Abstract
Cadmium (Cd) is a well-known heavy metal pollutant that is a toxic threat to human health. Cadmium can induce anemia and is involved in metabolic disorders. Heme-regulated eIF2α kinase (HRI) is the main regulator of terminal erythropoiesis and is required to prevent anemia and toxicity in the liver and kidneys in response to various stresses including Cd exposure. However, the involvement of HRI in Cd-induced metabolic disorders remains unclear. In this study, we performed proteomics on plasma collected from wild-type and Hri knockout mice treated with or without 5 and 10 mg/kg Cd. In total, 382 proteins were identified and indicated that the number of proteins in wild-type (Wt) mice was 2.4-fold higher than that in Hri knockout mice after Cd exposure, indicating the requirement of HRI for Cd exposure responses. Proteins associated with glycolysis were the most upregulated after Cd exposure in Wt mice, while, the induction of glycolysis after Cd exposure was interrupted in Hri knockout mice, suggesting the involvement of HRI in Cd-induced glycolysis upon acute exposure. Our results will help identify potential targets involved in metabolic disorders following acute exposure to high doses of cadmium.
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The data and materials used in the current study are available from the corresponding author on reasonable request.
References
Choo AY, Kim SG, Vander Heiden MG, Mahoney SJ, Vu HS, Yoon S-O, Cantley LC, Blenis J (2010) Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol Cell 38(4):487–499
European Food Safety Authority (2012) Cadmium dietary exposure in the European population. EFSA J 10(1):2551
Go Y-M, Roede JR, Orr M, Liang Y, Jones DP (2014) Integrated redox proteomics and metabolomics of mitochondria to identify mechanisms of cd toxicity. Toxicol Sci 139:59–73. https://doi.org/10.1093/toxsci/kfu018
Han A, Yu C, Lu L, Fujiwara Y, Browne C, Chin GT, Fleming MD, Leboulch P, Orkin SH, Chen J-J (2001) Heme-regulated eIF2α kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency. EMBO J 20:6909–6918
Horiguchi H, Oguma E, Kayama F (2011) Cadmium induces anemia through interdependent progress of hemolysis, body iron accumulation, and insufficient erythropoietin production in rats. Toxicol Sci 122(1):198–210
Järup L, Åkesson A (2009) Current status of cadmium as an environmental health problem. Toxicol Appl Pharm 238(3):201–208
Ke Q, Costa M (2006) Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 70(5):1469–1480
Li L, Tian X, Yu X, Dong S (2016) Effects of acute and chronic heavy metal (Cu, Cd, and Zn) exposure on sea cucumbers (Apostichopus japonicus). Biomed Res Int 2016:13
Lu L, Han A, Chen J-J (2001) Translation initiation control by heme-regulated eukaryotic initiation factor 2α kinase in erythroid cells under cytoplasmic stresses. Mol Cell Biol 21:7971–7980
Sabir S, Akash MSH, Fiayyaz F, Saleem U, Mehmood MH, Rehman K (2019) Role of cadmium and arsenic as endocrine disruptors in the metabolism of carbohydrates: inserting the association into perspectives. Biomed Pharmacother 114:108802
Satarug S, Garrett SH, Sens MA, Sens DA (2009) Cadmium, environmental exposure, and health outcomes. Environ Health Perspect 118:182–190
Schwartz GG, Il’yasova D, Ivanova A (2003) Urinary cadmium, impaired fasting glucose, and diabetes in the NHANES III. Diabetes Care 26(2):468–470
Semenza GL (1998) Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev 8(5):588–594
Suragani RNVS, Zachariah R, Velazquez J, Liu S, Sun CW, Townes TM, Chen J-J (2012) Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis. Blood 119(22):5276–5284
Tinkov AA, Filippini T, Ajsuvakova OP, Aaseth JO, Gluhcheva Y, Ivanova J, Bjorklund G, Skalnaya MG, Gatiatulina ER, Popova EV, Nemereshina ON, Vinceti M, Skalny AV (2017) The role of cadmium in obesity and diabetes. Sci Total Environ 601-602:741–755
Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92(12):5510–5514
Wang L, Wang X, Zhang S, Qu G, Liu S (2013) A protective role of heme-regulated eIF2α kinase in cadmium-induced toxicity in erythroid cells. Food Chem Toxicol 62:880–891
Wang L, Zhang S, Wang Z, Xu M, Yuan L, Cui J, Liu S (2017) A protective role of heme-regulated eIF2α kinase in cadmium-induced liver and kidney injuries. Chemosphere 185:284–289
Zhang S, Macias-Garcia A, Ulirsch JC, Velazquez J, Butty VL, Levine SS, Sankaran VG, Chen JJ (2019) HRI coordinates translation necessary for protein homeostasis and mitochondrial function in erythropoiesis. Elife 8:e46976
Zhang S, Macias-Garcia A, Velazquez J, Paltrinieri E, Kaufman RJ, Chen J-J (2018) HRI coordinates translation by eIF2αP and mTORC1 to mitigate ineffective erythropoiesis in mice during iron deficiency. Blood 131(4):450–461
Acknowledgements
We acknowledge Dr. Jane-Jane Chen at Massachusetts Institute of Technology for generously providing us Hri knockout mice.
Funding
This study was supported by the National Natural Science Foundation of China (grant number: 22076104) and the “Taishan Scholars” Program for Young Expert of Shandong Province (grant number: tsqn202103105).
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Q. W. and W. M. performed the experiments and analyzed the data. S. Z. designed the experiments and wrote the manuscript.
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The animal experiment in this study was approved by the Ethics Review Committees of Shandong First Medical University & Shandong Academy of Medical Sciences.
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Quanshu Wang and Wanqi Ma contributed to this work equally.
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Wang, ., Ma, W. & Zhang, S. Important roles of heme-regulated eIF-2α kinase in cadmium-induced glycolysis under acute exposure. Environ Sci Pollut Res 30, 88444–88449 (2023). https://doi.org/10.1007/s11356-023-28473-1
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DOI: https://doi.org/10.1007/s11356-023-28473-1