Friedman L, Weinberger M A, Farber T M, Moreland F M, Peters E L, Gilmore C E, Khan M A
J Environ Pathol Toxicol. 1979 Jan-Feb;2(3):687-706.
Experiments were designed to determine the effects of feeding the methylxanthines caffeine, theobromine, or theophylline to 4- to 6-week-old males rats at a dietary level of 0.5 percent for periods ranging from 14 to 75 weeks. In the first two experiments, Osborne-Mendel rats were fed the test substances alone or in combination with sodium nitrite to test the hypothesis that these amines might nitrosate in vivo to produce toxic nitrosamine compounds. The compounds failed to produce neoplastic or preneoplastic lesions, but a significant positive finding was the occurrence of severe bilateral testicular atrophy with aspermatogenesis or oligospermatogenesis in 85-100 percent of the rats fed caffeine or theobromine. In a third experiment the methylxanthines were fed to Holtzman rats for 19 weeks to determine whether testicular atrophy would be induced in a second strain of rat. The testicular effects were similar to those in Experiments I and II but were more pronounced. Caffeine and theobromine induced testicular injury in nearly all rats. Theophylline induced severe testicular atrophy in 14 percent of the rats, mild to moderate atrophy in 71 percent, and had no effect in 15 percent. The relative testicular toxicity of the methylxanthines was caffeine, most potent; theobromine, slightly less potent; and theophylline, considerably less potent. Somewhat variable atrophic changes of the accessory sexual organs (epididymis, prostate, and seminal vesicles) accompanied the testicular changes. Cytogenetic analysis of testes from caffeine- or theophylline-treated rats revealed a significantly reduced number of mitotic cells in the caffeine-treated group. Plasma testosterone concentrations were significantly elevated in the theobromine group and somewhat elevated in the caffeine-treated group; this correlated morphologically with an apparent hyperplasia of interstitial cells in severely atrophied testes in these groups. Plasma cholesterol concentrations were significantly increased in the caffeine and theobromine groups. Possible sites and mechanisms of action of the methylxanthines in the induction of testicular atrophy and impaired spermatogenesis are discussed.
实验旨在确定在饮食中添加0.5%的甲基黄嘌呤（咖啡因、可可碱或茶碱），对4至6周龄雄性大鼠连续喂养14至75周所产生的影响。在前两个实验中，给奥斯本-孟德尔大鼠单独喂食受试物质，或与亚硝酸钠一起喂食，以验证这些胺类物质可能在体内发生亚硝化反应，生成有毒亚硝胺化合物的假说。这些化合物未能产生肿瘤性或肿瘤前病变，但一个显著的阳性发现是，在喂食咖啡因或可可碱的大鼠中，85%至100%出现了严重的双侧睾丸萎缩，并伴有无精子症或少精子症。在第三个实验中，给霍尔兹曼大鼠喂食甲基黄嘌呤19周，以确定是否会在另一品系的大鼠中诱发睾丸萎缩。睾丸的影响与实验一和实验二相似，但更为明显。咖啡因和可可碱几乎在所有大鼠中都诱发了睾丸损伤。茶碱在14%的大鼠中诱发了严重的睾丸萎缩，71%的大鼠出现了轻度至中度萎缩，15%的大鼠没有受到影响。甲基黄嘌呤对睾丸的相对毒性为：咖啡因最强；可可碱稍弱；茶碱则弱得多。附属生殖器官（附睾、前列腺和精囊）也出现了一些变化不定的萎缩性改变，与睾丸变化相伴。对咖啡因或茶碱处理的大鼠睾丸进行细胞遗传学分析发现，咖啡因处理组的有丝分裂细胞数量显著减少。可可碱组的血浆睾酮浓度显著升高，咖啡因处理组也略有升高；这在形态学上与这些组严重萎缩睾丸中的间质细胞明显增生相关。咖啡因和可可碱组的血浆胆固醇浓度显著升高。文中讨论了甲基黄嘌呤诱导睾丸萎缩和精子发生受损的可能作用部位和机制。
