Methoxychlor induces atresia of antral follicles in ERalpha-overexpressing mice.
Methoxychlor induces atresia of antral follicles in ERalpha-overexpressing mice.
复制标题
甲氧滴滴涕诱导 ERalpha 过表达小鼠的窦卵泡闭锁。
DOI：
10.1093/toxsci/kfl040
复制
发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Flaws,JodiA
中科院分区：
文献类型：
--
作者：
Tomic,Dragana;Frech,MariaSilvina;Babus,JaniceK;Gupta,RupeshK;Furth,PriscillaA;Koos,RobertD;Flaws,JodiA
甲氧滴滴涕（MXC）是一种杀虫剂，已知可与雌激素受体α（ERα）结合并诱导窦状卵泡闭锁。虽然研究表明MXC对卵巢有毒，但我们假设对雌激素信号系统的干扰（即，雌激素敏感性的增加或降低）可能改变卵巢对MXC的反应性。因此，我们检测ERα过表达是否改变了MXC增加卵泡闭锁的能力。为此，我们采用了一种转基因小鼠模型，其中ERα可以在动物组织中诱导过表达（ERα过表达）。我们对雌性对照和ERα过表达者给予芝麻油（溶剂对照）或MXC（32和64 mg/kg/天），持续20天。给药后，采集卵巢用于卵泡数量和卵泡闭锁的组织学评价，同时采集血液用于激素测量。测定所有动物的发情周期，以确保所有动物均在发情期间终止。尽管MXC对对照组和ERα过表达组的原始卵泡、初级卵泡和腔前卵泡的数量没有显著影响，但对腔卵泡有影响。具体而言，我们的数据表明，在对照组和ERα过表达组中，与溶剂相比，32和64 mg/kg MXC增加了闭锁卵泡的百分比。此外，与对照动物相比，ERα过表达小鼠对64 mg/kg MXC的敏感性明显增加。具体而言，在64 mg/kg MXC剂量下，ERα过表达小鼠的闭锁卵泡百分比显著高于对照动物（对照组= 21.5 ± 3%，n = 5; ERα过表达组= 37 ± 23%，n = 9，p≤ 0.05 vs.对照组）。给药20天后，所有给药组中对照组和ERα过表达小鼠之间的雌二醇水平均无差异。芝麻油给药对照小鼠和32 mg/kg MXC给药对照小鼠的促卵泡激素（FSH）水平相似，而64 mg/kg MXC给药对照小鼠的FSH水平显著低于芝麻油给药对照小鼠（芝麻油= 4.31 ± 0.7，MXC [64 mg/kg/天] = 1.89 ± 0.4，n = 3，p≤ 0.02 vs.芝麻油）。接受芝麻油（32或64 mg/kg MXC）给药的ERα过表达小鼠的FSH水平相似。因此，我们观察到与用相同化合物处理的对照小鼠相比，用MXC处理的ERα过表达小鼠中闭锁窦状卵泡的百分比增加，表明ERα信号传导途径在MXC诱导的闭锁中起重要作用。与对照动物相比，ERα过表达小鼠对MXC的敏感性更高的趋势不能通过雌二醇和/或FSH水平的改变来解释。
Methoxychlor (MXC) is a pesticide that is known to bind to estrogen receptor alpha (ERα) and to induce atresia of antral ovarian follicles. Although studies have shown that MXC is toxic to the ovary, we hypothesize that perturbation to the estrogen-signaling system (i.e., increase or decrease in estrogen sensitivity) might alter ovarian responsiveness to MXC. Thus, we examined whether ERα overexpression alters the ability of MXC to increase follicle atresia. To do so, we employed a transgenic mouse model in which ERα can be inducibly overexpressed in animal tissues (ERα overexpressors). We dosed female controls and ERα overexpressors with sesame oil (vehicle control) or MXC (32 and 64 mg/kg/day) for 20 days. After dosing, the ovaries were collected for histological evaluation of follicle numbers and follicle atresia, while blood was collected for measurements of hormones. Estrous cycles were determined in all animals to ensure that all were terminated during estrus. Although there were no significant effects of MXC on the numbers of primordial, primary, and preantral follicles in both controls and ERα overexpressors, there was an effect on antral follicles. Specifically, our data indicate that 32 and 64 mg/kg MXC increased the percentage of atretic follicles compared to vehicle in both control and ERα overexpressor groups. Moreover, there was a clear trend toward greater sensitivity to 64 mg/kg MXC in ERα-overexpressing mice compared to control animals. Specifically, at the 64-mg/kg MXC dose, ERα-overexpressing mice had a significantly higher percentage of atretic follicles compared to control animals (controls = 21.5 ± 3%,n= 5; ERα overexpressors = 37 ± 23%,n= 9,p≤ 0.05 vs. controls). After 20 days of dosing, there were no differences in estradiol levels between controls and ERα-overexpressing mice in all treatment groups. Follicle-stimulating hormone (FSH) levels were similar in sesame oil–treated control mice and control mice treated with 32 mg/kg MXC, while control mice treated with 64 mg/kg MXC had significantly lower levels of FSH compared to sesame oil–treated controls (sesame oil = 4.31 ± 0.7, MXC [64 mg/kg/day] = 1.89 ± 0.4,n= 3,p≤ 0.02 vs. sesame oil). ERα-overexpressing mice treated with sesame oil, 32 or 64 mg/kg MXC, had similar FSH levels. Thus, we observed an increased percentage of atretic antral follicles in ERα-overexpressing mice treated with MXC compared to control mice treated with the same compound, suggesting that the ERα-signaling pathway plays an important role in MXC-induced atresia. The trend toward greater sensitivity to MXC in ERα-overexpressing mice compared to control animals cannot be explained by alterations in estradiol and/or FSH levels.