Rouiller-Fabre Virginie, Guerquin Marie Justine, N'Tumba-Byn Thierry, Muczynski Vincent, Moison Delphine, Tourpin Sophie, Messiaen Sébastien, Habert René, Livera Gabriel
Unit of Genetic Stability, Stem Cells and Radiation, Laboratory of Development of the Gonads, Sorbonne Paris Cité, Université Paris Diderot , Fontenay-aux-Roses , France ; CEA, DSV, iRCM, SCSR, LDG , Fontenay-aux-Roses , France ; Unité 967, INSERM , Fontenay aux Roses , France.
Front Endocrinol (Lausanne). 2015 May 7;6:58. doi: 10.3389/fendo.2015.00058. eCollection 2015.
During the last decades, many studies reported that male reproductive disorders are increasing among humans. It is currently acknowledged that these abnormalities can result from fetal exposure to environmental chemicals that are progressively becoming more concentrated and widespread in our environment. Among the chemicals present in the environment (air, water, food, and many consumer products), several can act as endocrine disrupting compounds (EDCs), thus interfering with the endocrine system. Phthalates, bisphenol A (BPA), and diethylstilbestrol (DES) have been largely incriminated, particularly during the fetal and neonatal period, due to their estrogenic and/or anti-androgenic properties. Indeed, many epidemiological and experimental studies have highlighted their deleterious impact on fetal and neonatal testis development. As EDCs can affect many different genomic and non-genomic pathways, the mechanisms underlying the adverse effects of EDC exposure are difficult to elucidate. Using literature data and results from our laboratory, in the present review, we discuss the role of classical nuclear receptors (genomic pathway) in the fetal and neonatal testis response to EDC exposure, particularly to phthalates, BPA, and DES. Among the nuclear receptors, we focused on some of the most likely candidates, such as peroxisome-proliferator activated receptor (PPAR), androgen receptor (AR), estrogen receptors (ERα and β), liver X receptors (LXR), and small heterodimer partner (SHP). First, we describe the expression and potential functions (based on data from studies using receptor agonists and mouse knockout models) of these nuclear receptors in the developing testis. Then, for each EDC studied, we summarize the main evidences indicating that the reprotoxic effect of each EDC under study is mediated through a specific nuclear receptor(s). We also point-out the involvement of other receptors and nuclear receptor-independent pathways.
在过去几十年中，许多研究报告称人类男性生殖障碍正在增加。目前人们认识到，这些异常可能源于胎儿在子宫内接触环境化学物质，而这些化学物质在我们的环境中正变得越来越浓缩和广泛存在。在环境（空气、水、食物和许多消费品）中存在的化学物质中，有几种可作为内分泌干扰化合物（EDC），从而干扰内分泌系统。邻苯二甲酸盐、双酚A（BPA）和己烯雌酚（DES）一直备受指责，尤其是在胎儿期和新生儿期，因为它们具有雌激素和/或抗雄激素特性。事实上，许多流行病学和实验研究都强调了它们对胎儿和新生儿睾丸发育的有害影响。由于EDC可影响许多不同的基因组和非基因组途径，因此难以阐明EDC暴露产生不良影响的潜在机制。在本综述中，我们利用文献数据和我们实验室的研究结果，讨论经典核受体（基因组途径）在胎儿和新生儿睾丸对EDC暴露（特别是对邻苯二甲酸盐、BPA和DES）的反应中的作用。在核受体中，我们重点关注了一些最有可能的候选者，如过氧化物酶体增殖物激活受体（PPAR）、雄激素受体（AR）、雌激素受体（ERα和β）、肝X受体（LXR）和小异二聚体伴侣（SHP）。首先，我们描述这些核受体在发育中的睾丸中的表达和潜在功能（基于使用受体激动剂和小鼠基因敲除模型的研究数据）。然后，对于每种研究的EDC，我们总结了主要证据，表明每种所研究的EDC的生殖毒性作用是通过一种或多种特定核受体介导的。我们还指出了其他受体和非核受体依赖性途径的参与情况。
