Reduced fecundity in female rats with surgically induced endometriosis and in their daughters: a potential role for tissue inhibitors of metalloproteinase 1.
Reduced fecundity in female rats with surgically induced endometriosis and in their daughters: a potential role for tissue inhibitors of metalloproteinase 1.
复制标题
DOI：
10.1095/biolreprod.108.073411
复制
发表时间：
2009-04
影响因子：
3.6
通讯作者：
Sharpe-Timms KL
中科院分区：
文献类型：
--
作者：
Stilley JA;Woods-Marshall R;Sutovsky M;Sutovsky P;Sharpe-Timms KL
子宫内膜异位症妇女生育力下降的原因尚不清楚。据报道，异位和在位子宫内膜表达基质金属蛋白酶（MMPs）及其抑制剂（TIMP）在子宫内膜异位症的发病机制中发挥作用。我们推测，异常的卵巢癌TIMP蛋白的合成，分泌和定位也会导致生殖病理，从而降低生育力。一个已建立的子宫内膜异位症大鼠模型（Endo）与非子宫内膜异位症对照组（Sham）相比，用于研究子宫内膜异位症的生育力降低。比较Endo和Sham大鼠，Endo大鼠的卵巢动力学发生改变，包括卵巢卵泡减少和黄体（CL）与黄素化未破裂卵泡。此外，仅在Endo大鼠中发现排卵后卵母细胞结构和植入前胚胎发育的体内异常，包括染色体排列不齐、核和细胞质碎片化、卵裂延迟或停滞以及自然流产。TIMP-1在这些现象中的致病作用得到了我们的研究结果的支持，即通过ELISA检测到的Endo大鼠的腹腔液中有更多的TIMP-1，并且通过计算机辅助形态学分析测量到的窦状卵泡的卵泡膜中有更多的TIMP-1免疫定位。这些数据表明，在子宫内膜异位症中，TIMP-1的积累破坏了正常的MMP/TIMP酶环境在腹腔和卵巢动力学，卵母细胞的质量和植入前胚胎发育产生负面影响，从而降低生育力。最有趣的是，没有实验干预的Endo大鼠的女儿表现出同样的生殖异常。我们预测子宫内膜异位症的发育暴露会导致后代的永久性表观遗传变化。
The cause of reduced fecundity in women with endometriosis is unknown. Expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) by both ectopic and eutopic endometrium reportedly play a role in the pathogenesis of endometriosis. We hypothesize that anomalous endometriotic TIMP protein synthesis, secretion, and localization also cause reproductive pathologies resulting in reduced fecundity. An established rat model for endometriosis (Endo) compared to non-endometriotic controls (Sham) was used to investigate reduced fecundity in endometriosis. Comparing Endo and Sham rats, Endo rats had altered ovarian dynamics including fewer ovarian follicles and corpora lutea (CL) with luteinized unruptured follicles. Further, in vivo anomalies in post-ovulatory oocyte structure and preimplantation embryo development including misaligned chromosomes, nuclear and cytoplasmic fragmentation and delayed or arrested cleavage as well as spontaneous abortions were found only in Endo rats. A causative role for TIMP-1 in these phenomena is supported by our findings that Endo rats have more TIMP-1 in their peritoneal fluid as detected by ELISA and more TIMP-1 immunolocalization in the theca of antral follicles as measured by computer-assisted morphometric analysis. These data suggest that in endometriosis, accumulation of TIMP-1 disrupts the normal MMP/TIMP enzymatic milieu in the peritoneal cavity and negatively impacts ovarian dynamics, oocyte quality and preimplantation embryo development, thereby decreasing fecundity. Most intriguingly, daughters from Endo rats which had no experimental interventions exhibited these same reproductive abnormalities. We predict that developmental exposure to endometriosis leads to permanent epigenetic changes in subsequent generations.
登录
查看更多内容
影响因子：
10.5
作者：
BRENNER, CA;ADLER, RR;WERB, Z
通讯作者：
WERB, Z
影响因子：
4
作者：
Bagavandoss, P
通讯作者：
Bagavandoss, P
影响因子：
3.1
作者：
Bergendal, A;Naffah, S;Hillensjo, T
通讯作者：
Hillensjo, T
影响因子：
6.7
作者：
Chung, HW;Wen, Y;Polan, ML
通讯作者：
Polan, ML
影响因子：
6.1
作者：
Gómez-Torres, MJ;Acién, P;Velasco, I
通讯作者：
Velasco, I