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. 2023 Jun 26;13(1):10354.
doi: 10.1038/s41598-023-37031-1.

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

Rocío Ayelem Conforti  1 , María Belén Delsouc  2 , Ana Sofia Zabala  1 , Sandra Silvina Vallcaneras  1 , Marilina Casais  3
Affiliations

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

"V体育2025版" Rocío Ayelem Conforti et al. Sci Rep. .

Abstract (V体育官网)

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. VSports手机版.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Effect of TM on the Cu concentration in the peritoneal fluid of TNFR1−/− mice. Cu was determined by ETAAS in sham-operated mice (KO Sham; triangles), EDT-induced mice (KO EDT; circles), and TM-treated EDT-induced mice (KO EDT+TM; squares). Results are expressed as mean ± SEM (n = 8 animals/group). One-way ANOVA followed by Tukey's test was used. ***P < 0.001.
Figure 2
Figure 2
Effect of TM on the development of endometriotic-like lesions in TNFR1−/− mice. The number of established lesions (a), their volume (b), and their weight (c) were evaluated in EDT-induced mice (KO EDT) and TM-treated EDT-induced mice (KO EDT+TM) after one month of inducing the pathology. Representative images of the morphology of endometriotic-like lesions are provided. Results are expressed as mean ± SEM (n = 8 animals/group). KO EDT: circles; KO EDT+TM: squares. Statistical comparisons were made using Student's t test. **P < 0.01; ***P < 0.001.
Figure 3
Figure 3
Effect of TM on the estradiol levels in the peritoneal fluid of TNFR1−/− mice. Estradiol was analyzed by ECLIA in sham-operated mice (KO Sham; triangles), EDT-induced mice (KO EDT; circles), and TM-treated EDT-induced mice (KO EDT+TM; squares) (a). Results are expressed as mean ± SEM (n = 8 animals/group). One-way ANOVA followed by Tukey's test was used. ***P < 0.001. In addition, a correlation study between the lesion volume and estradiol was performed for the entire group of mice with EDT (n = 16) (b). The normality of data was assessed with the Shapiro–Wilk test, and Spearman´s correlation method was applied. *P < 0.05, Spearman r = 0.5548.
Figure 4
Figure 4
Effect of TM on cell proliferation of endometriotic-like lesions in TNFR1−/− mice. The micrographs show representative histological sections of induced endometriotic-like lesions (magnification: 100 × and 400 ×) in untreated mice (KO EDT) (a) and TM-treated mice (KO EDT+TM) (b). Scale bar, 100 μm and 25 μm, respectively. The percentage of proliferating cells in endometriotic-like lesions was evaluated by immunohistochemistry for PCNA in both experimental groups (c). PCNA-positive cells were identified by the presence of brown nuclear reactivity. Results are expressed as mean ± SEM (n = 6 animals/group). KO EDT: circles; KO EDT+TM: squares. Statistical comparisons were made using Student's t test. ***P < 0.001.
Figure 5
Figure 5
Effect of TM on the angiogenic process in endometriotic-like lesions in TNFR1−/− mice. The micrographs show representative histological sections of endometriotic-like lesions induced in untreated (KO EDT) and TM-treated (KO EDT+TM) mice (a). Blood vessels of different calibers are marked with an asterisk. Magnification: 400 ×. Scale bar, 25 µm. The counting of blood vessels was performed on sections stained with hematoxylin–eosin using an optical light microscope for both experimental groups (b). Results are expressed as mean ± SEM (n = 6 animals/group). The mRNA expression of Vegfa (c), Fgf2 (d), and Pdgfb (e) in endometriotic-like lesions was evaluated for both experimental groups. The relative quantification of each mRNA was calculated from the Cq values obtained for the genes of interest and the reference gene (Rn18s) using the 2−ΔΔCt method. Results are expressed as mean ± SEM (n = 8 animals/group). KO EDT: circles; KO EDT+TM: squares. Statistical comparisons were made using Student's t test. *P < 0.05; **P < 0.01.
Figure 6
Figure 6
Effect of TM on oxidative stress in endometriotic-like lesions of TNFR1−/− mice. The activity of the antioxidant enzymes SOD (a), CAT (b), and GPX (c) and the levels of MDA (d) were analyzed in lesions of untreated mice (KO EDT; circles) and TM-treated mice (KO EDT+TM; squares). Results are expressed as mean ± SEM (n = 8 animals/group). Statistical comparisons were made using Student's t test. *P < 0.05; ***P < 0.001.
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