Yu X, Kamijima M, Ichihara G, Li W, Kitoh J, Xie Z, Shibata E, Hisanaga N, Takeuchi Y
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Toxicol Appl Pharmacol. 1999 Sep 15;159(3):185-93. doi: 10.1006/taap.1999.8730.
Ovarian dysfunction induced by 2-bromopropane (2-BP) has been described in female factory workers and experimental animals. However, the underlying mechanism is still unclear. To establish the reproductive target site and define mechanisms of 2-BP toxicity in adult female rats, we examined the effects of different doses and duration of exposure to 2-BP in female rats. In the dose-dependent experiments, female rats were exposed to 2-BP at 100, 300, or 1000 ppm or fresh air (n = 9 each) in exposure chambers for 8 h/day for 9 weeks. In the time-course experiments, female rats were exposed to 2-BP at 3000 ppm for 8 h (n = 7 each). The rats were then euthanized 1, 3, 5, and 17 days after exposure. Differential follicle counts and in situ terminal deoxynucleotidyl transferase assay were used to evaluate 2-BP effect on primordial, growing, and antral follicles. Exposure to 2-BP at 300 and 1000 ppm produced a significant reduction in the percentage of primordial, growing, and antral follicles in a dose-dependent manner. Significant reduction in the percentage of primordial follicles at 17 days after exposure was observed in time-course experiments. Exposure to 2-BP at 3000 ppm for 8 h resulted in histological changes in primordial follicles complex at 5 and 17 days after exposure. These changes consisted of distortion of the symmetry of oocytes and their nuclei at Day 5 after exposure and appearance of eccentric pyknotic cells and shrinkage of oocyte nuclei at Day 17 after exposure. In situ end labeling showed increased numbers of apoptotic oocytes and granulosa cells in primordial follicles at Days 5 and 17 after exposure. Our results suggested that ovarian dysfunction induced by 2-BP was caused by the destruction of primordial follicle and its oocyte due to the induction of apoptosis. Our studies also show that the follicle differential count is a more sensitive method than the vaginal smear in monitoring the female reproductive disorders induced by 2-BP.
在女性工厂工人和实验动物中，已发现2-溴丙烷（2-BP）会导致卵巢功能障碍。然而，其潜在机制仍不清楚。为确定成年雌性大鼠的生殖靶位点并明确2-BP毒性的机制，我们研究了不同剂量和暴露时长的2-BP对雌性大鼠的影响。在剂量依赖性实验中，雌性大鼠在暴露舱中分别暴露于100、300或1000 ppm的2-BP或新鲜空气（每组n = 9），每天暴露8小时，持续9周。在时间进程实验中，雌性大鼠暴露于3000 ppm的2-BP 8小时（每组n = 7）。然后在暴露后1、3、5和17天对大鼠实施安乐死。采用卵泡差异计数和原位末端脱氧核苷酸转移酶测定法评估2-BP对原始卵泡、生长卵泡和窦状卵泡的影响。暴露于300和1000 ppm的2-BP会使原始卵泡、生长卵泡和窦状卵泡所占百分比显著降低，且呈剂量依赖性。在时间进程实验中，观察到暴露后17天时原始卵泡所占百分比显著降低。暴露于3000 ppm的2-BP 8小时会导致暴露后5天和17天原始卵泡复合体出现组织学变化。这些变化包括暴露后第5天卵母细胞及其细胞核对称性的扭曲，以及暴露后第17天偏心固缩细胞的出现和卵母细胞核的缩小。原位末端标记显示，暴露后第5天和17天原始卵泡中凋亡的卵母细胞和颗粒细胞数量增加。我们的结果表明，2-BP诱导的卵巢功能障碍是由原始卵泡及其卵母细胞因凋亡诱导而遭到破坏所致。我们的研究还表明，在监测2-BP诱导的雌性生殖紊乱方面，卵泡差异计数比阴道涂片是更敏感的方法。
