Persistent Hepatic Structural Alterations Following Nanoceria Vascular Infusion in the Rat

Abstract

Understanding the long-term effects and possible toxicity of nanoceria, a widely utilized commercial metal oxide, is of particular importance as it is poised for development as a therapeutic agent based on its autocatalytic redox behavior. We show here evidence of acute and subacute adverse hepatic responses, after a single infusion of an aqueous dispersion of 85 mg/kg, 30 nm nanoceria into Sprague Dawley rats. Light and electron microscopic evidence of avid uptake of nanoceria by Kupffer cells was detected as early as 1 hr after infusion. Biopersistent nanoceria stimulated cluster of differentiation 3 þ lymphocyte proliferation that intermingled with nanoceria-containing Kupffer cells to form granulomata that were observed between days 30 and 90. Ultrastructural tracking of ceria nanoparticles revealed aggregated nanoceria in phagolysosomes. An increased formation of small nanoceria over time observed in the latter suggests possible dissolution and precipitation of nanoceria. However, the pathway for nanoceria metabolism/secretion remains unclear. Although frank hepatic necrosis was not observed, the retention of nanoceria increased hepatic apoptosis acutely, this persisted to day 90. These findings, together with our earlier reports of 5-nm ceria-induced liver toxicity, provide additional guidance for nanoceria development as a therapeutic agent and for its risk assessment.

The yin: an adverse health perspective of nanoceria: uptake, distribution, accumulation, and mechanisms of its toxicity

“…A 30 nm ceria showed similar Ce 3+ enrichment on its surface. Its core had a greater percentage of Ce 4+ 18, 38 . These results did not show nanoceria biotransformation over this short time.…”

“…Intravenous infusion of 85 mg/kg of a 30 nm ceria produced nanoceria-laden Kupffer cells. These stimulated CD3 + lymphocyte proliferation in the sinusoids to form granulomata, composed of ceria-laden Kupffer cells and a few non-ceria accumulating mononuclear cells, that were seen 30 days after the single nanoceria dose and persisted without great resolution or progression to 90 days after dosing 18, 38 . The granuloma were of the non-necrotizing type and did not progress to frank hepatic necrosis.…”

Prophylactic Treatment with Cerium Oxide Nanoparticles Attenuate Hepatic Ischemia Reperfusion Injury in Sprague Dawley Rats

“…Previous studies have shown that CeO 2 nanoparticles in therapeutic doses are non-toxic [14], relatively stable and accumulate in liver upon intravenous injection [15]. While some studies demonstrated toxicity of CeO 2 nanoparticles in high doses [16], it has now been shown that the toxicity is based on whether the particles exist in Ce +3 or Ce +4 and the relative ratio of Ce +3 /Ce +4 [17]. Furthermore, several studies have shown that CeO 2 nanoparticles can be used to treat stroke [18], ovarian cancer [19], cardiomyopathy [20], sepsis [21] and obesity [22].…”

In Vivo Processing of Ceria Nanoparticles inside Liver: Impact on Free‐Radical Scavenging Activity and Oxidative Stress

“…[17] When ceria nanoparticles (CeO 2 NPs) are sequestered in a rat liver, cytotoxicity occurs, as evidenced by hepatocyte enlargement, sinusoidal dilatation, accumulation of Kupffer cells, and formation of granuloma. [18, 19] In fact, it was recently shown that CeO 2 NPs uptake by the liver also coincides with early pro-oxidant effects in the rat brain, [20] which is followed by a transition to oxidative stress and then, unexpectedly, reverses back to no stress after ninety days. [21] Despite substantial studies that have focused on CeO 2 NPs uptake, distribution, and biopersistance, [1–4,22, 23] so far, no information has been available on its chemical and structural stability once sequestered inside the liver, the organ that stores the greatest amount of CeO 2 NPs.…”