Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro
Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro
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DOI：
10.1093/humrep/det112
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发表时间：
2013-07-01
影响因子：
6.1
通讯作者：
Jegou, B.
中科院分区：
文献类型：
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作者：
Albert, O.;Desdoits-Lethimonier, C.;Jegou, B.
轻度镇痛药对成人睾丸内分泌系统有影响吗？轻度镇痛剂可引起离体成人睾丸多种内分泌紊乱，近来被认为是潜在的内分泌干扰物。这些广泛使用的分子对男性雄激素状态的影响的研究是有限的，有些矛盾。这促使我们研究这些化合物是否可以改变成年人睾丸功能。因此，我们平行评估了扑热息痛、阿司匹林和吲哚美辛对器官培养的成人睾丸和产生类固醇的NCI-H295 R人细胞系的影响。成人睾丸外植体或NCI-H295 R肾上腺皮质人细胞与10（4）或10（5）M扑热息痛、阿司匹林或吲哚美辛一起培养2448小时。10（5）M酮康唑作为抗雄激素参照分子的作用也被评估。睾丸取自未接受任何激素治疗的前列腺癌患者。该方案由法国雷恩的当地伦理委员会批准，并由供体给予知情同意。本研究中仅使用了通过透照评估显示精子发生的睾丸。通过放射免疫测定法（睾酮、胰岛素样因子3）、酶联免疫吸附测定法（抑制素B）或酶免疫吸附测定法[前列腺素（PG）D2和PGE 2]测定培养基中的激素水平。用经典的免疫组织化学方法观察睾丸组织和细胞计数。三种轻度镇痛药引起成年人睾丸内分泌的多种紊乱。这在间质室中尤其明显。有效剂量与标准镇痛治疗后血浆中测量的剂量范围相同。睾丸间质细胞的睾酮和胰岛素样因子3的产生通过暴露于所有这些药物而改变。抑制素B生产的支持细胞的影响不大，阿司匹林。我们的实验还表明，轻度镇痛剂显示直接的抗PG活性，这取决于所使用的药物，剂量和暴露的持续时间。然而，PG和睾酮配置文件的改变之间的关联并没有系统地观察到，这表明内分泌干扰的机制相结合是在play.Our研究是在vitro进行的，我们提供的第一个证据表明，直接暴露于温和的镇痛剂可以导致在人类成年睾丸的多种内分泌紊乱。应加强对男性使用轻度镇痛剂的注意，特别是在高风险人群亚组，如优秀运动员中。国家卫生和医学研究所（Ecole des Hautes Etudes en Sant Publique），Ministre de lEnseignement Suprieur et de la Recherche，布列塔尼大区和国家医药和卫生产品管理局（IMPACTESTIS，项目编号AAP-2012-037）。提交人声明，他们没有任何竞争利益，无论是财务、个人还是专业利益。
Do mild analgesics affect the endocrine system of the human adult testis?Mild analgesics induce multiple endocrine disturbances in the human adult testis in vitro.Mild analgesics have recently been incriminated as potential endocrine disruptors. Studies of the effects of these widely used molecules on the androgenic status of men are limited and somewhat contradictory. This prompted us to investigate whether these compounds could alter the adult human testicular function. We therefore assessed in parallel the effects of paracetamol, aspirin and indomethacin on organo-cultured adult human testis and on the NCI-H295R steroid-producing human cell line.Adult human testis explants or NCI-H295R adrenocortical human cells were cultured with 10(4) or 10(5) M paracetamol, aspirin or indomethacin for 2448 h. The effect of 10(5) M ketoconazole, used as an anti-androgenic reference molecule, was also assessed.Testes were obtained from prostate cancer patients, who had not received any hormone therapy. The protocol was approved by the local ethics committee of Rennes, France and informed consent was given by the donors. Only testes displaying spermatogenesis, as assessed by transillumination, were used in this study. Hormone levels in the culture media were determined by radioimmunoassay (testosterone, insulin-like factor 3), Enzyme-Linked Immunosorbent Assay (inhibin B) or Enzyme Immunosorbent Assay [prostaglandin (PG) D2, and PGE2]. Tissues were observed and cells counted using classical immunohistochemical methods.The three mild analgesics caused multiple endocrine disturbances in the adult human testis. This was particularly apparent in the interstitial compartment. Effective doses were in the same range as those measured in blood plasma following standard analgesic treatment. The production of testosterone and insulin-like factor 3 by Leydig cells was altered by exposure to all these drugs. Inhibin B production by Sertoli cells was marginally affected by aspirin only. Our experiments also revealed that mild analgesics display direct anti-PG activity, which varied depending on the drug used, the dose and the duration of exposure. Nevertheless, associations between the alteration of the PG and testosterone profiles were not systematically observed, suggesting that a combination of mechanisms of endocrine disruption is at play.Our studies were performed in vitro.We provide the first evidence that direct exposure to mild analgesics can result in multiple endocrine disturbances in the human adult testis. Caution, concerning the consumption of mild analgesics by men, should be strengthened, particularly in high-risk population subgroups such as elite athletes.This work was funded by Inserm (Institut national de la sant et de la recherche mdicale), EHESP (Ecole des Hautes Etudes en Sant Publique), Ministre de lEnseignement Suprieur et de la Recherche, Rgion Bretagne and Agence Nationale de scurit du mdicament et des produits de sant (IMPACTESTIS, Project no. AAP-2012-037). The authors declare they have no competing interests, be it financial, personal or professional.