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Aflatoxin B₁ Induces Immunotoxicity through the DNA Methyltransferase-Mediated JAK2/STAT3 Pathway in 3D4/21 Cells

Zhou, Xuan, Gan, Fang, Hou, Lili, Liu, Zixuan, Su, Jiarui, Lin, Ziman, Le, Guannan, Huang, Kehe
Journal of agricultural and food chemistry 2019 v.67 no.13 pp. 3772-3780
DNA, DNA damage, DNA methylation, aflatoxin B1, apoptosis, carcinogenesis, cytokines, cytotoxicity, immunotoxicity, methyltransferases, non-specific protein-tyrosine kinase, oxidative stress, phosphorylation
As the most toxic mycotoxin of all of the fungal toxins, aflatoxin B₁ (AFB₁) has carcinogenesis, heptotoxicity, and immunotoxicity. DNA methylation plays a critical role in gene expression regulation of the pathological process. However, the relationship between DNA methylation and AFB₁-induced immunotoxicity was not yet reported. Therefore, the objectives of this study were to verify AFB₁-induced immunotoxicity and investigate the potential role of the DNA methyltransferase (DNMT) family in AFB₁-induced immunotoxicity and the pathway mechanism in 3D4/21 cells. The results showed that AFB₁ could induce cytotoxicity, apoptosis, pro-inflammatory cytokine expression, DNA damage, and oxidative stress and decrease phagocytotic capacity. Meanwhile, the levels of DNMT1 and DNMT3a were significantly increased in 0.04 and 0.08 μg/mL AFB₁ compared to the control. Inhibition of DNMT1 and DNMT3a by 5-Aza-2dc could reverse changes of the above parameters. Further, the JAK2/STAT3 pathway was significantly activated in 0.04 μg/mL AFB₁. Inhibition of p-JAK2 and p-STAT3 by AG490 could alleviate AFB₁-induced immunotoxicity. Moreover, inhibition of DNMT1 and DNMT3a by 5-Aza-2dc could suppress the phosphorylation of JAK2 and STAT3. Taken together, AFB₁-induced immunotoxicity is related to the JAK2/STAT3 pathway mediated by DNMTs in 3D4/21 cells.