Copper exposure induces inflammation and PANoptosis through the TLR4/NF-κB signaling pathway, leading to testicular damage and impaired spermatogenesis in Wilson disease.

Autor: Zhao D; Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, 230031, Anhui, China., Wu L; Reproductive and Genetic Branch, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China., Fang X; Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, 230031, Anhui, China., Wang L; Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, 230031, Anhui, China., Liu Q; Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, 230031, Anhui, China., Jiang P; Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, 230031, Anhui, China., Ji Z; Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, 230031, Anhui, China., Zhang N; Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, 230031, Anhui, China., Yin M; Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, 230031, Anhui, China., Han H; Department of Neurology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, 230031, Anhui, China. Electronic address: hanhuidoctor2022@163.com.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2024 Jun 01; Vol. 396, pp. 111060. Date of Electronic Publication: 2024 May 17.
DOI: 10.1016/j.cbi.2024.111060
Abstrakt: Copper is a toxic heavy metal that causes various damage when it accumulates in the body beyond the physiological threshold. Wilson disease (WD) is an inherited disorder characterized by impaired copper metabolism. Reproductive damage in male patients with WD is gradually attracting attention. However, the underlying mechanisms of copper toxicity are unclear. In this study, we investigated the role of inflammation and PANoptosis in testicular damage and impaired spermatogenesis caused by copper deposition using the WD model toxic milk (TX) mice. Copper chelator-penicillamine and toll-like receptor 4 (TLR4) inhibitor-eritoran were used to intervene in TX mice in our animal experiment methods. Testis samples were collected from mice for further analysis. The results showed that the morphology and ultrastructure of the testis and epididymis in TX mice were damaged, and the sperm counts decreased significantly. The TLR4/nuclear factor kappa-B (NF-κB) signaling pathway was activated by copper deposition, which led to the upregulation of serum and testicular inflammatory factors in TX mice. Meanwhile, pyroptosis, apoptosis, and necroptosis were significant in the testis of TX mice. Both chelated copper or inhibited TLR4 expression markedly suppressed the TLR4/NF-κB signaling pathway, thereby reducing the expression of inflammatory factors. PANoptosis in the testis of TX mice was also reversed. Our study indicated that pathological copper exposure induces inflammation and PANoptosis through the TLR4/NF-κB signaling pathway, leading to toxic testicular damage and impaired spermatogenesis in WD.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hui Han reports financial support was provided by the National Natural Science Foundation of China. Limin Wu reports financial support was provided by the National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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