Medical Research Council/University of Edinburgh Centre for Reproductive Health, The Queen's Medical Research Institute, Edinburgh Royal Hospital for Sick Children, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom.
J Clin Endocrinol Metab. 2012 Mar;97(3):E341-8. doi: 10.1210/jc.2011-2411. Epub 2012 Jan 11.
Phthalates are ubiquitous environmental chemicals. Fetal exposure to certain phthalates [e.g. di-n-butyl phthalate (DBP)] causes masculinization disorders in rats, raising concern for similar effects in humans. We investigated whether DBP exposure impairs steroidogenesis by the human fetal testis.
The aim of the study was to determine effects of DBP exposure on testosterone production by normally growing human fetal testis xenografts.
Human fetal testes (14-20 wk gestation; n=12) were xenografted into castrate male nude mice that were treated for 4-21 d with vehicle, or 500 mg/kg·d DBP, or monobutyl phthalate (active metabolite of DBP); all mice were treated with human chorionic gonadotropin to mimic normal human pregnancy. Rat fetal testis xenografts were exposed for 4 d to DBP as a positive control.
Testosterone production was assessed by measuring host serum testosterone and seminal vesicle (SV) weights at termination, plus testis gene expression (rats).
Human fetal testis xenografts showed similar survival (∼80%) and total graft weight (8.6 vs. 10.1 mg) in vehicle and DBP-exposed hosts, respectively. Serum testosterone (0.56 vs. 0.64 ng/ml; P>0.05) and SV weight (67.2 vs. 81.9 mg; P>0.05) also did not differ. Exposure to monobutyl phthalate gave similar results. In contrast, exposure of rat fetal xenografts to DBP significantly reduced SV weight and testis Cyp11a1/StAR mRNA expression and lowered testosterone levels, confirming that DBP exposure can inhibit steroidogenesis in xenografts, further validating the negative findings on testosterone production in the human.
Exposure of human fetal testes to DBP is unlikely to impair testosterone production as it does in rats. This has important safety and regulatory implications.
邻苯二甲酸酯是普遍存在的环境化学物质。胎儿暴露于某些邻苯二甲酸酯（如邻苯二甲酸二丁酯（DBP））会导致大鼠出现雄性化障碍，这引起了人们对人类出现类似影响的担忧。我们研究了 DBP 暴露是否会损害人胎儿睾丸的类固醇生成。
本研究旨在确定 DBP 暴露对正常生长的人胎儿睾丸异种移植物产生睾酮的影响。
将人胎儿睾丸（14-20 周妊娠；n=12）异种移植到去势雄性裸鼠体内，这些裸鼠在 4-21 天内用载体、500mg/kg·d DBP 或邻苯二甲酸单丁酯（DBP 的活性代谢物）处理；所有小鼠均用人绒毛膜促性腺激素处理以模拟正常的人类妊娠。将大鼠胎儿睾丸异种移植物暴露于 DBP 4 天作为阳性对照。
通过测量终止时宿主血清睾酮和精囊（SV）重量，以及睾丸基因表达（大鼠）来评估睾酮的产生。
在载体和 DBP 暴露的宿主中，人胎儿睾丸异种移植物的存活率（分别约为 80%和 8.6mg）和总移植物重量（分别为 8.6 和 10.1mg）相似。血清睾酮（0.56 与 0.64ng/ml；P>0.05）和 SV 重量（67.2 与 81.9mg；P>0.05）也没有差异。暴露于邻苯二甲酸单丁酯也得到了类似的结果。相比之下，DBP 暴露显著降低了大鼠胎儿异种移植物的 SV 重量和睾丸 Cyp11a1/StARmRNA 表达，并降低了睾酮水平，证实 DBP 暴露可抑制异种移植物中的类固醇生成，进一步验证了人胎儿睾酮产生的阴性结果。
DBP 暴露于人胎儿睾丸不太可能像在大鼠中那样损害睾酮的产生。这具有重要的安全性和监管意义。
