Health Effects Analysis Team, National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration, Seoul, South Korea.
J Toxicol Environ Health A. 2010;73(21-22):1544-59. doi: 10.1080/15287394.2010.511579.
The purpose of this study was to determine the effects of di(n-butyl) phthalate (DBP) administration on male reproductive organ development in F1 Sprague-Dawley rats following in utero exposure. During gestation days (GD) 10-19, pregnant rats were administered daily, orally, DBP at 250, 500, or 700 mg/kg or flutamide (1, 12.5, or 25 mg/kg/d) as a positive control. The male offspring were sacrificed at 31 d of age. DBP and flutamide dose-dependently significantly increased the incidence of hypospadias and cryptorchidism in F1 male offspring. The weights of testes and accessory sex organs (epididymides, seminal vesicles, ventral prostate, levator ani plus bulbocavernosus muscles (LABC), and Cowper's glands) were significantly reduced in DBP-treated animals. Furthermore, cauda agenesis of epididymides and ventral prostate atrophy were observed in high-dose 700-mg/kg DBP males. Anogenital distance (AGD) and levels of dihydrotestosterone (DHT) and testosterone were significantly decreased in the DBP (700 mg/kg/d)-treated groups. In particular, the expression of androgen receptor (AR) and 5α-reductase type 2 in the proximal penis was markedly depressed following administration of DBP (700 mg/kg/d) or flutamide (25 mg/kg/d). The expression of sonic hedgehog (Shh) in the urethral epithelium of the proximal penis was significantly less in the DBP (700 mg/kg/d)- or flutamide (25 mg/kg/d)-treated groups. In addition, DBP dose-dependently significantly increased the expression of estrogen receptor (ER α) in the undescended testis. Data demonstrated that in utero exposure to DBP produced several abnormal responses in male reproductive organs, and these effects may be due to disruption of the stage-specific expression of genes related to androgen-dependent organs development.
本研究旨在探讨孕期经口给予邻苯二甲酸二正丁酯（DBP）对 F1 代 Sprague-Dawley 大鼠雄性生殖器官发育的影响。在妊娠第 10-19 天，给予怀孕大鼠每日口服 DBP（250、500 或 700mg/kg）或氟他胺（1、12.5 或 25mg/kg/d）作为阳性对照。雄性仔鼠于 31 日龄处死。DBP 和氟他胺可剂量依赖性地显著增加 F1 雄性仔鼠尿道下裂和隐睾的发生率。DBP 处理组的睾丸和附性器官（附睾、精囊、前列腺腹侧叶、肛提肌加球海绵体肌（LABC）和 Cowper 氏腺）的重量显著降低。此外，在高剂量 700mg/kg DBP 雄性仔鼠中观察到附睾和前列腺腹侧叶尾部发育不全。DBP（700mg/kg/d）处理组的肛殖距（AGD）和二氢睾酮（DHT）和睾酮水平显著降低。特别是，给予 DBP（700mg/kg/d）或氟他胺（25mg/kg/d）后，近端阴茎中雄激素受体（AR）和 5α-还原酶 2 的表达明显降低。近端阴茎尿道上皮中的 sonic hedgehog（Shh）表达在 DBP（700mg/kg/d）或氟他胺（25mg/kg/d）处理组中显著减少。此外，DBP 可剂量依赖性地显著增加未降睾丸中雌激素受体（ER α）的表达。数据表明，孕期暴露于 DBP 可导致雄性生殖器官出现多种异常反应，这些影响可能是由于与雄激素依赖性器官发育相关的基因在特定阶段的表达受到干扰所致。
