Mahood I Kim, Scott Hayley M, Brown Richard, Hallmark Nina, Walker Marion, Sharpe Richard M
MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
Environ Health Perspect. 2007 Dec;115 Suppl 1(Suppl 1):55-61. doi: 10.1289/ehp.9366.
Fetal exposure of male rats to di(n-butyl) phthalate (DBP) induces reproductive disorders similar to those in human testicular dysgenesis syndrome (TDS), including infertility, cryptorchidism, focal "dysgenetic areas," and Sertoli cell-only tubules in the adult testis. Humans are widely exposed to DBP, but at much lower levels than those causing adverse effects in rats.
The objective of this study was to evaluate end points affected by DBP action in rats in fetal and adult life that are relevant to human TDS, and to compare their dose sensitivity.
Pregnant rats were gavaged daily with corn oil (control) or with 4, 20, 100, or 500 mg/kg DBP. We examined adult end points of TDS (infertility, cryptorchidism) and indicators within the fetal testis of dysgenesis [abnormal Leydig cell (LC) aggregation, multinucleated gonocytes (MNGs)], as well as conditions that may result from these indicators in adulthood (occurrence of focal dysgenetic areas). Fetal testis weight and testicular testosterone levels were also evaluated.
The fetal end points analyzed (testicular testosterone levels, abnormal LC aggregation, occurrence of MNGs) were most sensitive to disruption by DBP, as all were significantly affected at a dose of 100 mg/kg/day DBP, with a trend toward effects occurring at 20 mg/kg/day DBP; adult end points were affected consistently only by 500 mg/kg/day DBP.
The fetal end points we evaluated can be objectively quantified and may prove helpful in evaluating the health risk of exposure to DBP and other phthalates, as well as identifying DBP-sensitive fetal events that have adult consequences/end points that are identifiable in human TDS.
雄性大鼠在胎儿期接触邻苯二甲酸二丁酯（DBP）会引发与人类睾丸发育不全综合征（TDS）相似的生殖系统紊乱，包括成年睾丸出现不育、隐睾、局灶性“发育异常区域”以及仅含支持细胞的小管。人类广泛接触DBP，但接触水平远低于对大鼠产生不良影响的水平。
本研究的目的是评估DBP作用于大鼠胎儿期和成年期与人类TDS相关的受影响终点，并比较它们的剂量敏感性。
给怀孕大鼠每日灌胃玉米油（对照组）或4、20、100或500mg/kg DBP。我们检查了TDS的成年终点（不育、隐睾）以及胎儿睾丸发育异常的指标[异常的睾丸间质细胞（LC）聚集、多核生殖母细胞（MNGs）]，以及成年期可能由这些指标导致的情况（局灶性发育异常区域的出现）。还评估了胎儿睾丸重量和睾丸睾酮水平。
所分析的胎儿期终点（睾丸睾酮水平、异常LC聚集、MNGs的出现）对DBP干扰最为敏感，因为在DBP剂量为100mg/kg/天时所有这些终点均受到显著影响，在20mg/kg/天时呈现出受影响的趋势；成年期终点仅在DBP剂量为500mg/kg/天时持续受到影响。
我们评估的胎儿期终点可以客观量化，可能有助于评估接触DBP和其他邻苯二甲酸酯的健康风险，以及识别具有成年后果的DBP敏感胎儿事件/在人类TDS中可识别的终点。
