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Modulation of gene expression induced by cylindrospermopsin in human intestinal Caco-2 cells

ABSTRACT: Cylindrospermopsin (CYN) is a cyanotoxin that has been recognised as an emerging potential public health risk. Although CYN toxicity has been demonstrated, the mechanisms involved have not been fully characterised. To identify some key pathways related to this toxicity, we studied the transcriptomic profile of human intestinal Caco-2 cells exposed to a sub-toxic concentration of CYN (1.6 µM for 24hrs) using a non-targeted approach. CYN was shown to modulate different biological functions which were related to growth arrest (with down-regulation of cdkn1a and uhrf1 genes), and DNA recombination and repair (with up-regulation of aptx and pms2 genes). Our main results reported an increased expression of some histone-modifying enzymes (histone acetyl and methyltransferases MYST1, KAT5 and EHMT2) involved in chromatin remodelling, which is essential for initiating transcription. We also detected greater levels of acetylated histone H2A (Lys5) and dimethylated histone H3 (Lys4), two products of these enzymes. In conclusion, CYN overexpressed proteins involved in DNA damage repair and transcription, including modifications of nucleosomal histones. Our results highlighted some new cell processes induced by CYN.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55723 | GEO | 2014/03/11

SECONDARY ACCESSION(S): PRJNA240710

REPOSITORIES: GEO

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Modulation of gene expression induced by cylindrospermopsin in human intestinal Caco-2 cells

Project description:Cylindrospermopsin (CYN) is a cyanotoxin that has been recognised as an emerging potential public health risk. Although CYN toxicity has been demonstrated, the mechanisms involved have not been fully characterised. To identify some key pathways related to this toxicity, we studied the transcriptomic profile of human intestinal Caco-2 cells exposed to a sub-toxic concentration of CYN (1.6 M-BM-5M for 24hrs) using a non-targeted approach. CYN was shown to modulate different biological functions which were related to growth arrest (with down-regulation of cdkn1a and uhrf1 genes), and DNA recombination and repair (with up-regulation of aptx and pms2 genes). Our main results reported an increased expression of some histone-modifying enzymes (histone acetyl and methyltransferases MYST1, KAT5 and EHMT2) involved in chromatin remodelling, which is essential for initiating transcription. We also detected greater levels of acetylated histone H2A (Lys5) and dimethylated histone H3 (Lys4), two products of these enzymes. In conclusion, CYN overexpressed proteins involved in DNA damage repair and transcription, including modifications of nucleosomal histones. Our results highlighted some new cell processes induced by CYN. Modulation of gene expression in differentiated Caco-2 cells was measured at 24 hours after exposure to doses of 0 and 1.6 M-BM-5M of cylindrospermopsin. Six independent experiments were performed, but only 11 samples (5 controls and 6 exposed to cylindrospermopsin) had an RNA quality indicator M-bM-^IM-% 9 and were used for the microarray experiments.

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Project description:Cylindrospermopsin (CYN), a hepatotoxin produced by several cyanobacterial species, has been implied in human intoxications following ingestion. Although some pathways involved in CYN toxicity have been reported, the whole process is certainly more complex. In order to identify the mechanisms related to CYN toxicity on liver, we studied the transcriptomic profile of HepaRG human hepatic cells exposed to a low concentration of CYN (0.8 µM for 24 hrs). The affected pathways were further confirmed through the expression of key genes by qPCR, and the investigation of toxicity markers by high content analysis (HCA) on a broader CYN concentration range. Also CYP450 activities and cell redox homeostasis were investigated after acute and repeated exposure to CYN. Our results revealed that CYN induced up-regulation of genes implied in RNA modification and maturation, but also down-regulation of genes involved in xenobiotic metabolism and cell cycle progress. There was cell cycle disturbance characterised by an accumulation of G1/S and G2/M cells, and an increase of phospho-H3 positive cells. The cell cycle arrest was linked to the induction of DNA damage pointed out by an increase of γH2AX positive cells, but also an accumulation of sub G1 cells indicating apoptosis not involving caspase 3. While GSH content decreased strongly after acute exposure to CYN, it increased after a repeated exposure reflecting an adaptive response of cell redox homeostasis when exposure to CYN was prolonged. However, our data suggested also that CYN induced a down-regulation of phase I and II metabolism gene products, and CYP450 activities were affected following both acute and repeated exposure to CYN. Our study indicated that repeated exposure of liver cells to low concentrations of CYN may affect their detoxification capacities.

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