An Embryonic Zebrafish Model to Screen Disruption of Gut-Vascular Barrier upon Exposure to Ambient Ultrafine Particles.

Kyung In Baek,Constantinos Sioutas,Ryan O’Donnell,Chih-Chiang Chang,Tzung K Hsiai,Yi Qian,Rongsong Li,Ehsan Soleimanian

doi:10.3390/toxics8040107

Abstract

Epidemiological studies have linked exposure to ambient particulate matter (PM) with gastrointestinal (GI) diseases. Ambient ultrafine particles (UFP) are the redox-active sub-fraction of PM2.5, harboring elemental and polycyclic aromatic hydrocarbons from urban environmental sources including diesel and gasoline exhausts. The gut-vascular barrier (GVB) regulates paracellular trafficking and systemic dissemination of ingested microbes and toxins. Here, we posit that acute UFP ingestion disrupts the integrity of the intestinal barrier by modulating intestinal Notch activation. Using zebrafish embryos, we performed micro-gavage with the fluorescein isothiocynate (FITC)-conjugated dextran (FD10, 10 kDa) to assess the disruption of GVB integrity upon UFP exposure. Following micro-gavage, FD10 retained in the embryonic GI system, migrated through the cloaca. Conversely, co-gavaging UFP increased transmigration of FD10 across the intestinal barrier, and FD10 fluorescence occurred in the venous capillary plexus. Ingestion of UFP further impaired the mid-intestine morphology. We performed micro-angiogram of FD10 to corroborate acute UFP-mediated disruption of GVB. Transient genetic and pharmacologic manipulations of global Notch activity suggested Notch regulation of the GVB. Overall, our integration of a genetically tractable embryonic zebrafish and micro-gavage technique provided epigenetic insights underlying ambient UFP ingestion disrupts the GVB.

Highlights

Ultrafine particles (UFP, dp < 0.1 to 0.2 μm in diameter), comprised of a mixture of heavy transition metals and redox cycling organic chemicals, are redox-active components of ambient particulate matterToxics 2020, 8, 107; doi:10.3390/toxics8040107 www.mdpi.com/journal/toxics (PM, dp < 2.5 μm) [1,2]
In the FD10-gavaged controls, FD10 remained in the intestinal bulb and mid-intestine, migrating solely through the cloaca
We further examined whether acute ultrafine particles (UFP) ingestion regulates villus ultrastructure in the embryonic GI tract

Summary

Introduction

Ultrafine particles (UFP, dp < 0.1 to 0.2 μm in diameter), comprised of a mixture of heavy transition metals and redox cycling organic chemicals, are redox-active components of ambient particulate matterToxics 2020, 8, 107; doi:10.3390/toxics8040107 www.mdpi.com/journal/toxics (PM, dp < 2.5 μm) [1,2]. Recent epidemiological studies have supported the link between UFP exposure and gastrointestinal (GI) diseases such as inflammatory bowel disease [3]. While the cardiopulmonary system remains the main entry point for ambient UFP exposure, UFP are orally ingested via contaminated food and water supplies for intestinal pro-inflammatory potentials [4,5,6,7]. Dietary UFP, including titanium dioxide nanoparticles used as food additives and aluminosilicate minerals in drinking water, are absorbed by intestinal epithelial lymphocytes, potentiating pro-inflammatory cytokines and T-cell proliferation [8,9]. Inhaled UFP increases colonic inflammation and facilitates intestinal release of fatty acids and pro-inflammatory mediators as a result of bronchial mucocilliary removal to the oropharynx [10]. While intestinal inflammatory responses suppress mucosal stability and subsequent integrity of the intestinal epithelial barrier, the epigenetic cues underlying ambient

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Conclusion