J Agric Food Chem. 2019 Apr 3;67(13):3772-3780. doi: 10.1021/acs.jafc.8b07309. Epub 2019 Mar 18.
As the most toxic mycotoxin of all of the fungal toxins, aflatoxin B (AFB) 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 AFB-induced immunotoxicity was not yet reported. Therefore, the objectives of this study were to verify AFB-induced immunotoxicity and investigate the potential role of the DNA methyltransferase (DNMT) family in AFB-induced immunotoxicity and the pathway mechanism in 3D4/21 cells. The results showed that AFB 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 AFB 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 AFB. Inhibition of p-JAK2 and p-STAT3 by AG490 could alleviate AFB-induced immunotoxicity. Moreover, inhibition of DNMT1 and DNMT3a by 5-Aza-2dc could suppress the phosphorylation of JAK2 and STAT3. Taken together, AFB-induced immunotoxicity is related to the JAK2/STAT3 pathway mediated by DNMTs in 3D4/21 cells.
作为所有真菌毒素中毒性最强的黄曲霉毒素 B（AFB），具有致癌性、肝毒性和免疫毒性。DNA 甲基化在病理过程中的基因表达调控中起着关键作用。然而，DNA 甲基化与 AFB 诱导的免疫毒性之间的关系尚未报道。因此，本研究旨在验证 AFB 诱导的免疫毒性，并研究 DNA 甲基转移酶（DNMT）家族在 AFB 诱导的免疫毒性中的潜在作用及其在 3D4/21 细胞中的通路机制。结果表明，AFB 可诱导细胞毒性、细胞凋亡、促炎细胞因子表达、DNA 损伤和氧化应激，并降低吞噬能力。同时，与对照组相比，0.04 和 0.08μg/mL AFB 组中 DNMT1 和 DNMT3a 的水平显著增加。5-Aza-2dc 抑制 DNMT1 和 DNMT3a 可逆转上述参数的变化。此外，在 0.04μg/mL AFB 中 JAK2/STAT3 通路被显著激活。AG490 抑制 p-JAK2 和 p-STAT3 可减轻 AFB 诱导的免疫毒性。此外，5-Aza-2dc 抑制 DNMT1 和 DNMT3a 可抑制 JAK2 和 STAT3 的磷酸化。综上所述，AFB 诱导的免疫毒性与 3D4/21 细胞中 DNMTs 介导的 JAK2/STAT3 通路有关。
