Reduced Fecundity in Female Rats with Surgically Induced Endometriosis and in Their Daughters: A Potential Role for Tissue Inhibitors of Metalloproteinase 11

Julie A W Stilley, Renita Woods-Marshall, Miriam Sutovsky, Peter Sutovsky, Peter Šutovský, Kathy L Sharpe-Timms
Biology of reproduction · 2008 · vol. 80(4) , pp. 649–656 · doi:10.1095/biolreprod.108.073411 · PMID:19020297 · PMC2752155 · W2145128606
article OA: bronze CC0 ⤵ 43 in-corpus citations
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Surgically induced endometriosis in female rats and their daughters showed reduced fecundity, fewer follicles, abnormal oocytes, and impaired embryo development, linked to elevated tissue inhibitor of metalloproteinase 1.

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Abstract

The cause of reduced fecundity in women with endometriosis is unknown. Expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) by both ectopic and eutopic endometrium reportedly has 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 with nonendometriotic controls (Shams) 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 with luteinized unruptured follicles. Furthermore, in vivo anomalies in postovulatory 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 TIMP1 in these phenomena is supported by our findings that Endo rats have more TIMP1 in their peritoneal fluid as detected by ELISA and more TIMP1 immunolocalization in the theca of antral follicles as measured by computer-assisted morphometric analysis. These data suggest that in endometriosis the accumulation of TIMP1 disrupts the normal MMP/TIMP enzymatic milieu in the peritoneal cavity and negatively affects ovarian dynamics, oocyte quality, and preimplantation embryo development, thereby decreasing fecundity. Most intriguingly, daughters of Endo rats that had no experimental interventions exhibited these same reproductive abnormalities. We predict that developmental exposure to endometriosis leads to permanent epigenetic changes in subsequent generations.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Infertility, Female Nuclear Family Tissue Inhibitor of Metalloproteinase-1 Uterine Diseases Animals Ascitic Fluid Ascitic Fluid Embryonic Development Embryonic Development Endometriosis Endometriosis Endometriosis Endometriosis Female Fertility Fertility Hysterectomy Hysterectomy Infertility, Female

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