Skip to main content

Advertisement

SpringerLink
Log in

Subacute Cadmium Exposure Induces Necroptosis in Swine Lung via Influencing Th1/Th2 Balance

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Cadmium (Cd) is a type of toxic substance, which widely exists in nature. However, the effect of Cd exposure on the toxicity of swine lungs and its underlying mechanism involved have not yet been reported. In our study, we divided swine into two groups, including a control group (C group) and Cd-exposed group. Swine in the C group were fed a basic diet, whereas swine in the Cd group were fed a 20 mg Cd/kg diet. Immunofluorescence, qRT-PCR, western blot analysis, and H&E staining were performed to detect necroptosis-related indicators. Our results found that after Cd exposure, Th1/Th2 imbalance occurred, miR-181-5p was down-regulated, TNF-α expression was increased, and the NF-κB/NLRP3 and JAK/STAT pathways and RIPK1/RIPK3/MLKL axis were activated. Furthermore, histopathological examination showed necrosis in swine lung after Cd exposure. Together, the above-mentioned results indicate that subacute Cd exposure is closely linked with necroptosis in swine lung. Our study provided evidence that Cd may act through miR-181-5p/TNF-α to induce necroptosis in swine lung. The findings of this study supplement the toxicological study of Cd and provide a reference for comparative medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Zhang S et al (2021) Geogenic enrichment of potentially toxic metals in agricultural soils derived from black shale in northwest Zhejiang, China: pathways to and risks from associated crops. Ecotoxicol Environ Saf 215:112102

    Article  CAS  Google Scholar 

  2. Zhou Y et al (2020) Enrichment of cadmium in rice (Oryza sativa L.) grown under different exogenous pollution sources. Environ Sci Pollut Res Int 27(35):44249–44256

    Article  CAS  Google Scholar 

  3. Zhao X et al (2021) Cadmium exposure induces TNF-α-mediated necroptosis via FPR2/TGF-β/NF-κB pathway in swine myocardium. Toxicology 453:152733

    Article  CAS  Google Scholar 

  4. Hudson K, Belcher S, Cowley M (2019) Maternal cadmium exposure in the mouse leads to increased heart weight at birth and programs susceptibility to hypertension in adulthood. Sci Rep 9(1):13553

    Article  Google Scholar 

  5. Rahmani Talatappeh N, Ranji N, Beigi Harchegani A (2021) The effect of N-acetyl cysteine on oxidative stress and apoptosis in the liver tissue of rats exposed to cadmium. Arch Environ Occup Health 2021:1–8

    Google Scholar 

  6. Yu Z et al (2021) Puerarin induces Nrf2 as a cytoprotective mechanism to prevent cadmium-induced autophagy inhibition and NLRP3 inflammasome activation in AML12 hepatic cells. J Inorg Biochem 217:111389

    Article  CAS  Google Scholar 

  7. Madboli A, Seif M (2021) Immunohistochemical, histopathological, and biochemical studies of the NF-ҡB P65 marker in rat ovaries experimentally intoxicated by cadmium and the protective effect of the purslane plant extract. Environ Sci Pollut Res Int 28(14):17613–17626

    Article  CAS  Google Scholar 

  8. Ni H et al (2020) The role of zinc chelate of hydroxy analogue of methionine in cadmium toxicity: effects on cadmium absorption on intestinal health in piglets. Animal 14(7):1382–1391

    Article  CAS  Google Scholar 

  9. Flegal K et al (1980) Dietary selenium and cadmium interrelationships in growing swine. J Nutr 110(6):1255–1261

    Article  CAS  Google Scholar 

  10. Zhang W et al (2017) Cadmium exposure in newborn rats ovary induces developmental disorders of primordial follicles and the differential expression of SCF/c-kit gene. Toxicol Lett 280:20–28

    Article  CAS  Google Scholar 

  11. Straif K et al (2009) A review of human carcinogens–Part C: metals, arsenic, dusts, and fibres. Lancet Oncol 10(5):453–454

    Article  Google Scholar 

  12. Tanwar V et al (2019) Cadmium exposure upregulates SNAIL through miR-30 repression in human lung epithelial cells. Toxicol Appl Pharmacol 373:1–9

    Article  CAS  Google Scholar 

  13. Kiran Kumar K et al (2016) Cadmium induces oxidative stress and apoptosis in lung epithelial cells. Toxicol Mech Methods 26(9):658–666

    Article  CAS  Google Scholar 

  14. Jiang D et al (2021) The susceptibility of Lymantria dispar larvae to Beauveria bassiana under Cd stress: a multi-omics study. Environ Pollut (Barking, Essex: 1987) 276:116740

    Article  CAS  Google Scholar 

  15. Höckner M et al (2020) Cadmium-related effects on cellular immunity comprises altered metabolism in earthworm coelomocytes. Int J Mol Sci 21(2)

  16. Templeton D, Liu Y (2010) Multiple roles of cadmium in cell death and survival. Chem Biol Interact 188(2):267–275

    Article  CAS  Google Scholar 

  17. Li J et al (2021) Selenium deficiency induced apoptosis via mitochondrial pathway caused by Oxidative Stress in porcine gastric tissues. Research in veterinary science

  18. Li Z et al (2019) The interaction of Atg4B and Bcl-2 plays an important role in Cd-induced crosstalk between apoptosis and autophagy through disassociation of Bcl-2-Beclin1 in A549 cells. Free Radical Biol Med 130:576–591

    Article  CAS  Google Scholar 

  19. Zhang J et al (2020) Cadmium-induced oxidative stress promotes apoptosis and necrosis through the regulation of the miR-216a-PI3K/AKT axis in common carp lymphocytes and antagonized by selenium. Chemosphere 258:127341

  20. Che L et al (2021) Mitochondrial redox-driven mitofusin 2 S-glutathionylation promotes neuronal necroptosis via disrupting ER-mitochondria crosstalk in cadmium-induced neurotoxicity. Chemosphere 262:127878

  21. Wang Y et al (2020) Protective effects of selenium yeast against cadmium-induced necroptosis via inhibition of oxidative stress and MAPK pathway in chicken liver. Ecotoxicol Environ Saf 206:111329

  22. Huang H et al (2007) CD4+ Th1 cells promote CD8+ Tc1 cell survival, memory response, tumor localization and therapy by targeted delivery of interleukin 2 via acquired pMHC I complexes. Immunology 120(2):148–159

    Article  CAS  Google Scholar 

  23. Chen M et al (2019) Hydrogen sulfide exposure triggers chicken trachea inflammatory injury through oxidative stress-mediated FOS/IL8 signaling. J Hazard Mater 368:243–254

    Article  CAS  Google Scholar 

  24. Goyal T et al (2021) Estimation of lymphocyte subsets and cytokine levels in workers occupationally exposed to cadmium. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 64:126681

  25. Li Q et al (2021) Regulation of Th1/Th2 and Th17/Treg by pDC/mDC imbalance in primary immune thrombocytopenia. Experimental Biology and Medicine (Maywood, N.J.):15353702211009787

  26. Xie Y et al (2020) Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer. J Clin Investig 130(4):2111–2128

    Article  CAS  Google Scholar 

  27. Koike A, Hanatani M, Fujimori K (2019) Pan-caspase inhibitors induce necroptosis via ROS-mediated activation of mixed lineage kinase domain-like protein and p38 in classically activated macrophages. Exp Cell Res 380(2):171–179

    Article  CAS  Google Scholar 

  28. Tam V et al (2020) PPARα exacerbates necroptosis, leading to increased mortality in postinfluenza bacterial superinfection. Proc Natl Acad Sci USA 117(27):15789–15798

    Article  CAS  Google Scholar 

  29. Ishfaq M et al (2019) Baicalin ameliorates oxidative stress and apoptosis by restoring mitochondrial dynamics in the spleen of chickens via the opposite modulation of NF-κB and Nrf2/HO-1 signaling pathway during Mycoplasma gallisepticum infection. Poult Sci 98(12):6296–6310

    Article  CAS  Google Scholar 

  30. Ghorbani S et al (2017) miR-181 interacts with signaling adaptor molecule DENN/MADD and enhances TNF-induced cell death. PloS one 12(3):e0174368

    Article  Google Scholar 

  31. Cui Y et al (2019) Atrazine induces necroptosis by miR-181-5p targeting inflammation and glycometabolism in carp lymphocytes. Fish Shellfish Immunol 94:730–738

    Article  CAS  Google Scholar 

  32. Escate R et al (2018) miR-505-3p controls chemokine receptor up-regulation in macrophages: role in familial hypercholesterolemia. FASEB J 32(2):601–612

    CAS  Google Scholar 

  33. Yao Y et al (2021) Subacute cadmium exposure promotes M1 macrophage polarization through oxidative stress-evoked inflammatory response and induces porcine adrenal fibrosis. Toxicology 2021:152899

  34. Zhang Y et al (2021) Cadmium induced inflammation and apoptosis of porcine epididymis via activating RAF1/MEK/ERK and NF-κB pathways. Toxicol Appl Pharmacol 415:115449

  35. Yin K et al (2020) Antagonistic effect of selenium on lead-induced neutrophil apoptosis in chickens via miR-16-5p targeting of PiK3R1 and IGF1R. Chemosphere 246:125794

  36. Li X et al (2021) New insights into crosstalk between apoptosis and necroptosis co-induced by chlorothalonil and imidacloprid in Ctenopharyngodon idellus kidney cells. Sci Total Environ 780:146591

  37. Jiayong Z et al (2020) The antagonistic effect of selenium on lead-induced necroptosis via MAPK/NF-κB pathway and HSPs activation in the chicken spleen. Ecotoxicol Environ Saf 204:111049

  38. Xu X et al (2021) Establishment and characterization of a gill cell line from pearl gentian grouper (Epinephelus lanceolatus♂×Epinephelus fuscoguttatus♀) and its application in cadmium toxicology. Ecotoxicol Environ Saf 208:111614

  39. Yang G et al (2019) Serum cadmium and lead, current wheeze, and lung function in a nationwide study of adults in the United States. J Allergy Clin Immunol 7(8):2653-2660.e3

    Google Scholar 

  40. Xin C et al (2020) Astilbin protects chicken peripheral blood lymphocytes from cadmium-induced necroptosis via oxidative stress and the PI3K/Akt pathway. Ecotoxicol Environ Saf 190:110064

  41. Zhang Y et al (2018) Cd induces G2/M cell cycle arrest by up-regulating miR-133b via directly targeting PPP2R2D in L02 hepatocytes. Metallomics Integr Biomet Sci 10(10):1510–1523

    Article  CAS  Google Scholar 

  42. Sun Y et al (2021) C-myc promotes miR-92a-2-5p transcription in rat ovarian granulosa cells after cadmium exposure. Toxicol Appl Pharmacol 421:115536

  43. Tang X et al (2020) The miR-155 regulates cytokines expression by SOSC1 signal pathways of fish in vitro and in vivo. Fish Shellfish Immunol 106:28–35

    Article  CAS  Google Scholar 

  44. Han S et al (2021) Lactobacillus rhamnosus HDB1258 modulates gut microbiota-mediated immune response in mice with or without lipopolysaccharide-induced systemic inflammation. BMC Microbiol 21(1):146

    Article  CAS  Google Scholar 

  45. Xu L et al (2019) Chemokine and cytokine cascade caused by skewing of the Th1-Th2 balance is associated with high intracranial pressure in HIV-associated cryptococcal meningitis. Mediat Inflamm 2019:2053958

    Article  Google Scholar 

  46. Liang Z, Tang F (2020) The potency of lncRNA MALAT1/miR-155/CTLA4 axis in altering Th1/Th2 balance of asthma. Bioscie Rep 40(2)

  47. Xu S et al (2021) Pig lung fibrosis is active in the subacute CdCl exposure model and exerts cumulative toxicity through the M1/M2 imbalance. Ecotoxicol Environ Saf 225:112757

  48. Cui W et al (2021) Cadmium exposure activates the PI3K/AKT signaling pathway through miRNA-21, induces an increase in M1 polarization of macrophages, and leads to fibrosis of pig liver tissue. Ecotoxicol Environ Saf 228:113015

  49. Zhang Y et al (2021) Selenium deficiency induced necroptosis, Th1/Th2 imbalance, and inflammatory responses in swine ileum. J Cell Physiol 236(1):222–234

    Article  CAS  Google Scholar 

  50. Guo M et al (2019) Triggering MSR1 promotes JNK-mediated inflammation in IL-4-activated macrophages. EMBO J 38(11)

  51. Jiang K et al (2021) A negative feedback loop involving NF-κB/TIR8 regulates IL-1β-induced epithelial- myofibroblast transdifferentiation in human tubular cells. J Cell Commun Signal 15(3):393–403

    Article  CAS  Google Scholar 

  52. Zhou J et al (2002) A role for NF-kappa B activation in perforin expression of NK cells upon IL-2 receptor signaling. J Immunol (Baltimore, Md. : 1950) 169(3):1319–25

    Article  CAS  Google Scholar 

  53. Qin Y et al (2019) Interferon gamma inhibits the differentiation of mouse adult liver and bone marrow hematopoietic stem cells by inhibiting the activation of notch signaling. Stem Cell Res Ther 10(1):210

    Article  Google Scholar 

  54. Devin A et al (2001) The alpha and beta subunits of IkappaB kinase (IKK) mediate TRAF2-dependent IKK recruitment to tumor necrosis factor (TNF) receptor 1 in response to TNF. Mol Cell Biol 21(12):3986–3994

    Article  CAS  Google Scholar 

  55. Jackson-Bernitsas D et al (2007) Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma. Oncogene 26(10):1385–1397

    Article  CAS  Google Scholar 

  56. Galluzzi L et al (2011) Programmed necrosis from molecules to health and disease. Int Rev Cell Mol Biol 289:1–35

    Article  CAS  Google Scholar 

  57. Li J et al (2012) The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150(2):339–350

    Article  CAS  Google Scholar 

  58. Cai Z et al (2014) Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol 16(1):55–65

    Article  CAS  Google Scholar 

  59. Habbeddine M et al (2017) Receptor activator of NF-κB orchestrates activation of antiviral memory CD8 T cells in the spleen marginal zone. Cell Rep 21(9):2515–2527

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Supported by China Agriculture Research System of MOF and MARA. The authors extend their sincere thanks to the members of the veterinary internal medicine laboratory and Key Laboratory for Laboratory Animals at the College of Veterinary Medicine, Northeast Agricultural University.

Author information

Authors and Affiliations

  1. College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People’s Republic of China

    Wenyue Zhang, Xinyue Sun, Xu Shi, Xue Qi, Shaoqian Shang & Hongjin Lin

  2. Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People’s Republic of China

    Hongjin Lin

Authors
  1. Wenyue Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinyue Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xu Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xue Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shaoqian Shang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongjin Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Wenyue Zhang: investigation; formal analysis; writing—original draft. Xinyue Sun: draft layout, visualization. Xu Shi: software, investigation. Xue Qi: software. Hongjin Lin: conceptualization; resources; supervision; validation; writing—review and editing.

Corresponding author

Correspondence to Hongjin Lin.

Ethics declarations

Ethical approval

All other authors have read the manuscript and have agreed to submit it in its current form for consideration for publication in the Journal.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, W., Sun, X., Shi, X. et al. Subacute Cadmium Exposure Induces Necroptosis in Swine Lung via Influencing Th1/Th2 Balance. Biol Trace Elem Res 201, 220–228 (2023). https://doi.org/10.1007/s12011-022-03133-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-022-03133-6

Keywords

Search

Navigation