Reproductive malformation of the male offspring following maternal exposure to estrogenic chemicals
Reproductive malformation of the male offspring following maternal exposure to estrogenic chemicals
复制标题
DOI：
10.1046/j.1525-1373.2000.22402.x
复制
发表时间：
2000-06-01
影响因子：
--
通讯作者：
Gupta, C
中科院分区：
文献类型：
--
作者：
Gupta, C
近期，人们对具有持久雌激素活性的化学物质的广泛使用及其对人类健康的长期影响给予了极大关注。在本次研究中，我们探讨了胎儿在人类所接触的剂量下暴露于某些此类化学物质时，是否会对雄性后代的生殖功能产生长期影响。因此，在妊娠第16 - 18天，给怀孕的CD - 1小鼠分别喂食己烯雌酚（DES）、双酚A（BPA）和多氯联苯（Aroclor 1016），平均浓度分别为100纳克/千克/天、50微克/千克/天和50微克/千克/天。还测试了高剂量的DES（200微克/千克/天），以便将本研究结果与其他仅使用高剂量的研究结果进行比较。在出生后的第3天、第21天和第60天对后代进行检查。我们发现，BPA、多氯联苯和低剂量的DES增加了肛门与生殖器之间的距离，增大了前列腺体积，并降低了附睾重量。对睾丸重量或大小没有影响。在该剂量下，这些化学物质还永久性地提高了前列腺的雄激素受体（AR）结合活性。这首次证明环境化学物质在普通人群所接触的剂量下会永久性地影响AR功能。另一方面，高剂量的DES产生了相反的效果，降低了前列腺重量、前列腺AR结合以及肛门与生殖器之间的距离，从而证实了先前的报道。为了研究上述化学物质的影响是直接的还是间接的，我们还测试了这些化学物质在体外对前列腺发育的影响。因此，在妊娠第17天分离出的胎儿泌尿生殖窦（UGS）在有和无睾酮（10纳克/毫升）的情况下与化学物质一起培养6天，并通过组织学方法确定样本的大小和分支来监测前列腺的生长。结果表明，这些化学物质在有和无睾酮的情况下都能诱导前列腺生长。它们还提高了雄激素结合活性。因此，体内研究的结果在体外实验中得到了重现，表明这些化学物质对胎儿生殖器官的发育有直接影响。这首次证明雌激素类化学物质是通过直接干扰胎儿生殖器官而非干扰母体或胎儿内分泌系统来诱导生殖畸形的。这些化学物质即使在没有胎儿睾酮的情况下也能诱导畸形；然而，在有睾酮的情况下它们更有效。
Recently, significant concerns have been placed on the widespread use of chemicals with persistent estrogenic activity for their long-term effects on human health. In this communication, we investigated whether fetal exposure to some of these chemicals at doses consumed by people, has any long-term effect on the reproductive functions of the male offspring. Thus, time-pregnant CD-1 mice were fed diethylstilbestrol (DES), bisphenol A (BPA), and aroclor (aroclor 1016) at an average concentration of 100 ng/kg/day, 50 mu g/kg/day, and 50 mu g/kg/day, respectively, during Days 16-18 of gestation. A high dose of DES (200 mu g/kg/day) was also tested to compare the results of the current study with those of others using the high dose only. The offspring were examined at Day 3, Day 21, and Day 60 following birth. We demonstrated that BPA, aroclor, and the lower dose of DES enhanced anogenital distance, increased prostate sire, and decreased epididymal weight. No effect was found on the testicular weight or size. The chemicals also permanently increased androgen receptor (AR) binding activity of the prostate at this dosage. This is the first demonstration that environmental chemicals program AR function permanently at the dosage consumed by the general population. The higher dosage of DES, on the other hand, produced an opposite effect, decreasing prostate weight, prostate AR binding, and anogenital distance, thus confirming the previous reports. To investigate whether the above mentioned effects of the chemicals represent direct or indirect effects, we also tested the effect of the chemicals on prostate development in vitro. Thus fetal urogenital sinus (UGS), isolated at the 17th day of gestation was cultured with the chemicals in the presence and absence of testosterone (10 ng/ml) for 6 days, and prostate growth was monitored by determining the size and branching of the specimen following histology. Results showed that these chemicals induced prostate growth in the presence and absence of testosterone. They also increased androgen-binding activity. Thus, the results of the in vivo studies were reproduced in the in vitro experiments, suggesting a direct effect of these chemicals on the development of fetal reproductive organs. This is the first demonstration that estrogenic chemicals induce reproductive malformation by direct interference with the fetal reproductive organs and not by interfering with the maternal or fetal endocrine system. The chemicals are able to induce malformation even in the absence of fetal testosterone; however, they are more effective in the presence of testosterone.