Oxidative Stress, Mutations and Chromosomal Aberrations Induced by In Vitro and In Vivo Exposure to Furan

Abstract

Furan is a volatile compound that is formed in foods during thermal processing. It is classified as a possible human carcinogen by international authorities based on sufficient evidence of carcinogenicity from studies in experimental animals. Although a vast number of studies both in vitro and in vivo have been performed to investigate furan genotoxicity, the results are inconsistent, and its carcinogenic mode of action remains to be clarified. Here, we address the mutagenic and clastogenic activity of furan and its prime reactive metabolite cis-2 butene-1,4-dial (BDA) in mammalian cells in culture and in mouse animal models in a search for DNA lesions responsible of these effects. To this aim, Fanconi anemia-derived human cell lines defective in the repair of DNA inter-strand crosslinks (ICLs) and Ogg1−/− mice defective in the removal of 8-hydroxyguanine from DNA, were used. We show that both furan and BDA present a weak (if any) mutagenic activity but are clear inducers of clastogenic damage. ICLs are strongly indicated as key lesions for chromosomal damage whereas oxidized base lesions are unlikely to play a critical role.

Cytoarchitecture changes of the rat thyroid gland following Furan administration implemented Fas-apoptotic pathway with potential abrogating role of selenium

“…The furan group exhibited redox imbalance with increased MDA and decreased both GSH and GPX-1. In alignment with our results, furan administration in animals has been associated with not only increased serum and tissue levels of MDA and a significant decrease of GSH and GPX-1 but also, was accompanied with a decrease in glutathione-S-transferase (GST), catalase (CAT) and superoxide dismutase (SOD) [15][16][17][18]. The decline in serum GSH "the body's master intracellular non-enzymatic antioxidant and the active coenzyme for the enzyme GPX-1" was probably due to its covalent bonding with cis-2butene-1,4-dialdehyde (BDA) which is the primary metabolite of furan formed under the metabolic influence of the liver enzyme cytochrome P450 2E1 (CYP2E1) [7].…”

“…There is much evidence for the involvement of the furan intermediate metabolite "BDA" that binds covalently to DNA leading ultimately to epigenetic changes and hyperplasia [9]. Also, BDA forms DNA single-strand breaks, DNAprotein cross-links and DNA adducts in mammalian cells that intermingled together yielding abnormal transcription and replication and may be mutations which are depicted as precancerous attributes [18,46,47]. Finally, in this study, Se advocated antiproliferative potential as was evident from the emerged results of Furan/Se group that exhibited a weak immunoexpression of PCNA and a significant decline in its mean area % in PCNA immuonstained sections of the thyroid gland.…”

“…Also, furan was considered by National Toxicology Program (NTP) [14] and International Agency for Research on Cancer (IARC) [15] as "a possibly carcinogenic to humans". The proposed mechanisms by which furan exposure caused such tissue injury are the oxidative stress and the induction of tissue inflammation [16][17][18]. Furthermore, emerging evidence implicated furan as one of the endocrine disruptors [19].…”

Food-Borne Chemical Carcinogens and the Evidence for Human Cancer Risk

“…Nevertheless, in vivo DNA reactivity has not been rigorously excluded. In addition, there is evidence that oxidative stress and epigenetic alterations play a role [ 896 , 916 , 917 , 918 ].…”

A comprehensive review of furan in foods: From dietary exposures and in vivo metabolism to mitigation measures

“…Thus, the authors proposed an indirect mechanism of genotoxicity, in which chronic toxicity followed by inflammation and secondary cell proliferation triggered the development of cancer following furan exposure. A recent report showed that furan caused chromosomal damage in both in vitro and in vivo models, and DNA inter‐strand cross‐links played an important role in furan clastogenicity (Russo et al., 2021).…”