College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
Reprod Toxicol. 2010 Jun;29(3):306-16. doi: 10.1016/j.reprotox.2010.01.013. Epub 2010 Feb 2.
In this study, a female pubertal assay on the effects of parabens, including methyl-, ethyl-, propyl-, isopropyl-, butyl-, and isobutylparaben, was performed in a female Sprague-Dawley rat model during the juvenile-peripubertal period. The rats were orally treated with these parabens from postnatal day 21-40 in a dose-dependent manner (62.5, 250 and 1000 mg/kg body weight [BW]/day). 17alpha-Ethinylestradiol (1mg/kg BW/day) was used as a positive control and corn oil as a vehicle. A high dose of methyl- and isopropylparaben (1000 mg/kg BW/day) resulted in a significant delay in the date of vaginal opening and a decrease in length of the estrous cycle. In measurements of organ weight and body weight, we observed significant weight changes in ovaries, adrenal glands, thyroid glands, liver, and kidneys; conversely, body weight was not altered following paraben treatment. The potential effects of parabens on estrogenicity were shown in histopathological abnormities in the reproductive organs. Histological analysis of the ovaries from the peripubertal rats revealed a decrease of corpora lutea, increase in the number of cystic follicles, and thinning of the follicular epithelium. In addition, morphological studies of the uterus revealed the myometrial hypertrophy by a high dose of propyl- and isopropylparaben (1000 mg/kg-day), and in all dose groups of butyl- and isobutylparabens. However, no significant histopathological changes were observed in the other organs (i.e. adrenal and thyroid glands). We also observed a significant decrease in serum estradiol and thyroxine concentrations in methyl-, ethyl-, propyl-, isopropyl-, and isobutylparaben-treated groups. A receptor-binding assay indicated that the relative binding affinities of parabens to estrogen receptors occurred in the order: isobutylparaben>butylparaben>isopropylparaben=propylparaben>ethylparaben. These values were much lower than the binding affinity for 17beta-estradiol. Taken together, long-term exposure to parabens, which show less estrogenic activity than estradiol, can produce suppressive effects on hormonal responsiveness and can disrupt the morphology of reproductive target tissues. In addition, the relation between thyroid weight and thyroid hormone may influence circulating levels of parabens, suggesting the effects of parabens as thyrotoxic during this critical stage of development in female rats.
在这项研究中，使用雌性 Sprague-Dawley 大鼠模型，在幼年期到青春期进行了对包括甲基、乙基、丙基、异丙基、丁基和异丁基对苯二甲酸酯在内的对苯二甲酸酯类的雌性青春期效应的研究。这些对苯二甲酸酯以剂量依赖性的方式（62.5、250 和 1000mg/kg 体重/天）从出生后第 21 天至 40 天经口给予大鼠。17α-乙炔雌二醇（1mg/kg 体重/天）用作阳性对照，玉米油作为载体。高剂量的甲基和异丙基对苯二甲酸酯（1000mg/kg 体重/天）导致阴道开口日期显著延迟和动情周期长度缩短。在器官重量和体重测量中，我们观察到卵巢、肾上腺、甲状腺、肝脏和肾脏的体重发生显著变化；然而，在对苯二甲酸酯治疗后，体重没有改变。对苯二甲酸酯对雌激素的潜在影响表现在生殖器官的组织病理学异常中。青春期大鼠卵巢的组织学分析显示黄体减少，囊状卵泡数量增加，卵泡上皮变薄。此外，子宫的形态学研究显示高剂量的丙基和异丙基对苯二甲酸酯（1000mg/kg 天）以及所有剂量组的丁基和异丁基对苯二甲酸酯引起的子宫肌层肥大。然而，在其他器官（即肾上腺和甲状腺）中没有观察到显著的组织病理学变化。我们还观察到甲基、乙基、丙基、异丙基和异丁基对苯二甲酸酯处理组的血清雌二醇和甲状腺素浓度显著降低。受体结合测定表明，对苯二甲酸酯与雌激素受体的相对结合亲和力顺序为：异丁基对苯二甲酸酯>丁基对苯二甲酸酯>异丙基对苯二甲酸酯=丙基对苯二甲酸酯>乙基对苯二甲酸酯。这些值远低于 17β-雌二醇的结合亲和力。综上所述，长期接触对苯二甲酸酯（其雌激素活性低于雌二醇）会对激素反应产生抑制作用，并破坏生殖靶组织的形态。此外，甲状腺重量与甲状腺激素之间的关系可能会影响对苯二甲酸酯在循环中的水平，这表明在雌性大鼠发育的这个关键阶段，对苯二甲酸酯具有甲状腺毒性作用。
