Foster Paul M D, Harris Martha W
Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Toxicol Sci. 2005 Jun;85(2):1024-32. doi: 10.1093/toxsci/kfi159. Epub 2005 Mar 23.
Previous studies have indicated that the androgen receptor antagonist, flutamide, can produce a suite of reproductive malformations in the male rat when orally administered daily on gestation days (GD) 12-21. The objective of this study was to investigate the gestation time dependence for the induction of these malformations to establish a robust animal model for future studies of gene expression related to specific malformations. Groups of timed-pregnant Sprague-Dawley rats (GD 0 = day of mating) were administered flutamide as a single gavage dose (50 mg/kg) on GD 16, 17, 18, or 19 with 10 dams per group. Control animals (5 dams per time per group) were administered corn oil vehicle (2 ml/kg). Dams were allowed to litter, and their adult male offspring were killed at postnatal day (PND) 100 +/- 10. Anogenital distance was measured at PND 1 and 100. Areolae were scored at PND 13, and permanent nipples evaluated at PND 100. No reproductive tract malformations were found in control male offspring. In the treated groups, malformations were noted following exposure at every GD, although the incidence of specific malformations varied by GD. At GD 16, the highest incidence was noted for permanent nipples (46% pups, 60% litters), epispadias (12% pups, 30% litters), and missing epididymal components (5% pups, 20% litters). The highest incidences for hypospadias (58% pups, 80% litters), vaginal pouch (49% pups, 70% litters), cleft prepuce (29% pups, 60% litters), and missing prostate lobes (12% pups, 60% litters) were noted at GD 17. At GD 18 the highest incidence of malformations noted were epispadias (5% pups, 30% litters), reduced prostate size (32% pups, 90% litters), and abnormal kidneys (3% pups, 30% litters) and bladders (7% pups, 30% litters), while on GD 19 70% of the litters had animals with abnormal seminal vesicles. Testicular and epididymal morphological changes were noted at all GDs and were consistent with the gross observations and peaked in incidence and severity on GD17. The major discrepancy between this study and previous multiple-dose studies was in the very few numbers of animals presenting with cryptorchidism (only one each on GDs 16 and 17), suggesting that exposure over multiple days may be required to induce this malformation. Thus, a single gestational exposure of flutamide induced numerous reproductive tract malformations consistent with previously reports following multiple exposures, with the timing of the exposure producing marked tissue selectivity in the response noted in adult offspring.
先前的研究表明，雄激素受体拮抗剂氟他胺在妊娠第12 - 21天每天经口给予雄性大鼠时，可导致一系列生殖系统畸形。本研究的目的是调查这些畸形诱导的妊娠时间依赖性，以建立一个强大的动物模型，用于未来与特定畸形相关的基因表达研究。将定时怀孕的斯普拉格-道利大鼠（妊娠第0天 = 交配日）分组，在妊娠第16、17、18或19天以单次灌胃剂量（50 mg/kg）给予氟他胺，每组10只母鼠。对照动物（每组每次5只母鼠）给予玉米油载体（2 ml/kg）。母鼠分娩后，其成年雄性后代在出生后第100±10天处死。在出生后第1天和第100天测量肛门生殖距离。在出生后第13天对乳晕进行评分，在出生后第100天评估永久性乳头。对照雄性后代未发现生殖道畸形。在治疗组中，尽管特定畸形的发生率因妊娠天数而异，但在每个妊娠天数暴露后均观察到畸形。在妊娠第16天，永久性乳头（46%的幼崽，60%的窝）、尿道上裂（12%的幼崽，30%的窝）和附睾成分缺失（5%的幼崽，20%的窝）的发生率最高。尿道下裂（58%的幼崽，80%的窝）、阴道囊（49%的幼崽，70%的窝）、包皮裂（29%的幼崽，60%的窝）和前列腺叶缺失（12%的幼崽，60%的窝）的发生率在妊娠第17天最高。在妊娠第18天，观察到的畸形发生率最高的是尿道上裂（5%的幼崽，30%的窝）、前列腺尺寸减小（32%的幼崽，90%的窝）以及肾脏（3%的幼崽，30%的窝）和膀胱（7%的幼崽，30%的窝）异常，而在妊娠第19天，70%的窝中有动物出现精囊异常。在所有妊娠天数均观察到睾丸和附睾的形态变化，这些变化与大体观察结果一致，且在妊娠第17天发生率和严重程度达到峰值。本研究与先前多剂量研究的主要差异在于隐睾症动物数量极少（妊娠第16天和第17天各仅1只），这表明可能需要多日暴露才能诱导出这种畸形。因此，氟他胺的单次妊娠暴露诱导了许多与先前多次暴露后报道一致的生殖道畸形，暴露时间在成年后代的反应中产生了明显的组织选择性。
