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https://hdl.handle.net/10171/16742
2024-03-29T10:09:29ZSex differences in ochratoxin a toxicity in F344 rats after 7 and 21 days of daily oral administration
https://hdl.handle.net/10171/69062
Title: Sex differences in ochratoxin a toxicity in F344 rats after 7 and 21 days of daily oral administration
Abstract: Ochratoxin A (OTA) is a potent renal carcinogen in male rats but not in females. The mechanisms underlying
these differences are unknown. The sex-dependent response of F344 rats after a repeated OTA oral administration for 7 (0.50 mg/kg bw) or 21 days (0.21 and 0.50 mg/kg bw) was evaluated. General toxicity, sex and thyroid hormones and histopathology were studied. OTA was quantified (HPLC-FLD) in plasma, kidney and liver and the expression of kidney transporters (RT-qPCR) was studied. After 7 days, kidney histopathology showed more pronounced signs of toxicity in males than in females. After 21 days, a higher toxicity was observed but sex differences disappeared. OTA concentration in plasma and tissues was similar in both sexes. Downregulation was the general OTA-induced effect. Oats' downregulation was slow in males and Oat3 did not change in females. Oatp1 was strongly downregulated in males after 21 days. An opposite effect was observed in Bcrp after 21 days: downregulation in males and upregulation in females. Females showed a dose- and time-dependent decrease of progesterone. Despite the sex differences, the final balance in OTA toxicokinetics at renal cell level does not seem to support a higher accumulation of OTA in male kidneys.2018-01-01T00:00:00ZNew approach methodologies to facilitate and improve the hazard assessment of non-genotoxic carcinogens—a PARC project
https://hdl.handle.net/10171/69059
Title: New approach methodologies to facilitate and improve the hazard assessment of non-genotoxic carcinogens—a PARC project
Abstract: Carcinogenic chemicals, or their metabolites, can be classified as genotoxic or non-genotoxic carcinogens (NGTxCs). Genotoxic compounds induce DNA damage, which can be detected by an established in vitro and in vivo battery of genotoxicity assays. For NGTxCs, DNA is not the primary target, and the possible modes of action (MoA) of NGTxCs are much more diverse than those of genotoxic compounds, and there is no specific in vitro assay for detecting NGTxCs. Therefore, the evaluation of the carcinogenic potential is still dependent on long-term studies in rodents. This 2-year bioassay, mainly applied for testing agrochemicals and pharmaceuticals, is time-consuming, costly and requires very high numbers of animals. More importantly, its relevance for human risk assessment is questionable due to the limited predictivity for human cancer risk, especially with regard to NGTxCs. Thus, there is an urgent need for a transition to new approach methodologies (NAMs), integrating human-relevant in vitro assays and in silico tools that better exploit the current knowledge of the multiple processes involved in carcinogenesis into a modern safety assessment toolbox. Here, we describe an integrative project that aims to use a variety of novel approaches to detect the carcinogenic potential of NGTxCs based on different mechanisms and pathways involved in carcinogenesis. The aim of this project is to contribute suitable assays for the safety assessment toolbox for an efficient and improved, internationally recognized hazard assessment of NGTxCs, and ultimately to contribute to reliable mechanism-based next-generation risk assessment for chemical carcinogens.2023-01-01T00:00:00ZMutagenicity and genotoxicity assessment of the emerging mycotoxin Versicolorin A, an Aflatoxin B1 precursor
https://hdl.handle.net/10171/68778
Title: Mutagenicity and genotoxicity assessment of the emerging mycotoxin Versicolorin A, an Aflatoxin B1 precursor
Abstract: Aflatoxin B1 (AFB1) is the most potent natural carcinogen among mycotoxins. Versicolorin A (VerA) is a pre-
cursor 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 micro-
nucleus 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 (γH2AX and 53BP1/
FANCD2, respectively). In conclusion, VerA induces DNA damage without affecting cell viability at concentra-
tions 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.2023-01-01T00:00:00ZSex-dependent gene expression after ochratoxin A insult in F344 rat kidney
https://hdl.handle.net/10171/68728
Title: Sex-dependent gene expression after ochratoxin A insult in F344 rat kidney
Abstract: Ochratoxin A (OTA) is a potent rodent nephrocarcinogen; being males more sensitive than females. The objective was to study the response between sexes at gene expression level (whole genome transcriptomics) in kidneys of F344 rats treated with 0.21 or 0.50 mg/kg bw OTA for 21 days. DNA methylation analysis of selected genes was also studied (MALDI-TOF mass spectrometry). OTA-induced response was dose-dependent in males and females, although clearer in males. Females showed a higher number of altered genes than males but functional analysis revealed a higher number of significantly enriched toxicity lists in 0.21 mg/kg treated males. OTA modulated damage, signaling and metabolism related lists, as well as inflammation, proliferation and oxidative stress in both sexes. Eleven toxicity lists (damage, fibrosis, cell signaling and metabolism) were exclusively altered in males while renal safety biomarker and biogenesis of mitochondria lists were exclusively enriched in females. A high number of lists (39) were significantly enriched in both sexes. However, they contained many sex-biased OTA-modulated genes, mainly phase I and II, transporters and nuclear receptors, but also others related to cell proliferation/apoptosis. No biologically relevant changes were observed in the methylation of selected genes.2019-01-01T00:00:00Z