Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice

Abstract

Ovarian endometriosis (OE) provides women of reproductive age with not only severe menstrual pain but also infertility and an increased risk for ovarian carcinogenesis. Whereas peritoneal endometriosis models have been developed with syngeneic implantation of minced uterine tissue and oncogenic K-ras allele with conditional Pten deletion within ovarian surface epithelium generated preneoplastic endometrial glandular morphology, followed by endometrioid adenocarcinoma, there has been no mouse model of OE similar to human counterparts, applicable to preclinical studies. Here we for the first time established a murine OE model that reveals infertility, and evaluated the involvement of iron catalyzed oxidative stress in the pathogenesis. Minced uterine tissue from female mice was implanted on ovarian surface of syngeneic mice after bursectomy to induce OE. Ectopic growth of endometrium was observed in association with ovary 4 weeks after implantation in 85.7% (12/14) of the operated mice with our protocol. Endometriotic lesions involved intestine, pancreas and peritoneal wall. Fibrosis around the ovary was prominent and increased time-dependently in the OE group. Iron accumulation was significantly increased in the OE group, leading to oxidative stress in each stage of the follicles as evaluated by 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2′-deoxyguanosine. Expression of follicle stimulating hormone receptor in the follicles revealed a significant decrease during pre-antral, antral and pre-ovulatory phases in the OE group. Finally, the number of pups was significantly reduced in the OE group in comparison to the controls. This model affords an opportunity to evaluate agents or procedures to counteract ovarian endometriosis in the preclinical settings.

Molecular and Clinical Insights on the Complex Interaction between Oxidative Stress, Apoptosis, and Endobiota in the Pathogenesis of Endometriosis

“…The accumulation of iron ions was also reported by Polak et al [30] while studying the overall oxidative status of peritoneal fluid of EMS patients suggesting that iron metabolism could be disrupted in this disease. Furthermore, since iron could catalyze many ROS species production and was also implicated in cellular dysfunction, necrosis, and apoptosis, Chen, Hayashi, and co-authors [31,32] investigated the mitochondrial structure and function of endometrial stromal cells (ESCs) in ovarian endometriosis (OE) in relation to mitochondrial and iron metabolism. They found that in the ESCs, mitochondria generated more ROS, while SOD2 was highly expressed in the endometrium, suggesting an abnormal energetic metabolism of ectopic ESCs.…”

Bioadaptation of implants to In vitro and In vivo oxidative stress pathological conditions via nanotopography-induced FoxO1 signaling pathways to enhance Osteoimmunal regeneration

“…To analyze the oxidative stress in the peri-implant bone tissue, immunohistochemistry staining was performed on the specimens harvested on day 7 with antibodies specific for 4-hydroxy-2-nonenal (4-HNE, 1:100 dilution, bs-6313R), one of the most specific lipid peroxidation products, along with 8-OHdG (1:200 dilution, bs-1278R) [ 22 ]. Furthermore, the early immune response around the implants was evaluated by analyzing the expression of inflammatory cytokines in specimens harvested on day 7 using antibodies specific for TNF-α (1:200 dilution, bs-10802R) and IL-10 (1:200 dilution, bs-6761R) [ 23 ].…”

Brief Review of Endometriosis and the Role of Trace Elements

“…The analysis of the ovarian endometriotic stroll area revealed vas iron deposits, which may promote endometriosis through the oxidative stress processes. They underlined the role of increased oxidative stress in ovarian follicles and its association with the decreased FSHR expression as well as a decreased number of connected fetuses [ 97 ]. Moreover, endometriotic stroll cells were found to have high iron affinity [ 98 ].…”