Abstract: The aim of this study was to investigate the role of selenoprotein M (SelM) in endoplasmic reticulum stress and apoptosis in nickel-exposed mouse hearts and to explore the detoxifying effects of melatonin. At 21 d after intraperitoneal injection of nickel chloride (NiCl₂) and/or melatonin into male wild-type (WT) and SelM knockout (KO) C57BL/6J mice, NiCl₂ was found to induce changes in the microstructure and ultrastructure of the hearts of both WT and SelM KO mice, which were caused by oxidative stress, endoplasmic reticulum stress, and apoptosis, as evidenced by decreases in malondialdehyde (MDA) content and total antioxidant capacity (T-AOC) activity. Changes in the messenger RNA (mRNA) and protein expression of genes related to endoplasmic reticulum stress (activating transcription factor 4 (ATF4), inositol-requiring protein 1 (IRE1), c-Jun N-terminal kinase (JNK), and C/EBP homologous protein (CHOP)) and apoptosis (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, Caspase-9, and Caspase-12) were also observed. Notably, the observed damage was worse in SelM KO mice. Furthermore, melatonin alleviated the heart injury caused by NiCl₂ in WT mice but could not exert a good protective effect in the heart of SelM KO mice. Overall, the findings suggested that the antioxidant capacity of SelM, as well as its modulation of endoplasmic reticulum stress and apoptosis, plays important roles in nickel-induced heart injury.

硒蛋白M敲除在褪黑素拮抗镍诱导的小鼠心脏细胞凋亡和内质网应激中的作用

[1]CaiJZ, HuangJQ, YangJ, et al., 2022. The protective effect of selenoprotein M on non-alcoholic fatty liver disease: the role of the AMPKα1-MFN2 pathway and Parkin mitophagy. Cell Mol Life Sci, 79(7):354.

[2]CameronKS, BuchnerV, TchounwouPB, 2011. Exploring the molecular mechanisms of nickel-induced genotoxicity and carcinogenicity: a literature review. Rev Environ Health, 26(2):81-92.

[3]CaoJW, XuR, WangFH, et al., 2023. Polyethylene microplastics trigger cell apoptosis and inflammation via inducing oxidative stress and activation of the NLRP3 inflammasome in carp gills. Fish Shellfish Immunol, 132:108470.

[4]ChakrabartiSK, BaiCJ, 1999. Role of oxidative stress in nickel chloride-induced cell injury in rat renal cortical slices. Biochem Pharmacol, 58(9):1501-1510.

[5]ChenY, JingHY, ChenMY, et al., 2021. Transcriptional profiling of exosomes derived from Staphylococcus aureus-infected bovine mammary epithelial cell line MAC-T by RNA-seq analysis. Oxid Med Cell Longev, 2021:8460355.

[6]ChiQR, LuanYL, ZhangYM, et al., 2019. The regulatory effects of miR-138-5p on selenium deficiency-induced chondrocyte apoptosis are mediated by targeting SelM. Metallomics, 11(4):845-857.

[7]DasKK, ReddyRC, BagojiIB, et al., 2018. Primary concept of nickel toxicity‍—‍‍an overview. J Basic Clin Physiol Pharmacol, 30(2):141-152.

[8]DongWX, YanLQ, TanY, et al., 2022. Melatonin improves mitochondrial function by preventing mitochondrial fission in cadmium-induced rat proximal tubular cell injury via SIRT1-PGC-1α pathway activation. Ecotoxicol Environ Saf, 242:113879.

[9]DuXB, LiHP, WangZ, et al., 2013. Selenoprotein P and selenoprotein M block Zn²⁺-mediated Aβ⁴² aggregation and toxicity. Metallomics, 5(7):861-870.

[10]FanRF, TangKK, WangZY, et al., 2021. Persistent activation of Nrf2 promotes a vicious cycle of oxidative stress and autophagy inhibition in cadmium-induced kidney injury. Toxicology, 464:152999.

[11]FernandezA, OrdóñezR, ReiterRJ, et al., 2015. Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis. J Pineal Res, 59(3):292-307.

[12]GenchiG, CarocciA, LauriaG, et al., 2020. Nickel: human health and environmental toxicology. Int J Environ Res Public Health, 17(3):679.

[13]GongZG, ZhaoY, WangZY, et al., 2022. Epigenetic regulator BRD4 is involved in cadmium-induced acute kidney injury via contributing to lysosomal dysfunction, autophagy blockade and oxidative stress. J Hazard Mater, 423:127110.

[14]GuoHR, ChenL, CuiHM, et al., 2016. Research advances on pathways of nickel-induced apoptosis. Int J Mol Sci, 17(1):10.

[15]KleszczyńskiK, HardkopLH, FischerTW, 2011. Differential effects of melatonin as a broad range UV-damage preventive dermato-endocrine regulator. Dermatoendocrinol, 3(1):27-31.

[16]KubrakOI, PoignerH, HusakVV, et al., 2014. Goldfish brain and heart are well protected from Ni²⁺-induced oxidative stress. Comp Biochem Physiol C Toxicol Pharmacol, 162:43-50.

[17]LeeYK, YimSY, JungSE, et al., 2009. The costimulation of selenium treatment and selenoprotein M overexpression significantly induced the up- and down-regulation of ERK MAPK signaling pathway in various tissues. Lab Anim Res, 25(3):201-205.

[18]LiJH, ZhangWY, ZhouP, et al., 2022. Selenium deficiency induced apoptosis via mitochondrial pathway caused by oxidative stress in porcine gastric tissues. Res Vet Sci, 144:142-148.

[19]LiXJ, BaiRC, BaiYC, et al., 2022. ROS-mediated PPAR/RXR inhibition contributes to acetochlor-induced apoptosis and autophagy in Ctenopharyngodon idella hepatic cells. Fish Shellfish Immunol, 128:684-694.

[20]LiXY, ZhangHR, QiaoSQ, et al., 2022. Melatonin administration alleviates 2,2,4,4-tetra-brominated diphenyl ether (PBDE-47)‍-induced necroptosis and secretion of inflammatory factors via miR-140-5p/TLR4/NF-κB axis in fish kidney cells. Fish Shellfish Immunol, 128:228-237.

[21]LiuCM, ZhengGH, MingQL, et al., 2013. Sesamin protects mouse liver against nickel-induced oxidative DNA damage and apoptosis by the PI3K-Akt pathway. J Agric Food Chem, 61(5):1146-1154.

[22]LiuJB, LiZF, LuL, et al., 2022. Glyphosate damages blood-testis barrier via NOX1-triggered oxidative stress in rats: long-term exposure as a potential risk for male reproductive health. Environ Int, 159:107038.

[23]LiuQ, SunY, ZhuY, et al., 2022a. Melatonin relieves liver fibrosis induced by Txnrd3 knockdown and nickel exposure via IRE1/NF‍-‍‍κB/NLRP3 and PERK/TGF‍-‍‍β1 axis activation. Life Sci, 301:120622.

[24]LiuQ, DuPY, ZhuY, et al., 2022b. Thioredoxin reductase 3 suppression promotes colitis and carcinogenesis via activating pyroptosis and necrosis. Cell Mol Life Sci, 79(2):106.

[25]LiuXJ, WangYQ, ShangSQ, et al., 2022. TMT induces apoptosis and necroptosis in mouse kidneys through oxidative stress-induced activation of the NLRP3 inflammasome. Ecotoxicol Environ Saf, 230:113167.

[26]LuJY, ZhangM, JinHL, et al., 2014. Advances on molecular mechanism of chronic inflammation-driven lung cancer induced by environmental carcinogens. Prog Biochem Biophys, 41(1):41-51.

[27]LuW, LiWW, JinXK, et al., 2012. Reproductive function of Selenoprotein M in Chinese mitten crabs (Eriocheir sinesis). Peptides, 34(1):168-176.

[28]MiaoZR, MiaoZY, ShiX, et al., 2022a. The antagonistic effect of selenium on lead-induced apoptosis and necroptosis via P38/JNK/ERK pathway in chicken kidney. Ecotoxicol Environ Saf, 231:113176.

[29]MiaoZR, MiaoZY, WangSC, et al., 2022b. Exposure to imidacloprid induce oxidative stress, mitochondrial dysfunction, inflammation, apoptosis and mitophagy via NF-kappaB/JNK pathway in grass carp hepatocytes. Fish Shellfish Immunol, 120:674-685.

[30]PittsMW, HoffmannPR, 2018. Endoplasmic reticulum-resident selenoproteins as regulators of calcium signaling and homeostasis. Cell Calcium, 70:76-86.

[31]QiaoSQ, SunY, JiangYY, et al., 2022. Melatonin amelior

[32]ates nickel induced autophagy in mouse brain: diminution of oxidative stress. Toxicology, 473:153207.

[33]RehmanK, FatimaF, WaheedI, et al., 2018. Prevalence of exposure of heavy metals and their impact on health consequences. J Cell Biochem, 119(1):157-184.

[34]RoohbakhshA, ShamsizadehA, HayesAW, et al., 2018. Melatonin as an endogenous regulator of diseases: the role of autophagy. Pharmacol Res, 133:265-276.

[35]SelvikLKM, FjeldboCS, FlatbergA, et al., 2013. The duration of gastrin treatment affects global gene expression and molecular responses involved in ER stress and anti-apoptosis. BMC Genomics, 14:429.

[36]SongN, WangW, WangY, et al., 2021. Hydrogen sulfide of air induces macrophage extracellular traps to aggravate inflammatory injury via the regulation of miR-15b-5p on MAPK and insulin signals in trachea of chickens. Sci Total Environ, 771:145407.

[37]SureshC, DennisAO, HeinzJ, et al., 2006. Melatonin protection against lead-induced changes in human neuroblastoma cell cultures. Int J Toxicol, 25(6):459-464.

[38]WangCX, ZhangR, WangS, et al., 2021. Protective effects of nano-selenium on nickel-induced renal cell apoptosis in rats. J Toxicol, 35(3):193-197 (in Chinese).

[39]WangY, ZhaoHJ, LiuYC, et al., 2021. Environmentally relevant concentration of sulfamethoxazole-induced oxidative stress-cascaded damages in the intestine of grass carp and the therapeutic application of exogenous lycopene. Environ Pollut, 274:116597.

[40]ZhangHR, ZhaoFQ, GaiXX, et al., 2022. Astilbin attenuates apoptosis induced by cadmium through oxidative stress in carp (Cyprinus carpio L.) head kidney lymphocyte. Fish Shellfish Immunol, 125:230-237.

[41]ZhangWY, SunXY, ShiX, et al., 2023. Subacute cadmium exposure induces necroptosis in swine lung via influencing Th1/Th2 balance. Biol Trace Elem Res, 201(1):‍220-228.

[42]ZhangYH, XuS, LiK, et al., 2023. TBBPA induced ROS overproduction promotes apoptosis and inflammation by inhibiting autophagy in mice lung. Ecotoxicol Environ Saf, 252:114607.

[43]ZhaoHJ, WangY, LiuYC, et al., 2021. ROS-induced hepatotoxicity under cypermethrin: involvement of the crosstalk between Nrf2/Keap1 and NF‍-‍κB/iκB-‍α pathways regulated by proteasome. Environ Sci Technol, 55(9):‍6171-6183.

[44]ZhengYY, GuanHY, YangJ, et al., 2021. Calcium overload and reactive oxygen species accumulation induced by selenium deficiency promote autophagy in swine small intestine. Anim Nutr, 7(4):997-1008.