen. We conclude that, at concentrations relevant to human exposure and within a particular narrow ‘early window’ of sensitivity within first trimester, ibuprofen causes direct endocrine disturbances in the human fetal testis and alteration of the germ cell biology.