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Browsing by Issue Date, starting with "2019-06-15"

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  • A multi-endpoint approach to the combined toxic effects of patulin and ochratoxin A in human intestinal cells
    Publication . Assunção, Ricardo; Pinhão, Mariana; Loureiro, Susana; Alvito, Paula; Silva, Maria João
    Humans can be exposed to a complex and variable combination of mycotoxins. After ingestion, intestinal mucosa constitutes the first biological barrier that can be exposed to high concentrations of these toxins. The present study aimed to characterize the combined cytotoxicity, genotoxicity and impact on the gastrointestinal barrier integrity of patulin (PAT, 0.7 μM to 100 μM) and ochratoxin A (OTA, 1 μM to 200 μM) mixtures in Caco-2 cells. A dose-ratio deviation was verified for cytotoxicity, implying that OTA was mainly responsible for synergism when dominant in the mixture, while this pattern was changed to antagonism for the highest PAT concentrations. Genotoxicity (comet assay) results were compatible with an interactive DNA damaging effect at the highest PAT and OTA concentrations, not clearly mediated by the formation of oxidative DNA breaks. Regarding gastrointestinal barrier integrity, a potential synergism was attained at low levels of both mycotoxins, changing to antagonism at higher doses. The present results indicate that combined mycotoxins effects may arise at the intestinal level and should not be underestimated when evaluating their risk to human health.
    2019-06-15Journal article Restricted access Show more
  • Autism Spectrum Disorder: gene variants involved in the nonsense-mediated mRNA decay pathway
    Publication . Marques, Ana Rita; Martiniano, Hugo; Santos, J.X.; Vilela, Joana; Asif, M.; Rasga, C.; Oliveira, G.; Romão, Luísa; Vicente, Astrid
    Genetic factors account for 50-80% of the familial risk of Autism Spectrum Disorder (ASD), but most of the genetic determinants are still unknown and a role for other regulatory mechanisms is likely. The nonsense-mediated decay (NMD) pathway is essential to control mRNA quality and has an important role in the regulation of the transcriptome. Mutations in genes involved in the NMD pathway, such as the UPF3B gene, a core component of this pathway, were previously linked to ASD. In this study we explored the potential role of NMD factors in ASD. We generated a list of 153 genes involved in the NMD pathway using AmiGO, Reactome and a systematic literature review. To identify potentially pathogenic variants in the NMD genes, we analyzed whole exome sequencing data (WES) data from 1338 ASD subjects. We also searched for Copy Number Variants (CNVs) targeting NMD genes in ASD patients (n=3570) and checked their frequency in controls (n=9649). We identified 43 high impact variants in 28 NMD genes, including the UPF3B and ACE, two genes previously implicated in ASD. Importantly, 11 were novel candidate genes that carry loss-of-function and missense (deleterious and damaging) variants with a frequency of 1 to 5% in this ASD dataset. Additionally, 5 NMD genes were found to be targeted by CNVs in 12 ASD subjects but none of the controls. The discovery of 33 NMD genes that are intriguing candidates for ASD in large patient genomic datasets provides evidence supporting the involvement of the NMD pathway in ASD pathophysiology.
    2019-06-15Conference object Restricted access Show more