Human Intestinal Tissue Explant Exposure to Silver Nanoparticles Reveals Sex Dependent Alterations in Inflammatory Responses and Epithelial Cell Permeability

Abstract Background: Consumer products manufactured with antimicrobial silver nanoparticles (AgNPs) may affect the gastrointestinal (GI) system. The human GI-tract is complex and there are physiological and anatomical differences between human and animal models that limit comparisons between species. Additionally, induction of overt toxicity in animal and in vitro models by AgNP exposure can require doses that are well above what is feasible from environmental exposure or from the use of consumer products. This suggests that a practical assessment of potential AgNP effects on the human GI-tract may require tools that allow for the examination of subtle changes in inflammatory markers and indicators of epithelial perturbation. Methods: We utilize fresh tissue excised from the GI-tract of human male and female subjects to evaluate the effects of AgNPs on the GI-system. The purpose of this study was to perform an assessment on the ability of the ex vivo model to evaluate changes in levels of pro-/anti-inflammatory cytokines/chemokines and mRNA expression of intestinal permeability related genes induced by AgNPs in ileal tissues. Results: The ex vivo model preserved the structural and biological functions of the in-situ organ. Analysis of cytokine expression data indicated that intestinal tissue of male and female subjects responded differently to AgNP treatment, with male samples showing significantly elevated Granulocyte-macrophage colony-stimulating factor (GM-CSF) after treatment with 10-nm and 20-nm AgNPs for 2 hours and significantly elevated RANTES after treatment with 20-nm AgNPs for 24 hours. In contrast, tissues of female patients showed no significant effects of AgNP treatment at 2-hours and significantly decreased RANTES (20 nm), TNF-α (10 nm), and IFN-g (10 nm) at 24-hours. Smaller size AgNPs (10 nm) perturbed more permeability-related genes in samples of male subjects (38 up-regulated, 18 down-regulated), than samples of female subjects (23 up-regulated, 15 down-regulated). In contrast, exposure to 20-nm AgNPs resulted in upregulation of a greater number of genes in female-derived samples (36 genes) than in male-derived samples (8 genes). Conclusion: Results of this study suggest that the ex vivo tissue model deserves further evaluation as a tool to assess the impacts of nanomaterials and other xenobiotic compounds on human intestinal mucosa.