Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, USA.
Toxicol Sci. 2012 Oct;129(2):235-48. doi: 10.1093/toxsci/kfs206. Epub 2012 Jun 14.
For over 15 years, reproductive toxicologists have explored the physiological outcomes and mechanism of fetal phthalate exposure to determine the risk posed to human male reproductive health. This review examines the fetal male reproductive system response to phthalate exposure across species including rat, mouse, and human, with emphasis on the testis. In the rat, in utero phthalate exposure causes male reproductive tract malformations, in large part, by targeting the testis and inhibiting fetal Leydig cell hormone production. Despite mouse phthalate pharmacokinetics being similar to the rat, inhibition of fetal Leydig cell hormone synthesis is not observed in the mouse. The species-specific differences in testicular response following in utero phthalate exposure and the discordant reaction of the rodent fetal testis when exposed to phthalates ex vivo versus in vivo have made determining risk to humans difficult, yet critically important. The recent use of fetal testis xenotransplants to study phthalate toxicity suggests that the human fetal testis responds like the mouse fetal testis; it appears refractory to phthalate-induced inhibition of testosterone production. Although this result is unfulfilling from the perspective of identifying environmental contributions to human reproductive maldevelopment, it has important implications for phthalate risk assessment.
15 多年来，生殖毒理学家一直在探索胎儿接触邻苯二甲酸酯的生理后果和机制，以确定其对人类男性生殖健康的风险。本综述考察了包括大鼠、小鼠和人类在内的不同物种中胎儿雄性生殖系统对邻苯二甲酸酯暴露的反应，重点是睾丸。在大鼠中，宫内邻苯二甲酸酯暴露导致雄性生殖道畸形，这在很大程度上是通过靶向睾丸并抑制胎儿睾丸间质细胞激素产生来实现的。尽管小鼠邻苯二甲酸酯的药代动力学与大鼠相似，但在小鼠中未观察到胎儿睾丸间质细胞激素合成的抑制。在宫内接触邻苯二甲酸酯后，睾丸的反应在物种间存在差异，并且在体内和体外暴露于邻苯二甲酸酯时，啮齿动物胎儿睾丸的反应不一致，这使得确定对人类的风险变得困难，但又至关重要。最近使用胎儿睾丸异种移植来研究邻苯二甲酸酯毒性表明，人类胎儿睾丸的反应与小鼠胎儿睾丸相似；它似乎对邻苯二甲酸酯诱导的睾酮产生抑制具有抗性。尽管从确定环境对人类生殖发育异常的贡献的角度来看，这一结果并不令人满意，但它对邻苯二甲酸酯风险评估具有重要意义。
