Dietary Aflatoxin G1 exposure causes an imbalance between pulmonary tissue-resident alveolar macrophages and monocyte-derived macrophages in both mother and offspring mice

Abstract

Aflatoxin G₁ (AFG₁) is a mycotoxin commonly found in agricultural products, including dried fruits, meat, and milk products. Oral AFG₁ administration induced tumor necrosis factor (TNF)-α-dependent chronic pulmonary inflammation, promoting AFG₁-induced damage in alveolar epithelial cell, which is associated with lung adenocarcinoma. Pulmonary macrophages may be divided into tissue-resident alveolar macrophages (TRAMs) and monocyte-derived macrophages (MoMs), which involve in chronic lung inflammation. However, whether these macrophages contribute to AFG₁-induced chronic pulmonary inflammation remains unknown. In this study, we found oral AFG₁ administration disrupted the balance between TRAMs and MoMs, increasing MoMs infiltration and decreasing the number of TRAMs. AFG₁ upregulated TNF-α expression in MoMs, but downregulated sialic acid binding Ig-like lectin F (Siglec-F) expression in TRAMs. Inhibition of TNF-α-dependent inflammation rescued the imbalance between TRAMs and MoMs in AFG₁-treated lung tissues. Additionally, AFG₁ stimulated MoMs differentiation to the proinflammatory M1 phenotype in vitro. Using a specific in vitro TRAM model, AFG₁ downregulated Siglec-F and the M2 phenotypic markers arginase 1 and YM1, and upregulated the M1 phenotypic markers IL-6, iNOS and TNF-α, altering the TRAMs phenotype to the pro-inflammatory M1 phenotype in vitro. Additionally, mouse maternal dietary exposure to AFG₁ caused an imbalance in pulmonary macrophages, decreasing TRAMs and increasing MoMs population in offspring, which was associated with proliferative lesions in the alveolar septa. Thus, dietary AFG₁ exposure triggered an imbalance in pulmonary macrophages in both mother and offspring mice, and induced pro-inflammatory phenotypic alterations, which contributed to AFG₁-induced chronic lung inflammation. These results provide clues to how AFG₁-induced immunotoxicity and genotoxicity in humans might be prevented.