Ameliorative Effect of Selenomethionine on Cadmium-Induced Hepatocyte Apoptosis via Regulating PI3K/AKT Pathway in Chickens


Selenium (Se) is a trace element for human and animal health. Cadmium (Cd) is a known human carcinogen. The effects of Cd on the environment and humans are well known. Because chickens are at the top of the food chain, it is a good experimental animal model for assessing heavy metal toxicity and its potential threat to humans. Selenomethionine (Se-met) is a suitable form for nutritional Se supplementation. Therefore, the toxicity of Cd to the chicken liver and the antagonistic effects of Se-met on Cd were examined at the molecular level in the present study. The results showed that oxidative stress indicators (apoptosis-related genes, P13K/AKT pathway–related genes, and heat shock proteins (HSPs)–related genes) in the Cd group have changed significantly, indicating Cd induced hepatocyte stress and apoptosis. Interestingly, the changes in oxidative stress indicators (apoptosis-related genes, P13K/AKT pathway–related genes, and HSPs-related genes) in the Cd-Se-met group were mitigated compared with the control group. Our results indicated that Cd can induce hepatocyte apoptosis and stress in the chickens. Se-met has an ameliorative effect on Cd-induced apoptosis of chicken hepatocyte by regulating PI3K/AKT pathway. Our findings will provide a new insight for better understanding of the detoxification function of Se-met to heavy metals.

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  1. 1.

    Zhang Z, Zheng Z, Cai J, Liu Q, Yang J, Gong Y, Wu M, Shen Q, Xu S (2017) Effect of cadmium on oxidative stress and immune function of common carp (Cyprinus carpio L.) by transcriptome analysis. Aquat Toxicol 192:171–177

    CAS  Article  Google Scholar 

  2. 2.

    Chen J, Xu Y, Han Q, Yao Y, Xing H, Teng X (2019) Immunosuppression, oxidative stress, and glycometabolism disorder caused by cadmium in common carp (Cyprinus carpio L.): application of transcriptome analysis in risk assessment of environmental contaminant cadmium. J Hazard Mater 366:386–394

    CAS  Article  Google Scholar 

  3. 3.

    Wei Y, Zheng X, Shohag MJI, Gu M (2017) Bioaccessibility and human exposure assessment of cadmium and arsenic in pakchoi genotypes grown in co-contaminated soils. Int J Environ Res Public Health 14(9):977–993

    Article  Google Scholar 

  4. 4.

    Ataei N, Aghaei M, Panjehpour M (2019) Evidences for involvement of estrogen receptor induced ERK1/2 activation in ovarian cancer cell proliferation by cadmium chloride. Toxicol in Vitro 56:184–193.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Chen QY, DesMarais T, Costa M (2019) Metals and mechanisms of carcinogenesis. Annu Rev Pharmacol Toxicol 59:537–554.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Jin X, Jia T, Liu R, Xu S (2018) The antagonistic effect of selenium on cadmium-induced apoptosis via PPAR-γ/PI3K/Akt pathway in chicken pancreas. J Hazard Mater 357:355–362

    CAS  Article  Google Scholar 

  7. 7.

    Qu KC, Wang ZY, Tang KK, Zhu YS, Fan RF (2019) Trehalose suppresses cadmium-activated Nrf2 signaling pathway to protect against spleen injury. Ecotoxicol Environ Saf 181:224–230

    CAS  Article  Google Scholar 

  8. 8.

    Akahoshi N, Anan Y, Hashimoto Y, Tokoro N, Mizuno R, Hayashi S, Yamamoto S, Shimada K, Kamata S, Ishii I (2019) Dietary selenium deficiency or selenomethionine excess drastically alters organ selenium contents without altering the expression of most selenoproteins in mice. J Nutr Biochem 69:120–129

    CAS  Article  Google Scholar 

  9. 9.

    Yao HD, Wu Q, Zhang ZW, Zhang JL, Li S, Huang JQ, Ren FZ, Xu SW, Wang XL, Lei XG (2013) Gene Expression of endoplasmic reticulum resident selenoproteins correlates with apoptosis in various muscles of Se-deficient chicks. J Nutr 143(5):613–620

    CAS  Article  Google Scholar 

  10. 10.

    Sun Z, Xu Z, Wang D, Yao H, Li S (2018) Selenium deficiency inhibits differentiation and immune function and imbalances the Th1/Th2 of dendritic cells. Metallomics 10(5):759–767.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Yang T, Cao C, Yang J, Liu T, Lei XG, Zhang Z, Xu S (2018) miR-200a-5p regulates myocardial necroptosis induced by Se deficiency via targeting RNF11. Redox Biol 15:159–169

    CAS  Article  Google Scholar 

  12. 12.

    Chi Q, Luan Y, Zhang Y, Hu X, Li S (2019) The regulatory effects of miR-138-5p on selenium deficiency-induced chondrocyte apoptosis are mediated by targeting SelM. Metallomics 11:845–857

    CAS  Article  Google Scholar 

  13. 13.

    Krysiak R, Okopień B (2011) The effect of levothyroxine and selenomethionine on lymphocyte and monocyte cytokine release in women with Hashimoto’s thyroiditis. J Clin Endocrinol Metab 96:2206–2215

    CAS  Article  Google Scholar 

  14. 14.

    Krysiak R, Kowalcze K, Okopień B (2019) Selenomethionine potentiates the impact of vitamin D on thyroid autoimmunity in euthyroid women with Hashimoto’s thyroiditis and low vitamin D status. Pharmacol Rep 71:367–373

    CAS  Article  Google Scholar 

  15. 15.

    Santra D, Sen K (2019) Generating cellulose-agar composite hydrogels for uptake-release kinetic studies of selenate and selenomethionine. Int J Biol Macromol 122:395–404

    CAS  Article  Google Scholar 

  16. 16.

    Toulis KA, Anastasilakis AD, Tzellos TG, Goulis DG, Kouvelas D (2010) Selenium supplementation in the treatment of Hashimoto’s thyroiditis: a systematic review and a meta-analysis. Thyroid 20:1163–1173

    CAS  Article  Google Scholar 

  17. 17.

    Wichman J, Winther KH, Bonnema SJ, Hegedüs L (2016) Selenium supplementation signicantly reduces thyroid autoantibody levels in patients with chronic autoimmune thyroiditis: a systematic review and meta-analysis. Thyroid 26:1681–1699

    CAS  Article  Google Scholar 

  18. 18.

    Fu J, Yang T, Wang W, Xu S (2019) Effect of selenium antagonist lead-induced damage on Th1/Th2 imbalance in the peripheral blood lymphocytes of chickens. Ecotoxicol Environ Saf 175:74–82

    CAS  Article  Google Scholar 

  19. 19.

    Rahman MM, Uson-Lopez RA, Sikder MT, Tan G, Hosokawa T, Saito T, Kurasaki M (2018) Ameliorative effects of selenium on arsenic-induced cytotoxicity in PC12 cells via modulating autophagy/apoptosis. Chemosphere 196:453–466

    CAS  Article  Google Scholar 

  20. 20.

    Agnihotri SK, Agrawal U, Ghosh I (2015) Brain most susceptible to cadmium induced oxidative stress in mice. J Trace Elem Med Biol 30:184–193

    CAS  Article  Google Scholar 

  21. 21.

    Liu F, Wang XY, Zhou XP, Liu ZP, Song XB, Wang ZY, Wang L (2017) Cadmium disrupts autophagic flux by inhibiting cytosolic Ca2+-dependent autophagosome-lysosome fusion in primary rat proximal tubular cells. Toxicology 383:13–23

    CAS  Article  Google Scholar 

  22. 22.

    Chen M, Li X, Fan R, Yang J, Jin X, Hamid S, Xu S (2018) Cadmium induces BNIP3-dependent autophagy in chicken spleen by modulating miR-33-AMPK axis. Chemosphere 194:396–402

    CAS  Article  Google Scholar 

  23. 23.

    Johansen P, Mulvad G, Pedersen HS, Hansen JC, Riget F (2006) Accumulation of cadmium in livers and kidneys in Greenlanders. Sci Total Environ 372:58–63

    CAS  Article  Google Scholar 

  24. 24.

    Gong ZG, Wang XY, Wang JH, Fan RF, Wang L (2019) Trehalose prevents cadmium-induced hepatotoxicity by blocking Nrf2 pathway, restoring autophagy and inhibiting apoptosis. J Inorg Biochem 192:62–71

    CAS  Article  Google Scholar 

  25. 25.

    Xing H, Wang C, Wu H, Chen D, Li S, Xu S (2015) Effects of atrazine and chlorpyrifos on DNA methylation in the brain and gonad of the common carp. Comp Biochem Physiol C 168:11–19

    CAS  Google Scholar 

  26. 26.

    Hu X, Chi Q, Liu Q, Wang D, Zhang Y, Li S (2019) Atmospheric H 2 S triggers immune damage by activating the TLR-7/MyD88/NF-κB pathway and NLRP3 inflammasome in broiler thymus. Chemossphere 237:124427.

    CAS  Article  Google Scholar 

  27. 27.

    Kalantari H, Khodayar MJ, Saki N, Khorsandi L, Teymoori A, Alidadi H, Samimi A (2019) Microarray analysis of apoptosis gene expression in liver injury induced by chronic exposure to arsenic and high-fat diet in male mice. Environ Sci Pollut Res Int.

  28. 28.

    Wang S, Ren X, Hu X, Zhou L, Zhang M, Zhang C (2019) Cadmium-induced apoptosis through reactive oxygen species-mediated mitochondrial oxidative stress and the JNK signaling pathway in TM3 cells, a model of mouse Leydig cells. Toxicol Appl Pharmacol 368:37–48

    CAS  Article  Google Scholar 

  29. 29.

    Xing H, Li S, Wang Z, Gao X, Xu S, Wang X (2012) Oxidative stress response and histopathological changes due to atrazine and chlorpyrifos exposure in common carp. Pestic Biochem Physiol 103(1):74–80

    CAS  Article  Google Scholar 

  30. 30.

    Xing H, Li S, Wang Z, Gao X, Xu S, Wang X (2012) Histopathological changes and antioxidant response in brain and kidney of common carp exposed to atrazine and chlorpyrifos. Chemossphere 88(4):377–383

    CAS  Article  Google Scholar 

  31. 31.

    Hanana H, Kleinert C, André C, Gagné F (2019) Influence of cadmium on oxidative stress and NADH oscillations in mussel mitochondria. Comp Biochem Physiol C Toxicol Pharmacol 216:60–66

    CAS  Article  Google Scholar 

  32. 32.

    Ansari MN, Ganaie MA, Rehman NU, Alharthy KM, Hamad AM (2019) Protective role of roflumilast against cadmium-induced cardiotoxicity through inhibition of oxidative stress and NF-κB signaling in rats. Saudi Pharm J 27:673–681

    Article  Google Scholar 

  33. 33.

    Zheng S, Zhao J, Xing H, Xu S (2019) Oxidative stress, inflammation, and glycometabolism disorder-induced erythrocyte hemolysis in selenium-deficient exudative diathesis broilers. J Cell Physiol 234:16328–16337.

    CAS  Article  Google Scholar 

  34. 34.

    Xing H, Peng M, Li Z, Chen J, Zhang H, Teng X (2019) Ammonia inhalation-mediated mir-202-5p leads to cardiac autophagy through PTEN/AKT/mTOR pathway. Chemosphere 235:858–866.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Dkhil MA, Moneim E, Abdel AL-Quraishy S (2016) Indigofera oblongifolia ameliorates lead acetate-induced testicular oxidative damage and apoptosis in a ratmodel. Biol Trace Elem Res 173:354–361

    CAS  Article  Google Scholar 

  36. 36.

    Abu-Khudir R, Habieb ME, Mohamed MA, Hawas AM, Mohamed TM (2017) Anti-apoptotic role of spermine against lead and/or gamma irradiation-induced hepatotoxicity in male rats. Environ Sci Pollut Res 24:24272–24283

    CAS  Article  Google Scholar 

  37. 37.

    Abdel-Zaher AO, Abd-Ellatief RB, Aboulhagag NA, Farghaly HSM, Wasei FMM (2019) The interrelationship between gasotransmitters and lead-induced renal toxicity in rats. Toxicol Lett 310:39–50.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Zheng S, Jin X, Chen M, Shi Q, Zhang H, Xu S (2019) Hydrogen sulfide exposure induces jejunum injury via CYP450s/ROS pathway in broilers. Chemosphere 214:25–34.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Chen W, Cui Y, Zheng S, Huang J, Li P, Simoncini T, Zhang Y, Fu X (2015) 2-Methoxyestradiol induces vasodilation by stimulating NO release via PPARγ/PI3K/Akt pathway. PLoS One 10:e0118902

    Article  Google Scholar 

  40. 40.

    Zhai Y, Lu Q, Liu Y, Cheng Q, Wei Y, Zhang F, Li C, Yin X (2013) Overproduction of nitric oxide by oxidative stress-induced activation of the TGF-β1/PI3K/Akt pathway in mesangial cells cultured in high glucose. Acta Pharmacol Sin 34:507–514

    CAS  Article  Google Scholar 

  41. 41.

    Liu S, Xu F, Fu J, Li S (2015) Protective roles of selenium on nitric oxide and the gene expression of inflammatory cytokines induced by cadmium in chicken splenic lymphocytes. Biol Trace Elem Res 168:252–260

    CAS  Article  Google Scholar 

  42. 42.

    Zhu ZC, Liu JW, Yang C, Zhao M, Xiong ZQ (2019) XPO1 inhibitor KPT-330 synergizes with Bcl-xL inhibitor to induce cancer cell apoptosis by perturbing rRNA processing and Mcl-1 protein synthesis. Cell Death Dis 10(6):395–408

    Article  Google Scholar 

  43. 43.

    He J, Mi S, Qin XW, Weng SP, Guo CJ, He JG (2019) Tiger frog virus ORF104R interacts with cellular VDAC2 to inhibit cell apoptosis. Fish Shellfish Immunol 92:889–896.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Tsai YH, Lin JJ, Ma YS, Peng SF, Huang AC, Huang YP, Fan MJ, Lien JC, Chung JG (2019) Fisetin inhibits cell proliferation through the induction of G/G phase arrest and caspase-3-mediated apoptosis in mouse leukemia cells. Am J Chin Med 47(4):1–23

    Article  Google Scholar 

  45. 45.

    Zhou BH, Tan PP, Jia LS, Zhao WP, Wang JC, Wang HW (2018) PI3K/AKT signaling pathway involvement in fluoride-induced apoptosis in C2C12 cells. Chemosphere 199:297–302

    CAS  Article  Google Scholar 

  46. 46.

    Xing H, Li S, Wang X, Gao X, Xu S, Wang X (2013) Effects of atrazine and chlorpyrifos on the mRNA levels of HSP70 and HSC70 in the liver, brain, kidney and gill of common carp (Cyprinus carpio L.). Chemosphere 90(3):910–916

    CAS  Article  Google Scholar 

  47. 47.

    Giri SS, Sen SS, Jun JW, Sukumaran V, Park SC (2016) Immunotoxicological effects of cadmium on Labeo rohita, with emphasis on the expression of HSP genes. Fish Shellfish Immunol 54:164–171

    CAS  Article  Google Scholar 

  48. 48.

    Martín-Folgar R, Martínez-Guitarte JL (2017) Cadmium alters the expression of small heat shock protein genes in the aquatic midge Chironomus riparius. Chemosphere 169:485–492

    Article  Google Scholar 

  49. 49.

    Zhang R, Liu Y, Xing L, Zhao N, Zheng Q, Li J, Bao J (2019) The protective role of selenium against cadmium-induced hepatotoxicity in laying hens: expression of Hsps and inflammation-related genes and modulation of elements homeostasis. Ecotoxicol Environ Saf 159:205–212

    Article  Google Scholar 

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The study was financially supported by the Project Fund of Academic Cadre of Northeast Agricultural University (Project No. 700-507001).

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Correspondence to Houjuan Xing or Shiwen Xu.

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All experiments were approved by the Institutional Animal Care and Use Committee of Northeast Agricultural University.

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Xiong, X., Zhang, Y., Xing, H. et al. Ameliorative Effect of Selenomethionine on Cadmium-Induced Hepatocyte Apoptosis via Regulating PI3K/AKT Pathway in Chickens. Biol Trace Elem Res 195, 559–568 (2020).

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  • Selenomethionine
  • Cadmium
  • Oxidative stress
  • Apoptosis
  • P13K/AKT pathway
  • HSPs