Bisphenol A promotes macrophage proinflammatory subtype polarization via upregulation of IRF5 expression in vitro

Exposure to environmental endocrine-disrupting chemical Bisphenol-A (BPA) is closely associated with an imbalance of immune homeostasis, but the underlying mechanisms are not fully understood. In the present study, the effects of BPA on the polarization of mouse peritoneal macrophages were investigated in vitro. Environmentally relevant low concentrations of BPA treatment under M1 type polarization conditions increased the number of M1 subtype macrophages, the gene expression of M1 phenotypic marker CD11c and the activity and gene expression of M1 functional marker iNOS, as well as the production of pro-inflammatory cytokines. However, The same dose BPA treatment under M2 type polarization conditions reduced the number of M2 subtype macrophages, the gene expression of M2 phenotypic marker CD206 and the activity and gene expression of M2 functional marker Arg-1, along with the production of anti-inflammatory cytokines. We also identified that the expression of transcription factor IRF5 was upregulated by BPA exposure in M1 macrophages under M1 type polarization conditions. Our results demonstrate that BPA promotes macrophage polarization toward proinflammatory M1 subtype and M1 activity, associated with upregulated expression of IRF5, while BPA inhibits macrophage toward anti-inflammatory M2 subtype polarization. These findings provide new insight into the link between exposure to BPA and impairment of immune functions

Maternal Vitamin D Supplementation inhibits Bisphenol A-induced proliferation of Th17 cells in adult offspring

Bisphenol A (BPA) exposure can increase the risk of immune-related diseases in later life. Vitamin D3 (Vit D3) has been shown to have multiple immunomodulatory actions and has been used to treat immune diseases. However, the potential beneficial effects of Vit D3 on BPA-induced adverse effects in the immune system have not explored. We hypothesize that VitD3 may ameliorate BPA-induced side effects in the immune system, even in offspring of VitD3-supplemented mothers. Here, we established our experimental model by exposing pregnant dams with 1000 nM BPA with or without VitD3 (0.25 μg/kg, 1 μg/kg and 4 μg/kg) treatment. We show that mother’s exposure to BPA increases proliferation of the spleen T helper 17 (Th17) cells and serum protein level of IL-17 in the offspring; however, VitD3 supplementation in mothers dose-dependently ameliorated these BPA-induced side effects on the immune system in the offspring as evidenced by attenuated upregulation of Th17 proliferation, and RORγt, IL-17, IL-6, and IL-23 expressions in the offspring. Our data provide the first evidence that maternal VitD3 supplementation offers benefits to the offspring by attenuating BPA-induced side effects on the immune system through vitamin D receptor (VDR)-dependent regulation of transcription factors and cytokines, suggesting its translational potential

ATG7 upregulation contributes to malignant transformation of human bronchial epithelial cells by B[a]PDE via DNMT3B protein degradation and miR-494 promoter methylation

Lung cancer primarily arises from exposure to various environmental factors, particularly airborne pollutants. Among the various lung carcinogens, benzo(a)pyrene and its metabolite B[a]PDE are the strongest ones that actively contribute to lung cancer development. ATG7 is an E1-like activating enzyme and contributes to activating autophagic responses in mammal cells. However, the potential alterations of ATG7 and its role in B[a]PDE-caused lung carcinogenesis remain unknown. Here, we found that B[a]PDE exposure promoted ATG7 expression in mouse lung tissues, while B[a]PDE exposure resulted in ATG7 induction in human normal bronchial epithelial cells. Our studies also demonstrated a significant correlation between high ATG7 expression levels and poor overall survival in lung cancer patients. ATG7 knockdown significantly repressed Beas-2B cell transformation upon B[a]PDE exposure, and such promotive effect of ATG7 on cell transformation mediated the p27 translation inhibition. Further studies revealed that miR-373 inhibition was required to stabilize ATG7 mRNA, therefore increasing ATG7 expression following B[a]PDE exposure, while ATG7 induction led to the autophagic degradation of the DNA methyltransferase 3 Beta (DNMT3B) protein, in turn promoted miR-494 transcription via its promoter region methylation status suppression. We also found that the miR-494 upregulation inhibited p27 protein translation and promoted bronchial epithelial cell transformation via its directly targeting p27 mRNA 3′-UTR region. Current studies, to the best of our knowledge, are for the first time to identify that ATG7 induction and its mediated autophagy is critical for B[a]PDE-induced transformation of human normal epithelial cells

Endoplasmic reticulum stress mediates nickel chloride-induced epithelial‑mesenchymal transition and migration of human lung cancer A549 cells through Smad2/3 and p38 MAPK activation

Background: The endoplasmic reticulum (ER) is a cellular membrane-bound organelle whereby proteins are synthesized, folded and glycosylated. Due to intrinsic (e.g., genetic) and extrinsic (e.g., environmental stressors) perturbations, ER proteostasis can be deregulated within cells which triggers unfolded protein response (UPR) as an adaptive stress response that may impact the migration and invasion properties of cancer cells. However, the mechanisms underlying the nickel compounds on lung cancer cell migration and invasion remain uncertain. Objective: We aimed to study whether Nickel chloride (NiCl2) induces ER stress in lung cancer cells, and whether ER stress is involved in modulating epithelial-mesenchymal transition (EMT) and migration by Smads and MAPKs pathways activation following NiCl2 treatment. Methods: A549 cells were treated with NiCl2 to determine the cell viability using MTT assay. The wound healing assay was used to evaluate cell migration ability. ER ultrastructure was observed by transmission electron microscopy. Western blotting assay was performed to evaluate the protein levels of BIP, PERK, IRE-1α, XBP-1 s, and ATF6 for ER stress and UPR, E-cadherin and Vimentin for EMT, p-Smad2/3, p-ERK, p-JNK, and p-P38 for activation of Smads and MAPKs signaling pathways. Results: The expression levels of BIP, PERK, IRE-1α, XBP-1 s, and ATF6 were significantly increased following treatment with NiCl2 in time- and dose-effect relationship. The ER stress inhibitor 4-PBA downregulated the expression levels of the above five proteins, and reversed the decrease in E-cadherin protein level and the increase in vimentin protein expression and cell migration abilities caused by NiCl2. Furthermore, 4-PBA significantly reduced nickel chloride-induced Smad2/3 and p38 MAPK pathway activation, while not affected ERK and JNK MAPK pathways. Conclusion: NiCl2 triggers ER stress and UPR in A549 cells. Moreover, 4-PBA alleviates NiCl2-induced EMT and migration ability of A549 cells possibly through the Smad2/3 and p38 MAPK pathways activation, rather than ERK and JNK MAPK pathways