Effects of Chronic Cr and Ni Co-Exposure on Liver Inflammation and Autophagy in Mice by Regulating the Tlr4/Mtor Pathway

To ascertain the combined toxic effects of chronic Cr and Ni co-exposure on liver damage in mice, 80 6-week-old female C57BL/6J mice were randomly divided into 4 groups: the Con group, Cr group (Cr+6 50 mg/L), Ni group (Ni+2 110 mg/L), and Cr+Ni group (Cr+6 50 mg/L + Ni+2 110 mg/L). The trial period lasted for 16 weeks. The results showed that Cr+6 and/or Ni+2 increased liver weight and liver index in mice, caused histological abnormality and ultrastructural damage, and micronutrients imbalance in mice liver. Meanwhile, compared with the individual exposure group, chronic Cr and Ni co-exposure resulted in decreased levels and activities of ALT, AST, MDA, T-AOC, and T-SOD in liver tissue, and decreased the mRNA expression levels of the TLR4/mTOR pathway related factors (TLR4, TRAM, TRIF, TBK-1, IRF-3, MyD88, IRAK-4, TRAF6, TAK-1, IKKβ, NF-κB, IL-1β, IL-6, TNFα, ULK1, Beclin 1, LC3) (P < 0.05) and decreased the protein expression levels of the factors (TLR4, MyD88, TRAF6, NF-κB p50, IL-6, TNFα, ULK1, LC3II/LC3I) (P < 0.05). Moreover, factorial analysis revealed the interaction between Cr and Ni, which was manifested as antagonistic effects on chromium content, nickel content, and TLR4, MyD88, NF-κB, mTOR, LC3, and p62 mRNA expression levels. In conclusion, chronic Cr and Ni co-exposure induced liver inflammation and autophagy in mice through the TLR4/mTOR pathway, and there was an antagonistic effect between Cr and Ni. The above results provided an important theoretical basis for the mechanism of chronic Cr and Ni co-exposure-induced liver toxicity in mice.