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A new study finds a chemical formed when we digest a widely used sweetener is “genotoxic,” meaning it breaks up DNA. The chemical is also found in trace amounts in the sweetener itself, and the finding raises questions about how the sweetener may contribute to health problems.

This article was originally published on May 31, 2023 by Matt Shipman at NC State University News and can be found here

At issue is sucralose, a widely used artificial sweetener sold under the trade name Splenda®. Previous work by the same research team established that several fat-soluble compounds are produced in the gut after sucralose ingestion. One of these compounds is sucralose-6-acetate.

“Our new work establishes that sucralose-6-acetate is genotoxic,” says Susan Schiffman, corresponding author of the study and an adjunct professor in the joint department of biomedical engineering at North Carolina State University and the University of North Carolina at Chapel Hill. “We also found that trace amounts of sucralose-6-acetate can be found in off-the-shelf sucralose, even before it is consumed and metabolized.

“To put this in context, the European Food Safety Authority has a threshold of toxicological concern for all genotoxic substances of 0.15 micrograms per person per day,” Schiffman says. “Our work suggests that the trace amounts of sucralose-6-acetate in a single, daily sucralose-sweetened drink exceed that threshold. And that’s not even accounting for the amount of sucralose-6-acetate produced as metabolites after people consume sucralose.”

For the study, researchers conducted a series of in vitro experiments exposing human blood cells to sucralose-6-acetate and monitoring for markers of genotoxicity.

“In short, we found that sucralose-6-acetate is genotoxic, and that it effectively broke up DNA in cells that were exposed to the chemical,” Schiffman says.

The researchers also conducted in vitro tests that exposed human gut tissues to sucralose-6-acetate.

“Other studies have found that sucralose can adversely affect gut health, so we wanted to see what might be happening there,” Schiffman says. “When we exposed sucralose and sucralose-6-acetate to gut epithelial tissues – the tissue that lines your gut wall – we found that both chemicals cause ‘leaky gut.’ Basically, they make the wall of the gut more permeable. The chemicals damage the ‘tight junctions,’ or interfaces, where cells in the gut wall connect to each other.

“A leaky gut is problematic, because it means that things that would normally be flushed out of the body in feces are instead leaking out of the gut and being absorbed into the bloodstream.”

The researchers also looked at the genetic activity of the gut cells to see how they responded to the presence of sucralose-6-acetate.

“We found that gut cells exposed to sucralose-6-acetate had increased activity in genes related to oxidative stress, inflammation and carcinogenicity,” Schiffman says.

“This work raises a host of concerns about the potential health effects associated with sucralose and its metabolites. It’s time to revisit the safety and regulatory status of sucralose, because the evidence is mounting that it carries significant risks. If nothing else, I encourage people to avoid products containing sucralose. It’s something you should not be eating.”

The paper, “Toxicological and pharmacokinetic properties of sucralose-6-acetate and its parent sucralose: in vitro screening assays,” is published in the Journal of Toxicology and Environmental Health, Part B. The paper was co-authored by Troy Nagle, Distinguished Professor of Biomedical Engineering at NC State and UNC and Distinguished Professor of Electrical and Computer Engineering at NC State; Terrence Furey, professor of genetics and biology at UNC; and Elizabeth Scholl, a former researcher at NC State who is currently at Sciome LLC.

The authors have no conflicts of interest. The research was done with support from the Engineering Foundation at NC State.


Note to Editors: The study abstract follows.

“Toxicological and pharmacokinetic properties of sucralose-6-acetate and its parent sucralose: in vitro screening assays”

Authors: Susan S. Schiffman and H. Troy Nagle, North Carolina State University and University of North Carolina at Chapel Hill; Elizabeth H. Scholl, Sciome LLC; Terrence S. Furey, University of North Carolina at Chapel Hill

Published: May 29, Journal of Toxicology and Environmental Health, Part B

DOI: 10.1080/10937404.2023.2213903

Abstract: The purpose of this study was to determine the toxicological and pharmacokinetic properties of sucralose-6-acetate, a structural analog of the artificial sweetener sucralose. Sucralose-6-acetate is an intermediate and impurity in the manufacture of sucralose, and recent commercial sucralose samples were found to contain up to 0.67% sucralose-6-acetate. Studies in a rodent model found that sucralose-6-acetate is also present in fecal samples with levels up to 10% relative to sucralose which suggest that sucralose is also acetylated in the intestines. A MultiFlow® assay, a high-throughput genotoxicity screening tool, and a micronucleus (MN) test that detects cytogenetic damage both indicated that sucralose-6-acetate is genotoxic. The mechanism of action was classified as clastogenic (produces DNA strand breaks) using the MultiFlow® assay. The amount of sucralose-6-acetate in a single daily sucralose-sweetened drink might far exceed the threshold of toxicological concern for genotoxicity (TTCgenotox) of 0.15 µg/person/day. The RepliGut® System was employed to expose human intestinal epithelium to sucralose-6-acetate and sucralose, and an RNA-seq analysis was performed to determine gene expression induced by these exposures. Sucralose-6-acetate significantly increased the expression of genes associated with inflammation, oxidative stress, and cancer with greatest expression for the metallothionein 1 G gene (MT1G). Measurements of transepithelial electrical resistance (TEER) and permeability in human transverse colon epithelium indicated that sucralose-6-acetate and sucralose both impaired intestinal barrier integrity. Sucralose-6-acetate also inhibited two members of the cytochrome P450 family (CYP1A2 and CYP2C19). Overall, the toxicological and pharmacokinetic findings for sucralose-6-acetate raise significant health concerns regarding the safety and regulatory status of sucralose itself.

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