Novel Approach for Characterizing Exposure and Response to Engineered Nanomaterials in the Gut

Despite the expanding number of applications for engineered nanoparticles (ENP), human health concerns associated with ingested nanoparticles are poorly understood. In this study, we utilized a 3D human small intestinal tissue model to develop a physiologically relevant test system that can assess the toxicological profiles of ingestible nanomaterials. We examined the effects of Cupric (II) Oxide (CuO) (50 nm), Zinc Oxide (ZnO, 35-45 nm), and Titanium Oxide (TiO2, 40 nm) nanoparticles on the small intestinal tissues by monitoring: 1) barrier integrity (TEER), 2) tissue viability (MTT assay), 3) oxidative stress (8-isoprostane release), and 4) inflammatory response (IL-8). The tissues were exposed to 40 uL of 4 different doses of sonicated and dispersed nanoparticles under rocking conditions for 4 hr and the tissues were further cultured for 20 hr under static conditions (24 hrs total). We observed a dose response reduction of barrier integrity and tissue viability for CuO, ZnO, and single wall carbon nanotubes (SWCNT), but titanium oxide did not induce significant changes for the concentrations tested. Analysis of culture supernatants collected at 24 hr showed a dose dependent release of IL-8 for CuO and ZnO and 8-isoprostane for CuO. Overall, TEER measurements were a more sensitive endpoint compared to the MTT tissue viability assay. In additional experiments modeling chronic exposure (dosing every 48 hrs for 18 days), concentrations which had no effect after 24 hr exposure showed signs of barrier impairment. In summary, use of the SMI tissue model to examine the toxicity profile of ingested nanoparticles will enhance our understanding of nanoparticle-host cell interactions, improve the design of nanoparticle-based formulations, generate physiologically relevant data for ENP effects to the GI tract, and provide greater insight into in vivo responses induced by ENP.

EpiIntestinal, SMI-100, engineered nanoparticles, nanomaterials, Cupric II Oxide, CuO, Zinc Oxide, ZnO, Titanium Oxide, TiO2, silver, gold, iron oxide, ferrous oxide, FeO, silica, TEER, barrier integrity, MTT assay, oxidative stress, 8-isoprostane, inflammatory response, IL-8, chronic exposure

Cupric II Oxide, CuO, Zinc Oxide, ZnO, Titanium Oxide, TiO2, silver nanoparticles, gold, iron oxide, ferrous oxide, FeO, silica