The copper chelator ammonium tetrathiomolybdate inhibits the progression of experimental endometriosis in TNFR1-deficient mice

by Selleckchem | Oct 24 2023

The TNF-α/TNFR system is involved in endometriosis (EDT), a gynecologic estrogen-dependent disease. Elevated copper concentrations have also been associated with EDT, even in TNFR1-deficient mice where disease worsening occurs. We aimed to evaluate whether treatment with ammonium tetrathiomolybdate (TM, copper chelator) is beneficial in TNFR1-deficient mice presenting with worsened EDT status. Female C57BL/6 mice were divided into three groups: KO Sham, KO EDT, and KO EDT+TM. TM was administered from the 15th postoperative day, and samples were collected one month after inducing pathology. In peritoneal fluid, copper and estradiol levels were determined by electrothermal atomic absorption spectrometry and electrochemiluminescence, respectively. Lesions were processed for the analysis of cell proliferation (PCNA immunohistochemistry), expression of angiogenic markers (RT-qPCR), and oxidative stress (spectrophotometric methods). We found that EDT increased copper and estradiol levels compared to the KO Sham group, while the TM administration restored the levels of both factors. TM also reduced the volume and weight of the lesions and cell proliferation rate. Besides, TM treatment decreased the number of blood vessels and the Vegfa, Fgf2, and Pdgfb expression. Furthermore, superoxide dismutase and catalase activity decreased, and lipid peroxidation increased. TM administration inhibits EDT progression in TNFR1-deficient mice where the pathology is exacerbated.

Comments:

The study aimed to evaluate the potential benefits of treating TNFR1-deficient mice with ammonium tetrathiomolybdate (TM), a copper chelator, in the context of worsened endometriosis (EDT) status. Female C57BL/6 mice were divided into three groups: KO Sham (control), KO EDT (endometriosis), and KO EDT+TM (endometriosis treated with TM). TM was administered from the 15th postoperative day, and samples were collected one month after inducing the pathology.

The researchers analyzed the peritoneal fluid to determine copper and estradiol levels using electrothermal atomic absorption spectrometry and electrochemiluminescence, respectively. They also processed the lesions to analyze cell proliferation (PCNA immunohistochemistry), expression of angiogenic markers (RT-qPCR), and oxidative stress (spectrophotometric methods).

The results indicated that endometriosis increased copper and estradiol levels compared to the control group (KO Sham), while TM administration restored the levels of both factors. TM treatment also reduced the volume and weight of the lesions and inhibited cell proliferation. Additionally, TM decreased the number of blood vessels and the expression of angiogenic markers Vegfa, Fgf2, and Pdgfb. Moreover, TM administration led to a decrease in superoxide dismutase and catalase activity, indicating a decrease in antioxidant defenses, and an increase in lipid peroxidation, indicating increased oxidative stress.

Overall, the findings suggest that TM administration can inhibit the progression of endometriosis in TNFR1-deficient mice, even when the pathology is exacerbated. The treatment restored copper and estradiol levels, reduced lesion size, inhibited cell proliferation and angiogenesis, and modulated oxidative stress markers. These results highlight the potential therapeutic benefit of TM, a copper chelator, in the management of endometriosis, particularly in the context of TNFR1 deficiency.