Barlow Norman J, McIntyre Barry S, Foster Paul M D
CIIT Centers for Health Research, Research Triangle Park, North Carolina, USA.
Toxicol Pathol. 2004 Jan-Feb;32(1):79-90. doi: 10.1080/01926230490265894.
In utero exposure of male rats to the antiandrogen di(n-butyl) phthalate (DBP) leads to decreased anogenital distance (AGD) on postnatal day (PND) 1, increased areolae retention on PND 13, malformations in the male reproductive tract, and histologic testicular lesions including marked seminiferous epithelial degeneration and a low incidence of Leydig cell (LC) adenomas on PND 90. One objective of this study was to determine the incidence and persistence of decreased AGD, increased areolae retention, and LC adenomas in adult rats following in utero DBP exposure. A second objective was to determine whether AGD and areolae retention during the early postnatal period are associated with lesions in the male reproductive tract. Pregnant Crl:CD(SD)BR rats were gavaged with corn oil or DBP at 100 or 500 mg/kg/day, 10 dams per group. Three replicates of rats (n = 30 rats per replicate) were exposed from gestation day 12 to 21 and the male offspring allowed to mature to 6, 12, or 18 months of age. Gross malformations in the male reproductive tract and histologic lesions in the testes were similar to those previously described. However, testicular dysgenesis, a lesion of proliferating LCs and aberrant tubules that has not been previously described in DBP-exposed testes, was diagnosed. The incidence of this lesion was approximately 20% unilateral and 7-18% bilateral in the high-dose group and was similar among all ages examined, implicating a developmental alteration rather than an age-related change. AGD and areolae retention were found to be permanent changes following in utero exposure to 500 mg/kg/day of DBP. Decreased AGD was a sensitive predictor of lesions in the male reproductive tract, relatively small changes in AGD were associated with a significant incidence of male reproductive malformations. In utero DBP exposure induced proliferative developmental lesions, some of which would have been diagnosed as LC adenomas by the morphological criteria set forth by the Society of Toxicologic Pathology. However, these lesions were dissimilar to traditional LC adenomas as the LCs were poorly differentiated and the lesions contained aberrant seminiferous tubules. While the morphology and incidence of this DBP-induced testicular developmental lesion has been fully characterized by this study, the detailed pathogenesis warrants further investigation.
雄性大鼠在子宫内暴露于抗雄激素邻苯二甲酸二正丁酯（DBP）会导致出生后第1天（PND 1）的肛门生殖器距离（AGD）缩短、PND 13时乳晕保留增加、雄性生殖道畸形以及组织学上的睾丸病变，包括明显的生精上皮变性和PND 90时睾丸间质细胞（LC）腺瘤的低发生率。本研究的一个目的是确定成年大鼠在子宫内暴露于DBP后AGD缩短、乳晕保留增加和LC腺瘤的发生率及持续性。第二个目的是确定出生后早期的AGD和乳晕保留是否与雄性生殖道病变有关。将怀孕的Crl:CD(SD)BR大鼠以100或500 mg/kg/天的剂量灌胃玉米油或DBP，每组10只母鼠。三组大鼠（每组重复3次，每次重复n = 30只大鼠）从妊娠第12天至21天进行暴露，雄性后代饲养至6、12或18月龄。雄性生殖道的大体畸形和睾丸的组织学病变与先前描述的相似。然而，诊断出了睾丸发育不全，这是一种增殖性LCs和异常小管的病变，此前在DBP暴露的睾丸中未曾描述过。该病变在高剂量组中的发生率约为单侧20%，双侧7 - 18%，在所有检查年龄中相似，提示是一种发育改变而非年龄相关变化。发现子宫内暴露于500 mg/kg/天的DBP后，AGD和乳晕保留是永久性变化。AGD缩短是雄性生殖道病变的敏感预测指标，AGD相对较小的变化与雄性生殖畸形的高发生率相关。子宫内暴露于DBP会诱导增殖性发育病变，根据毒理病理学会制定的形态学标准，其中一些病变会被诊断为LC腺瘤。然而，这些病变与传统的LC腺瘤不同，因为LCs分化不良，且病变中含有异常的生精小管。虽然本研究已充分描述了这种DBP诱导的睾丸发育病变的形态和发生率，但其详细发病机制仍需进一步研究。
