Ohsako Seiichiroh, Miyabara Yuichi, Sakaue Motoharu, Ishimura Ryuta, Kakeyama Masaki, Izumi Hiroyuki, Yonemoto Junzo, Tohyama Chiharu
Molecular and Cellular Toxicology Section, Environmental Health Sciences Division, Endocrine Disruptors and Dioxin Research Project, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8506, Japan.
Toxicol Sci. 2002 Apr;66(2):283-92. doi: 10.1093/toxsci/66.2.283.
Exposure to a relatively low dose of 2,3,7,8-tetrachlorodebenzo-p-dioxin (TCDD) during mid-gestation induces a reduction of ventral prostate weight in rat offspring. Recently we reported that a single administration of TCDD (12.5-800 ng/kg body weight) to pregnant Holtzman rats on gestational day (GD) 15 caused a decrease in androgen receptor (AR) mRNA level in the ventral prostate during the prepubertal period, and we proposed that this reduction of AR mRNA is one of the most sensitive adverse endpoints due to perinatal exposure to TCDD (S. Ohsako et al., 2001, TOXICOL: Sci. 60, 132-143). In the present study, to investigate the mechanism of a decrease in AR mRNA level, we administered TCDD to rats at other developmental stages and compared possible alterations of the male reproductive system. Pregnant Sprague-Dawley rats were given a single oral dose of 1 microg TCDD/kg body weight on GD 15 or GD 18, or male pups born from untreated dams were subcutaneously given a single dose of 1 microg TCDD/kg body weight on postnatal day 2 (PND 2). Offspring exposed on GD 15, GD 18, and PND 2 were sacrificed on PND 70. TCDD exposure on GD 15 resulted in significant decreases in the urogenital complex and ventral prostate weights and urogenital-glans penis length of male rat offspring, but not on GD 18 and PND 2. Testicular and epididymal weights were also lower than control group only in the TCDD-exposed GD 15 group. Anogenital distance was significantly reduced in the TCDD-exposed GD 15 and GD 18 groups, but not in the TCDD-exposed PND 2 group. Semiquantitative RT-PCR analysis showed that AR mRNA levels were decreased in the TCDD-exposed GD 15 group only, and that the constitutive level of cytochrome P450 1A1 (CYP1A1) mRNA in the ventral prostate was not changed by TCDD in any of the exposed groups. No changes in AR mRNA level were detected in the testis or brain in any of the TCDD-exposed groups. These results suggest the presence of a critical window during development with regard to impairments of male reproductive organs by in utero and lactational exposure to a low dose of TCDD.
在妊娠中期接触相对低剂量的2,3,7,8-四氯二苯并对二恶英（TCDD）会导致大鼠后代腹侧前列腺重量减轻。最近我们报道，在妊娠第15天（GD15）给怀孕的霍尔兹曼大鼠单次注射TCDD（12.5 - 800 ng/kg体重）会导致青春期前腹侧前列腺中雄激素受体（AR）mRNA水平降低，并且我们提出AR mRNA的这种降低是围产期接触TCDD最敏感的不良终点之一（S. Ohsako等人，2001年，《毒理学：科学》60卷，132 - 143页）。在本研究中，为了探究AR mRNA水平降低的机制，我们在其他发育阶段给大鼠注射TCDD，并比较雄性生殖系统可能的改变。在GD15或GD18给怀孕的斯普拉格 - 道利大鼠单次口服1 μg TCDD/kg体重，或者给未处理母鼠所生的雄性幼崽在出生后第2天（PND2）皮下注射单次剂量1 μg TCDD/kg体重。在GD15、GD18和PND2接触TCDD的后代在PND70时处死。在GD15接触TCDD导致雄性大鼠后代的泌尿生殖复合体和腹侧前列腺重量以及泌尿生殖 - 阴茎头长度显著降低，但在GD18和PND2接触TCDD时未出现这种情况。仅在GD15接触TCDD的组中睾丸和附睾重量也低于对照组。在GD15和GD18接触TCDD的组中肛门与生殖器之间的距离显著缩短，但在PND2接触TCDD的组中未出现这种情况。半定量RT - PCR分析表明，仅在GD15接触TCDD的组中AR mRNA水平降低，并且在任何接触组中腹侧前列腺中细胞色素P450 1A1（CYP1A1）mRNA的组成水平均未因TCDD而改变。在任何接触TCDD的组中，睾丸或大脑中的AR mRNA水平均未检测到变化。这些结果表明，在发育过程中存在一个关键窗口期，在此期间子宫内和哺乳期接触低剂量TCDD会对雄性生殖器官造成损害。
