Ronis M J, Badger T M, Shema S J, Roberson P K, Shaikh F
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
Toxicol Appl Pharmacol. 1996 Feb;136(2):361-71. doi: 10.1006/taap.1996.0044.
The reproductive toxicity and growth effects of developmental lead exposure were assessed using a rat model in which 0.6% (w/v) lead acetate was administered in the drinking water ad libitum. Three series of experiments were conducted in which lead exposure was initiated beginning in utero, prepubertally, or postpubertally. Lead effects were measured on reproductive physiology and endocrinology, sexually dimorphic hepatic testosterone hydroxylation, and growth rates in both male and female animals. In male animals secondary sex organ weights were significantly decreased only in animals exposed prepubertally. In addition, serum testosterone levels were significantly suppressed, most severely in animals exposed from in utero (in the in utero group). Little effect was observed in adult female rats. However, in female animals exposed prepubertally, delayed vaginal opening and disrupted estrus cycling was observed. More severe reproductive disruption was accompanied by suppression of circulating estradiol in the in utero group. Effects on circulating sex steroids were accompanied by variable effects on circulating luteinizing hormone (LH) levels, pituitary LH, and pituitary LH beta mRNA, suggesting a dual site of lead action: (a) at the level of the hypothalamic pituitary unit, and (b) directly at the level of gonadal steroid biosynthesis. Prepubertal growth in both sexes was suppressed 25% in the in utero group. However, pubertal growth rates were significantly suppressed only in male animals and postpubertal growth was not significantly different from controls in any of the experiments, despite continued exposure to high lead levels in the drinking water. In addition, at age 85 days, male-specific hepatic hydroxylation of testosterone at positions 2 alpha and 16 alpha, which is catalyzed by a cytochrome P450 isozyme CYP 2C11, itself regulated by sexually dimorphic growth hormone secretion, was unaffected. This suggests that the growth effects of lead are possibly due to a delay in the development of sex-specific pituitary growth hormone secretion patterns rather than a persistent developmental defect. Thus, the reproductive and growth effects of lead are complex and sex-dependent, and appear to involve multiple sites on the hypothalamic-pituitary-gonadal axis.
利用大鼠模型评估发育性铅暴露的生殖毒性和生长效应，该模型中随意饮用含0.6%（w/v）醋酸铅的饮用水。进行了三个系列的实验，铅暴露分别从子宫内、青春期前或青春期后开始。测量了铅对生殖生理学和内分泌学、性二态性肝脏睾酮羟化作用以及雄性和雌性动物生长速率的影响。在雄性动物中，仅青春期前暴露的动物次级性器官重量显著降低。此外，血清睾酮水平显著受到抑制，在子宫内暴露的动物（子宫内组）中抑制最为严重。成年雌性大鼠几乎未观察到影响。然而，在青春期前暴露的雌性动物中，观察到阴道开口延迟和发情周期紊乱。子宫内组更严重的生殖紊乱伴随着循环雌二醇的抑制。对循环性类固醇的影响伴随着对循环促黄体生成素（LH）水平、垂体LH和垂体LHβmRNA的不同影响，表明铅作用的双重位点：（a）在下丘脑 - 垂体单位水平，以及（b）直接在性腺类固醇生物合成水平。子宫内组两性的青春期前生长均受到25%的抑制。然而，仅雄性动物的青春期生长速率显著受到抑制，并且在任何实验中青春期后生长与对照组无显著差异，尽管持续饮用高铅水平水。此外，在85日龄时，由细胞色素P450同工酶CYP 2C11催化的睾酮在2α和16α位的雄性特异性肝脏羟化作用未受影响，该同工酶本身受性二态性生长激素分泌调节。这表明铅的生长效应可能是由于性特异性垂体生长激素分泌模式发育延迟，而非持续性发育缺陷。因此，铅的生殖和生长效应是复杂的且具有性别依赖性，并且似乎涉及下丘脑 - 垂体 - 性腺轴上的多个位点。
