In vivo genotoxicity of furan in F344 rats at cancer bioassay doses

Ding, Wei; Petibone, Dayton M.; Latendresse, John R.; Pearce, Mason G.; Muskhelishvili, Levan; White, Gene A.; Chang, Ching‐Wei; Mittelstaedt, Roberta A.; Shaddock, Joseph G.; McDaniel, L. Patrice; Doerge, Daniel R.; Morris, Suzanne M.; Bishop, Mark; Manjanatha, Mugimane G.; Aidoo, Anane; Heflich, Robert H.

doi:10.1016/j.taap.2012.03.021

Cited by 52 publications

(40 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings are also consistent with previous reports indicating that several weeks of treatment with carcinogenic doses of furan up-regulated genes related to oxidative stress, inflammation and DNA-damage responses in mouse liver [20,45]. Comparable observations have been reported for furan-treated rats [22,46]. Therefore, it is possible that furan induces oxidative stress, which, in turn, results in DNA damage.…”

Section: Discussionsupporting

confidence: 93%

Mutagenicity of furan in female Big Blue B6C3F1 mice

Terrell

Huynh

Grill

et al. 2014

Mutation Research/Genetic Toxicology and Environmental Mutagene

View full text Add to dashboard Cite

Furan is an abundant food and environmental contaminant that is a potent liver carcinogen in rodent models. To determine if furan is genotoxic in vivo, female B6C3F1 Big Blue transgenic mice were treated with 15 mg/kg bw furan by gavage 5 days a week for 6 weeks, or once weekly for 3 weeks. Liver cII trans-gene mutation-frequency and mutation spectra were determined. Furan did not increase the mutation frequency under either treatment condition. In the 6-week treatment regimen, there was a change in the cII transgene mutation-spectrum, with the fraction of GC to AT transitions significantly reduced. The only other significant change was an increase in GC to CG transversions; these represented a minor contribution to the overall mutation spectrum. A much larger furan-dependent shift was observed in the 3-week study. There was a significant increase in transversion mutations, predominantly GC to TA transversions as well as smaller non-significant changes in GC to CG and AT to TA transversions. To determine if these mutations were caused by cis-2-butene-1,4-dial (BDA), a reactive metabolite of furan, the mutagenic activity and the mutation spectrum of BDA was determined in vitro, in Big Blue mouse embryonic fibroblasts. This compound did not increase the cII gene mutation-frequency but caused a substantial increase in AT to CG transversions. This increase, however, lost statistical significance when adjusted for multiple comparisons. Together, these findings suggest that BDA may not be directly responsible for the in-vivo effects of furan on mutational spectra. Histopathological analysis of livers from furan-treated mice revealed that furan induced multifocal, hepatocellular necrosis admixed with reactive leukocytes and pigment-laden Kupffer cells, enhanced oval-cell hyperplasia, and increased hepatocyte mitoses, some of which were atypical. An indirect mechanism of genotoxicity is proposed in which chronic toxicity followed by inflammation and secondary cell proliferation triggers cancer development in furan-exposed rodents.

show abstract

Section: Discussionsupporting

confidence: 93%

Mutagenicity of furan in female Big Blue B6C3F1 mice

Terrell

Huynh

Grill

et al. 2014

Mutation Research/Genetic Toxicology and Environmental Mutagene

View full text Add to dashboard Cite

show abstract

“…Furan causes DNA damage and double‐strand breaks in hepatocytes (Ding et al, ; Mugford & Kedderis, ). This damage appears after cellular ATP depletion and before cell death (Elia et al, ).…”

Section: Review Of Furan Toxicitymentioning

confidence: 99%

Industrial furan and its biological effects on the body systems

et al. 2018

View full text Add to dashboard Cite

Furan as a product of thermal processing is found in many foods and beverages. In vitro and in vivo genotoxicity was positive for furan, also when metabolic preconditions for the formation of Z‐2‐butene‐1,4dialdehyde (BDA), the reactive compound, was met. However, in major studies, high doses represented the genotoxic effect. Moreover, data on toxicity in different cells and organs are inconsistent. For preparing remarkable risk assessments in human, providing bioassay data is necessary. We aimed to review available evidences about furan and BDA. A vast number of studies have been published on toxicity of furan in vitro and in vivo. Thus, we present a comprehensive review on the current status of furan in inducing toxic effects in different body systems, and possible mechanisms involved in the negative effects of this compound. In this article, furan mitigation procedures in foods have been taken into account. Practical applications From industrial point, furan is repeatedly used as an intermediate chemical in the process of producing some compounds such as resins, lacquers, pesticides and drugs. Furthermore, it is common as a side‐product of high‐energy radiation and thermal processes in food production. The current study focused on the effects of furan on the body organs. Furthermore, furan mitigation procedures in foods have been addressed in the current study. Nearly all previous studies on the industrial furan demonstrated that it has adverse health effects on the organs of the body. In order to prove specific results, further studies regarding furan risk assessment is of great importance.

show abstract

“…34 Furthermore, furan induced liver DNA damage as detected by the comet assay. 29,34,35 Finally, a metabolite of furan is mutagenic in a number of model systems 28,36 and reacts with DNA. 37–40 …”

Section: Furanmentioning

confidence: 99%

“…35,47,48 Genes related to cell cycle regulation and DNA repair were down regulated. 35 Alterations in cell cycle and apoptotic genes were observed in the livers of rats treated daily with 0.1 mg/kg for four weeks. 49 Toxicity and proliferation precedes the development of cholangiofibrosis and subsequent cholangiocarcinomas in rats.…”

Section: Furanmentioning

confidence: 99%

Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring

Peterson

2012

Chem. Res. Toxicol.

168

160

View full text Add to dashboard Cite

Many xenobiotics containing a furan ring are toxic and/or carcinogenic. The harmful effects of these compounds require furan ring oxidation. This reaction generates an electrophilic intermediate. Depending on the furan ring substituents, the intermediate is either an epoxide or a cis-enedione with more ring substitution favoring epoxide formation. Either intermediate reacts with cellular nucleophiles such as protein or DNA to trigger toxicities. The reactivity of the metabolite determines which cellular nucleophiles are targeted. The toxicity of a particular furan is also influenced by the presence of competing metabolic pathways or efficient detoxification routes. GSH plays an important role in modulating the harmful effects of this class of compound by reacting with the reactive metabolite. However, this may not represent a detoxification step in all cases.

show abstract

In vivo genotoxicity of furan in F344 rats at cancer bioassay doses

Cited by 52 publications

References 36 publications

Mutagenicity of furan in female Big Blue B6C3F1 mice

Mutagenicity of furan in female Big Blue B6C3F1 mice

Industrial furan and its biological effects on the body systems

Reactive Metabolites in the Biotransformation of Molecules Containing a Furan Ring

Contact Info

Product

Resources

About