Mylchreest E, Sar M, Cattley R C, Foster P M
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina, 27709, USA.
Toxicol Appl Pharmacol. 1999 Apr 15;156(2):81-95. doi: 10.1006/taap.1999.8643.
Gestational and lactational exposure to di(n-butyl) phthalate (DBP) at >/=250 mg/kg/day disrupts male rat reproductive development and function. Although this indicates an antiandrogenic mechanism, DBP and its biologically active metabolite do not interact with the androgen receptor (AR) in vitro. In the present study, we compared the effects of DBP and the antiandrogen flutamide using a shorter exposure during the prenatal period of male sexual differentiation in rats. Pregnant CD rats received DBP at 0, 100, 250, or 500 mg/kg/day po (n = 10) or flutamide at 100 mg/kg/day po (n = 5) from Gestation Days 12 to 21. In F1 males, DBP (500 mg/kg/day) and flutamide caused hypospadias; cryptorchidism; agenesis of the prostate, epididymis, and vas deferens; degeneration of the seminiferous epithelium; and interstitial cell hyperplasia of the testis. Flutamide and DBP (250 and 500 mg/kg/day) also produced retained thoracic nipples and decreased anogenital distance. Interstitial cell adenoma occurred at 500 mg DBP/kg/day in two males. The only effect seen at 100 mg DBP/kg/day was delayed preputial separation. In contrast to flutamide, DBP caused a low incidence of prostate agenesis and hypospadias with no vaginal pouch. The low incidence of DBP-induced intraabdominal testes contrasted with the high incidence of inguinal testes seen with flutamide. Thus prenatal male sexual differentiation is a sensitive period for the reproductive toxicity of DBP. A no observed adverse effect level was not established and the lowest observed (adverse) effect level was 100 mg/kg/day. Flutamide and DBP disrupted the androgen signaling necessary for male sexual differentiation but with a different pattern of antiandrogenic effects. DBP is an example of an environmental antiandrogen that disrupts androgen-regulated male sexual differentiation without interacting directly with the AR, as does flutamide.
孕期和哺乳期暴露于邻苯二甲酸二丁酯（DBP），剂量≥250毫克/千克/天，会破坏雄性大鼠的生殖发育和功能。尽管这表明存在抗雄激素机制，但DBP及其生物活性代谢物在体外并不与雄激素受体（AR）相互作用。在本研究中，我们在大鼠雄性性分化的产前阶段使用较短的暴露时间，比较了DBP和抗雄激素氟他胺的作用。怀孕的CD大鼠在妊娠第12天至21天经口接受0、100、250或500毫克/千克/天的DBP（n = 10）或100毫克/千克/天的氟他胺（n = 5）。在F1雄性大鼠中，DBP（500毫克/千克/天）和氟他胺导致尿道下裂；隐睾；前列腺、附睾和输精管发育不全；生精上皮变性；以及睾丸间质细胞增生。氟他胺和DBP（250和500毫克/千克/天）还导致胸部乳头残留和肛门生殖距离缩短。在500毫克DBP/千克/天的剂量下，两只雄性大鼠出现了间质细胞瘤。在100毫克DBP/千克/天的剂量下，唯一观察到的效应是包皮分离延迟。与氟他胺不同，DBP导致前列腺发育不全和无阴道囊的尿道下裂发生率较低。DBP诱导的腹内睾丸发生率较低，与氟他胺导致的腹股沟睾丸发生率较高形成对比。因此，产前雄性性分化是DBP生殖毒性的敏感期。未确定无观察到不良作用水平，最低观察到（不良）作用水平为100毫克/千克/天。氟他胺和DBP破坏了雄性性分化所需的雄激素信号传导，但具有不同的抗雄激素作用模式。DBP是一种环境抗雄激素的例子，它像氟他胺一样，在不直接与AR相互作用的情况下破坏雄激素调节的雄性性分化。
