PM2.5 caused ferroptosis in spermatocyte via overloading iron and disrupting redox homeostasis

Wang, Jiankang; Zhang, Zhonghao; Shi, Fuquan; Li, Ying-Qing; Tang, Ying; Liu, Chang; Wang, Yimeng; Chen, Jianping; Xiao, Jin-Fen; Yang, Huan; Sun, Lei; Chen, Qing; Ao, Lin; Han, Fang; Liu, Jinyi; Cao, Jun

doi:10.1016/j.scitotenv.2023.162089

Cited by 13 publications

(8 citation statements)

References 47 publications

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“…Presently, a connection between ferroptosis and male reproduction disorder has been established 39 . In fact, some studies have reported that the induction of testicular oxidative stress leading to ferroptosis by substances such as arsenite, copper, and PM2.5 particles 33 , 40 , 41 , while Di (2-ethylhexyl) phthalate has been shown to induce ferroptosis via HIF-1α/HO-1 signaling pathway and transferrin receptor 1 , 42 . Relevant for the present work, Zhao et al recently reported that ferroptosis is involved in BU-induced oligospermia in mice and that such effect is mediated by inhibition of Nrf2-GPX4 (FPN1) signaling pathway 2 .…”

Section: Discussionmentioning

confidence: 99%

NAD⁺ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis

Feng,

Liu,

Zuo

et al. 2024

Theranostics

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Rationale: In recent years, nicotinamide adenine dinucleotide (NAD + ) precursors (Npre) have been widely employed to ameliorate female reproductive problems in both humans and animal models. However, whether and how Npre plays a role in the male reproductive disorder has not been fully clarified. Methods: In the present study, a busulfan-induced non-obstructive azoospermic mouse model was used, and Npre was administered for five weeks following the drug injection, with the objective of reinstating spermatogenesis and fertility. Initially, we assessed the NAD + level, germ cell types, semen parameters and sperm fertilization capability. Subsequently, testis tissues were examined through RNA sequencing analysis, ELISA, H&E, immunofluorescence, quantitative real-time PCR, and Western blotting techniques. Results: The results indicated that Npre restored normal level of NAD + in blood and significantly alleviated the deleterious effects of busulfan (BU) on spermatogenesis, thereby partially reestablishing fertilization capacity. Transcriptome analysis, along with recovery of testicular Fe 2+ , GSH, NADPH, and MDA levels, impaired by BU, and the fact that Fer-1, an inhibitor of ferroptosis, restored spermatogenesis and semen parameters close to CTRL values, supported such possibility. Interestingly, the reduction in SIRT2 protein level by the specific inhibitor AGK2 attenuated the beneficial effects of Npre on spermatogenesis and ferroptosis by affecting PGC-1α and ACLY protein levels, thus suggesting how these compounds might confer spermatogenesis protection. Conclusion: Collectively, these findings indicate that NAD + protects spermatogenesis against ferroptosis, probably through SIRT2 dependent mechanisms. This underscores the considerable potential of Npre supplementation as a feasible strategy for preserving or restoring spermatogenesis in specific conditions of male infertility and as adjuvant therapy to preserve male fertility in cancer patients receiving sterilizing treatments.

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Section: Discussionmentioning

confidence: 99%

NAD⁺ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis

Feng,

Liu,

Zuo

et al. 2024

Theranostics

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“… Factor/reagent Categories Mechanism Ref. Busulfan Drug Downregulated NRF2ˎGPX4 and FPN expression [ 70 ] Tripterygium wilfordii polyglycoside tablet Drug Inhibit NRF2/xCT/GPX4 axis and FPN espression [ 118 , 119 ] Ischemia-reperfusion Testicular torsion Downregulated NRF2ˎGPX4 and FPN expression [ 71 ] Scrotal hyperthermia High temperature exposure Increase ACSL4 expression [ 107 ] Smoking (nicotine) Habit Downregulated NRF2 and GPX4 expression [ 82 , 108 ] 2.5-micron particulate matter Environmental factor Depletion of GSH and reduce GPX4 expression [ 83 , 110 ] DEHP Environmental factor Increase TFR1 and HO1 expression Reduce GPX4 level [ 27 , 126 , 135 ] BisphenolA Environmental factor Downregulate NRF2/HO1 and xCT/GPX4 pathwayˎActivate ACSL4 expression and ROS accumulation [ 111 , 112 ] Arsenite Heavy mental Downregulate xCT/GPX4 pathwayˎInduce ROS release and increase iron levels [ 84 ] Cdmium Heavy mental Reduce FTHˎFPN and xCT expressionˎDownregulate NRF2/HO1 pathway and enhance lipid peroxidation [ 69 , 115 ] Hexavalent chromium Heavy mental Inhibit xCT/GPX4 and mTOR [ 99 ] Co...…”

Section: The Role Of Ferroptosis In the Testismentioning

confidence: 99%

“…In another study, sperm specimens from smoking patients showed decreased spermatozoal motility and decreased GPX4 expression [ 82 ]. In addition, reduced SLC7A11 and GPX4 expression was reported in testicular injury induced by 2.5-micron particulate matter and arsenite [ 83 , 84 ]. Elevated iron levels were associated with these causes of testicular injury.…”

Section: The Role Of Ferroptosis In the Testismentioning

confidence: 99%

Emerging roles of ferroptosis in male reproductive diseases

Yuan,

Sun,

et al. 2023

Cell Death Discov.

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Ferroptosis is a type of programmed cell death mediated by iron-dependent lipid peroxidation that leads to excessive lipid peroxidation in different cells. Ferroptosis is distinct from other forms of cell death and is associated with various diseases. Iron is essential for spermatogenesis and male reproductive function. Therefore, it is not surprising that new evidence supports the role of ferroptosis in testicular injury. Although the molecular mechanism by which ferroptosis induces disease is unknown, several genes and pathways associated with ferroptosis have been linked to testicular dysfunction. In this review, we discuss iron metabolism, ferroptosis, and related regulatory pathways. In addition, we analyze the endogenous and exogenous factors of ferroptosis in terms of iron metabolism and testicular dysfunction, as well as summarize the relationship between ferroptosis and male reproductive dysfunction. Finally, we discuss potential strategies to target ferroptosis for treating male reproductive diseases and provide new directions for preventing male reproductive diseases.

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“…[26][27][28] Certain iron-based MOFs not only have the above advantages but also release iron ions to promote ferroptosis triggered by iron overload in the microenvironment of tumor cells, making them an ideal drug-carrying nanomaterial. 29,30 On the basis of the above background, we successfully constructed the Sora-loaded nanoparticles SM@F by loading Sora into the cage structure of iron-based nMOF (MOF) and modifying the surface with tumour-targeted molecular folic acid (FA). We investigated the antiproliferative activity of SM@F in SMMC-7721 cells with and without the addition of ferroptosis regulators by CCK-8 assay.…”

Section: Introductionmentioning

confidence: 99%

“…Metal–organic frameworks (MOFs) have the advantages of large pore volume and high specific surface area, the ability to introduce functional groups on the surface by post‐modification method, and good biodegradability compared with the traditional nano drug carriers 26–28 . Certain iron‐based MOFs not only have the above advantages but also release iron ions to promote ferroptosis triggered by iron overload in the microenvironment of tumor cells, making them an ideal drug‐carrying nanomaterial 29,30 …”

Section: Introductionmentioning

confidence: 99%

Tumor‐targeted and microenvironment‐activatable iron‐based nMOF for synergistic inducing ferroptosis

Gao,

Xie,

Zhang

et al. 2024

Applied Organom Chemis

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Ferroptosis is a new form of cell death that relies on iron and involves an imbalance of intracellular reactive oxygen species (ROS), which is expected to help alleviate bottlenecks in tumor treatment. Herein, a sorafenib‐loaded folic acid‐armored iron‐based nMOF was designed for synergistic inducing ferroptosis of tumors. The particle size of the synthesized SM@F is about 210nm, and the drug loading rate is 24.74%. SM@F can be degraded and releases sorafenib and iron ions slowly, resulting in intracellular drug release and iron overload after being highly uptaken by SMMC‐7721 cells. SM@F can effectively inhibit the proliferation of SMMC‐7721 cells, and this effect can be significantly attenuated by ferroptosis inhibitors. Mechanistic investigations revealed that SM@F could increase the content of ROS, and lipid peroxides; decrease the content of glutathione (GSH); and down‐regulate the GXP4 expression in SMMC‐7721 cells. The results indicate that the synthesized SM@F could effectively inhibit the proliferation of tumor cells with synergistic inducing ferroptosis.

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PM2.5 caused ferroptosis in spermatocyte via overloading iron and disrupting redox homeostasis

Cited by 13 publications

References 47 publications

NAD⁺ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis

NAD⁺ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis

Emerging roles of ferroptosis in male reproductive diseases

Tumor‐targeted and microenvironment‐activatable iron‐based nMOF for synergistic inducing ferroptosis

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PM2.5 caused ferroptosis in spermatocyte via overloading iron and disrupting redox homeostasis

Cited by 13 publications

References 47 publications

NAD+ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis

NAD+ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis

Emerging roles of ferroptosis in male reproductive diseases

Tumor‐targeted and microenvironment‐activatable iron‐based nMOF for synergistic inducing ferroptosis

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NAD⁺ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis

NAD⁺ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis