Research Paper Volume 8, Issue 11 pp 3009—3027

Nickel chloride (NiCl2) in hepatic toxicity: apoptosis, G2/M cell cycle arrest and inflammatory response

Hongrui Guo1, , Hengmin Cui1,2, , Jing Fang1,2, , Zhicai Zuo1,2, , Junliang Deng1,2, , Xun Wang1,2, , Ling Zhao1,2, , Kejie Chen1, , Jie Deng1, ,

  • 1 College of Veterinary Medicine, Sichuan Agricultural University Ya’an 625014, China
  • 2 Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agricultural University Ya’an 625014, China

Received: September 5, 2016       Accepted: October 18, 2016       Published: November 5, 2016
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Up to now, the precise mechanism of Ni toxicology is still indistinct. Our aim was to test the apoptosis, cell cycle arrest and inflammatory response mechanism induced by NiCl2 in the liver of broiler chickens. NiCl2 significantly increased hepatic apoptosis. NiCl2 activated mitochondria-mediated apoptotic pathway by decreasing Bcl-2, Bcl-xL, Mcl-1, and increasing Bax, Bak, caspase-3, caspase-9 and PARP mRNA expression. In the Fas-mediated apoptotic pathway, mRNA expression levels of Fas, FasL, caspase-8 were increased. Also,NiCl2 induced ER stress apoptotic pathway by increasing GRP78 and GRP94 mRNA expressions. The ER stress was activated through PERK, IRE1 and ATF6 pathways, which were characterized by increasing eIF2α, ATF4, IRE1, XBP1 and ATF6 mRNA expressions. And, NiCl2 arrested G2/M phase cell cycle by increasing p53, p21 and decreasing cdc2, cyclin B mRNA expressions. Simultaneously, NiCl2 increased TNF-α, IL-1β, IL-6, IL-8 mRNA expressions through NF-κB activation. In conclusion, NiCl2 induces apoptosis through mitochondria, Fas and ER stress-mediated apoptotic pathways and causes cell cycle G2/M phase arrest via p53-dependent pathway and generates inflammatory response by activating NF-κB pathway.


Ni: nickel; NiCl2: nickel chloride; NiSO4: nickel sulfate; HEp-2: human airway epithelial; MCF-7: human breast cancer; CHO: Chinese hamster ovary; ER: endoplasmic reticulum; MMP: mitochondrial membrane potential; cyt c: cytochrome c; AIF: apoptosis inducing factor; CHOP: C/EBP homologous protein; IL-1β: interleukin-1β; TNF-α: tumor necrosis factor α; ICAM-1: intercellular cell adhesion molecule-1; AST: aspartate aminotransferase; ALT: alanine aminotransferase; ALP: Alkaline phosphatase; GGT: Glutamyltransferase; ALB: albumin; GLB: globulin; TP: total protein; TBIL: total bilirubin; TUNEL: terminal deoxynucleotidyl transferase 2ʹ-deoxyuridine 5ʹ-triphosphate dUTP nick end-labeling; Bcl-xL: Bcl-extra long; Mcl-1: myeloid cell leukemia factor-1; PARP: poly ADP-ribose polymerase; FasL: Fas ligand; GRP78: glucose-regulated protein 78; UPR: unfolded protein response; PERK: protein kinase RNA (PKR)-like ER kinase; IRE1: inositol-requiring enzyme 1; ATF6: activated transcription factor 6; eIF2α: elongation initiation factor 2α; XBP1: X-boxbinding protein 1; NF-κB: nuclear factor-κB; NiONPs: NiO nanoparticles; Ni3S2: nickel sulfide; GADD34: growth arrest and DNA-damage-inducible 34; ERO1α: endoplasmic reticulum oxidoreductase 1α; TRAF2: TNF receptor-associated factor 2; ASK1/JNK: apoptosis signal-regulating kinase 1/c-Jun amino terminal kinase; FCE: feed conversion efficiency; PI: propidium iodide; GFAAS: graphite furnace atomic absorption spectrometry.