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Versicolorin A (VerA), a precursor of the potent carcinogen Aflatoxin B1 (AFB1), is an emerging mycotoxin. Recent research has highlighted the mutagenic and genotoxic properties of VerA, yet several facets of its pronounced toxicity remain unexplored. In the present study, we investigated early (6 h) transcriptomic changes induced by VerA in differentiated intestinal cells in non-cytotoxic conditions (1 and 3 μM) and compared its effects to those of AFB1 at 1 μM. Our findings indicated that VerA led to substantial alterations in global gene expression profiles, while AFB1 did not exhibit the same effects. As expected, both toxins caused alterations in gene expression associated with well-known aspects of their toxicity, including mutagenicity, genotoxicity, oxidative stress, and apoptosis. However, we also observed novel features of VerA toxicity, including the ability to cause mitochondrial dysfunction and to trigger a type-1 interferon response, at least partially mediated by cGAS-STING. VerA also induced changes in the expression of genes involved in the regulation of cell shape and adhesion, transcription/translation as well as genes associated with tumor biology. Our results provide new evidence of the high toxicity of VerA and underscore the importance of further assessing the risks associated with its presence in food. [Display omitted] • VerA and AFB1 triggered genotoxicity-linked gene expression profiles. • VerA induced a larger remodeling in gene expression than AFB1. • VerA distinctly causes mitochondrial toxicity, immune and transcription dysfunction. • Results suggest that VerA has a carcinogenic potential. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1) is the most potent natural carcinogen among mycotoxins. Versicolorin A (VerA) is a precursor of AFB1 biosynthesis and is structurally related to the latter. Although VerA has already been identified as a genotoxin, data on the toxicity of VerA are still scarce, especially at low concentrations. The SOS/umu and miniaturised version of the Ames test in Salmonella Typhimurium strains used in the present study shows that VerA induces point mutations. This effect, like AFB1, depends primarily on metabolic activation of VerA. VerA also induced chromosomal damage in metabolically competent intestinal cells (IPEC-1) detected by the micronucleus assay. Furthermore, results from the standard and enzyme-modified comet assay confirmed the VerA-mediated DNA damage, and we observed that DNA repair pathways were activated upon exposure to VerA, as indicated by the phosphorylation and/or relocation of relevant DNA-repair biomarkers (γ H2AX and 53BP1/FANCD2, respectively). In conclusion, VerA induces DNA damage without affecting cell viability at concentrations as low as 0.03 μM, highlighting the danger associated with VerA exposure and calling for more research on the carcinogenicity of this emerging food contaminant. [Display omitted] • VerA exhibits mutagenic properties when metabolically activated. • VerA induces DNA damage without affecting cell viability. • VerA is mutagenic and genotoxic at very low concentrations. • VerA presents a high carcinogenic potential, warranting further research. [ABSTRACT FROM AUTHOR]

Abstract: The occurrence of DNA double-strand breaks (DSBs) induced by ionizing radiation has been extensively studied by biochemical or cell imaging techniques. Cell imaging development relies on technical advances as well as our knowledge of the cell DNA damage response (DDR) process. The DDR involves a complex network of proteins that initiate and coordinate DNA damage signaling and repair activities. As some DDR proteins assemble at DSBs in an established spatio-temporal pattern, visible nuclear foci are produced. In addition, post-translational modifications are important for the signaling and the recruitment of specific partners at damaged chromatin foci. We briefly review here the most widely used methods to study DSBs. We also discuss the development of indirect methods, using reporter expression or intra-nuclear antibodies, to follow the production of DSBs in real time and in living cells. [Copyright &y& Elsevier]

Crossovers involve the reciprocal exchange of large fragments of genetic material between homologous chromosomes during meiosis. In this way, crossovers are the basis of genetics. Remarkably, the number and distribution of crossovers on chromosomes are closely controlled. Data from various model organisms (notably Saccharomyces cerevisiae) show that the distribution of crossovers results from a series of tightly regulated events involving the formation and repair of double-strand breaks and interference. Recent advances in genetic and cytological tools, particularly for studying Arabidopsis thaliana, have enabled crossover control in plants to be studied in more detail. In this article, we discuss the contribution of plant studies to meiosis research, particularly to our understanding of crossover control and interference, and we evaluate models of interference. [Copyright &y& Elsevier]

• VerA displays a higher cytotoxic potency than AFB 1 against intestinal cells. • VerA disturbs the expression of a huge number (18 002) of genes. • VerA triggers DNA strand breaks, slows down cell division and induces apoptosis. • The toxic effects are mainly independent of the p53 pathway. Aflatoxin B 1 (AFB 1) is the most potent carcinogen among mycotoxins. Its biosynthesis involves the formation of versicolorin A (VerA), whose chemical structure shares many features with AFB 1. Our data revealed significant levels of VerA in foodstuff from Central Asia and Africa. Given this emerging food risk, it was of prime interest to compare the toxic effects of the two mycotoxins against cells originating from the intestinal tract. We used human colon cell lines (Caco-2, HCT116) to investigate the cytotoxic process induced by the two mycotoxins. Contrary to AFB 1 , a low dose of VerA (1 µM) disturbed the expression level of thousands of genes (18 002 genes). We show that the cytotoxic effects of low doses of VerA (1–20 µM) were stronger than the same low doses of AFB 1 in both Caco-2 and HCT116 cell lines. In Caco-2 cells, VerA induced DNA strand breaks that led to apoptosis and reduced DNA replication of dividing cells, consequently inhibiting cell proliferation. Although VerA was able to induce the p53 signaling pathway in p53 wild-type HCT116 cells, its toxicity process did not mainly rely on p53 expression since similar cytotoxic effects were also observed in HCT116 cells that do not express p53. In conclusion, this study provides evidence of the risk of food contamination by VerA and shed light on its toxicological effect on human colon cells. [ABSTRACT FROM AUTHOR]

Colloidal silver products are sold for a wide range of disinfectant and health applications. This has increased the potential for human exposure to silver nanoparticles (AgNPs) and ions (Ag+), for which oral ingestion is considered to be a major route of exposure. Our objective was to evaluate and compare the toxicity of two commercially available colloidal silver products on two human intestinal epithelial models under realistic exposure conditions. Mesosilver™ and AgC were characterized and a concentration range between 0.1 and 12 μg/mL chosen. Caco-2 cells vs. co-culture of Caco-2 and mucus-secreting HT29-MTX cells (90/10) were used. Repeated exposure was carried out to determine cell viability over 18 days of cell differentiation in 24-well plates. Selected concentrations (0.1, 1, and 3 μg/mL) were tested on cells cultured in E -plates and Transwells with the same repeated exposure regimen, to determine cell impedance, and cell viability and trans-epithelial electrical resistance (TEER), respectively. Silver uptake, intracellular localisation, and translocation were determined by CytoViva™, HIM-SIMS, and ICP-MS. Genotoxicity was determined on acutely-exposed proliferating Caco-2 cells by γH2AX immunofluorescence staining. Repeated exposure of a given concentration of AgC, which is composed solely of ionic silver, generally exerted more toxic effects on Caco-2 cells than Mesosilver™, which contains a mix of AgNPs and ionic silver. Due to its patchy structure, the presence of mucus in the Caco-2/HT29-MTX co-culture only slightly mitigated the deleterious effects on cell viability. Increased genotoxicity was observed for AgC on proliferating Caco-2 cells. Silver uptake, intracellular localisation, and translocation were similar. In conclusion, Mesosilver™ and AgC colloidal silver products show different levels of gut toxicity due to the forms of distinct silver (AgNPs and/or Ag+) contained within. This study highlights the applicability of high-resolution (chemical) imaging to detect and localize silver and provides insights into its uptake mechanisms, intracellular fate and cellular effects. Unlabelled Image • Mesosilver™ and AgC products have different silver composition and gut toxicity. • Repeated low-dose exposure regimen better mimics human exposure. • Mesosilver™ and AgC are able to induce genotoxicity in Caco-2 cells. • AgC exerts the most deleterious effects in Caco-2 and Caco-2/HT29-MTX cells. • CytoViva™ and HIM-SIMS imaging demonstrates silver uptake for Mesosilver™ and AgC. [ABSTRACT FROM AUTHOR]