Bone marrow mesenchymal stem cells repair hexavalent chromium‐induced testicular injury by regulating autophagy and ferroptosis mediated by the AKT/mTOR pathway in rats

Abstract

There is no ideal therapy for testicular damage induced by Cr(VI); however, bone marrow mesenchymal stem cells (BMSCs) transplantation may be a promising therapy. A Cr(VI) solution was administered to rats by intraperitoneal injection for 30 days, then BMSCs from donor rats were transplanted. Two weeks later, decreased activity and appetite, along with other pathological changes, were improved in the BMSCs group. The location of BMSCs in damaged testes was observed via laser confocal microscopy. Chromium content in the Cr(VI) and BMSCs groups significantly increased compared with that in the control group, but there was no significant difference between the two groups, as revealed by atomic absorption spectrometry.The ferrous iron and the total iron content of testes in the BMSCs group were significantly lower than those in the Cr(VI) group, as observed by Lillie staining and a tissue iron assay kit. Western blotting and immunohistochemical analyses revealed that the expression of Beclin 1, LC3B, 4-hydroxynonenal, and transferrin receptor 1 was decreased in the BMSCs group, compared with the Cr(VI) group. The expression of glutathione peroxidase 4 (GPX4), SLC7A11, p-AKT, mammalian target of rapamycin (mTOR), and p-mTOR in the BMSCs group was higher than that in the Cr(VI) group.Taken together, we propose that BMSCs repair Cr(VI)-damaged testes by alleviating ferroptosis and downregulating autophagy-associated proteins through the upregulation of AKT and mTOR phosphorylation.autophagy, bone marrow mesenchymal stem cells, ferroptosis, hexavalent chromium, testes | INTRODUCTIONAbout 9% of couples around the world are affected by infertility, and about 40%-50% of those are affected by male infertility. 1,2 There are various reasons for the decline of sperm quality, among which the toxicity of heavy metals is one of the main factors. 3 Chromium is a heavy metal with reproductive toxicity; even so, hexavalent chromium (Cr(VI)) is used in industrial production such as textile printing, electroplating, and dyeing. 4 In addition to occupational exposure, chromium from food sources, such as dairy products, bread, and tea, is also a cause of Cr(VI) poisoning. 5 Cr(VI) compounds not only cause damage to the skin and respiratory systems, 6,7 but also have strong geneticRuijian Zhuge and Zhongrun Li should be considered joint first author.

Mesenchymal stem cells and ferroptosis: Clinical opportunities and challenges

“…In cancer cells, ferroptosis is suppressed through activation of the PI3K/AKT/mTOR pathway [ 180 ]. Taken together, BMSCs repair Cr(VI)-damaged testes by attenuating ferroptosis and downregulating proteins associated with autophagy through the positive regulation of AKT and mTOR phosphorylation [ 165 ], this provides a potential therapeutic target for infertility caused by damage by Cr (VI) in the testis.…”

Investigations into ferroptosis in methylmercury‐induced acute kidney injury in mice

“…20 Previous research has shown that cadmium exposure triggers ferroptosis by interrupting iron homeostasis and redox equilibrium in renal tubular dysfunction. 53 Furthermore, arsenic exposure was found to generate ferroptosis by promoting iron overload in the context of pancreatic dysfunction, 54,55 thereby highlighting the participation of ferroptosis in heavy metal toxicity. According to current research, MeHg exposure affects redox homeostasis and accelerates lipid peroxidation in the body by binding to mercaptan and selenol.…”

Emerging roles of ferroptosis in male reproductive diseases

“… 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...…”

“…In a zinc-induced porcine model of testicular dysfunction, zinc induces ferroptosis by regulating mitochondrial autophagy [ 98 ]. Hexavalent chromium also causes testicular autophagy and ferroptosis in rats [ 99 ]. In addition, classical ferroptosis activators (such as ML-210) or inhibitors (such as ferrostatin-1, Fer-1) modulate intracellular autophagic flux in testicular injury.…”