Gene expression changes induced by ochratoxin A in renal and hepatic tissues of male F344 rat after oral repeated administration

Arbillaga, Leire; Vettorazzi, Ariane; Gil, Ana Gloria; Delft, J.H.M. van; García-Jalón, Jose Antonio; Cerain, Adela López de

doi:10.1016/j.taap.2008.02.018

Cited by 52 publications

(51 citation statements)

References 37 publications

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“…Leire et al reported that the hepatic gene expression changes induced by OTA. The authors also observed that circadian exercise, cholesterol biosynthesis and lipid metabolism were influenced in the rat liver which is similar with our high dose group 30 . In another study with 300 ml OTA/kg bw, similar dose in our study, carbon metabolism, amino acid metabolism were influenced in the liver 31 .…”

Section: Discussionsupporting

confidence: 88%

“…Male Tsc2 EKER rats gavaged with OTA also changed their energy provision 43 . In addition, liver lipid metobolism was down-regulated of male F344 rats after OTA treatments in several studies 30,31 . In our result, the protein (such as Hmgcs2) was down-regulated in PPAR pathway, which is the major regulator of lipid and fatty acid metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that in the current manuscript, we only studied the toxicological mechanisms between the high-dose and medial-dose OTA at thirteen weeks. However, various toxic mechanisms could be expected at the different time intervals 30 . Moreover, several studies have been carried out to elucidate the impacts of different doses of other substances.…”

Section: Discussionmentioning

confidence: 99%

“…the role of biotransformation in OTA toxicity has already been addressed in previous studies. Some of these investigators reported a down-regulation in the expression of the representative genes of transporters and xenobiotic metabolism 30,42 , while the remaining reports found an elevation in their expression 43 . Furthermore, energy metabolism was deregulated induced by OTA in vitro and in vivo studies.…”

Section: Discussionmentioning

confidence: 99%

“…In our result, the protein (such as Hmgcs2) was down-regulated in PPAR pathway, which is the major regulator of lipid and fatty acid metabolism. Also, the amino acids metabolism (such as alanine and aspartame metabolism, tryptophane metabolism) was affected in rats' liver 30 . We compared the miRNA pathways with at least two and three algorithms, and found that the lost pathways with at least three algorithms mainly concentrated on amino acid metabolism, carbohydrate metabolism, glycan biosynthesis, lipid metabolism, and metabolism of cofactors and vitamins.…”

Section: Discussionmentioning

confidence: 99%

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Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies

Yang

Chen

et al. 2014

Sci Rep

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The mycotoxin ochratoxin A (OTA) is found widely in agricultural commodities. OTA can induce various toxicities. In this study, rats were gavaged with OTA for different weeks. Then, the expression of microRNAs, mRNAs and proteins were measured in the rat livers treated with OTA for 13 weeks. Our sequencing data suggests that the medial and the high doses of OTA exert different effects on livers. Five distinctive pathways were induced after OTA treatment as collectively demonstrated at miRNA, mRNA and protein levels. Two (primary bile acid biosynthesis, and metabolism of xenobiotics by cytochrome P450) are directly associated with liver damage, whereas the remaining pathways (arginine and proline metabolism, cysteine and methionine metabolism, and PPAR signaling pathway) cause metabolic disease. This study reveals OTA-induced early hepatotoxicity for the first time by combining multi-omics methods. The novel metabolic pathways may contribute to the pathogenesis of metabolic diseases later in life.O chratoxin A (OTA) is a low molecular weight mycotoxin produced by certain strains of filamentous fungi of the Aspergillus and Penicillium genera and has been detected in a large variety of agricultural commodities. OTA carries potential health-associated risks and has been classified as a possible human carcinogen (group 2B) by the International Agency for Research on Cancer 1 . OTA has previously been found to induce various toxic effects including nephrotoxicity, hepatotoxicity, immunotoxicity, genotoxicity, carcinogenicity, teratogenicity, neurotoxicity and mutagenicity.The liver is one of the major target organs of OTA biotransformation. Although, some early hepatotoxicity studies employed relative high concentrations of OTA and found remarkable liver lesion 2,3 , lower doses of OTA did not provoke significant pathological changes 4-6 . Most of the previous studies have been extensively focused on OTA-induced kidney damage, less on liver. However, it is still unknown how OTA affects the liver which is the largest detoxification organ of body. Therefore, the identification of early hepatotoxicity can be helpful to understand the mechanism of some diseases that may be developed and progressed by OTA in later stage, and to prevent these diseases in early stage to improve human health.Omics approaches, such as transcriptome and proteome, are promising to detect the pathological changes of liver at a molecular level. Till date, omics technology has been employed only in a few studies to understand the mechanism of OTA hepatotoxicity. Moreover, a high-throughput microarray profiling study on HepG2 liver cell transcriptome demonstrated that multiple hepatic metabolism genes are modulated by OTA exposure 7 . In addition, proteomic approaches have helped identify key proteins in the livers of pigs treated with OTA 8 . These omics approaches have widened our view about OTA hepatotoxicity, however the mechanism of OTA actions remains largely unknown.Recently, microRNAs (miRNAs) in animals and plants are shown to play an impor...

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies

Yang

Chen

et al. 2014

Sci Rep

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Mycotoxins and the kidney: Modes of action for renal tumor formation by ochratoxin A in rodents

Mally

Dekant

2009

Molecular Nutrition Food Res

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The mycotoxin ochratoxin A (OTA) is a potent renal carcinogen in rodents. OTA is only slowly eliminated due to high affinity to plasma proteins and inefficient biotransformation. A number of mechanisms have been proposed to account for renal tumor formation. DNA adduct formation, mainly based on the( 32)P-postlabeling assay, was postulated as a mode of action (MoA). However, studies using radiolabeled OTA or MS failed to demonstrate formation of OTA-derived DNA-adducts. While some studies have demonstrated generation of oxidative stress by OTA, the oxidative stress response appears to be not very pronounced and therefore may not explain the high potency of OTA in rodents. A number of recent investigations support the hypothesis that OTA causes disruption of mitosis resulting in blocked or asymmetric cell division. This may present an increased risk of aneuploidy acquisition and may play a critical role in OTA-induced tumor formation. The absence of DNA-adducts derived from OTA supports a thresholded MoA, and a tolerable weekly intake (TWI) of 120 ng OTA/kg bw has been derived by the European Food Safety Authority. The estimated intake of OTA in Europe is below this TWI for most of the population.

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Functional proteomics reveals hepatotoxicity and the molecular mechanisms of different forms of chromium delivered by skin administration

et al. 2012

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Chromium compounds are known to be associated with cytotoxicity and carcinogenicity when applied via the skin. However, there is no perspective research to elucidate the causations between chromium exposure and hepatotoxicity. In the present study, the impact of hexavalent/trivalent chromium on the liver and the underlying pathogenic processes were revealed in the female nude mice model. The liver damage under different treatments was evaluated by histologic examination. Functional proteome tools combined with a network analysis revealed statistically significant candidate protein networks predicted to be changed in the presence of chromium compounds. RNA interference-mediated silencing and immunohistochemistry were used to confirm whether the candidate protein was capable of resulting in hepatotoxicity elicited by chromium. Potassium chromate as the Cr(VI) compound generated greater oxidative stress, apoptosis and hepatotoxicity compared to chromium nitrate [Cr(III)]-treated samples. The most meaningful changes were observed amongst proteins involved in carbohydrate metabolism, endoplasmic reticulum (ER) stress, calcium homeostasis and apoptosis. Furthermore, abrogation of transitional ER ATPase (VCP) led to significant inhibition in hepatic cell viability under Cr(VI) administration, and the expression profiles of cytokeratin were closely correlated with apoptotic degrees of liver tissue. Collectively, our findings suggest that Cr(VI) might induce the accumulation of misfolded proteins and adverse effects leading to cell apoptosis and liver injury. These signature networks represent an approach to discover novel relationships in complex data, and functional proteomics of liver may provide solid evidence of chromium-caused hepatic damage via the skin.

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Gene expression changes induced by ochratoxin A in renal and hepatic tissues of male F344 rat after oral repeated administration

Cited by 52 publications

References 37 publications

Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies

Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies

Mycotoxins and the kidney: Modes of action for renal tumor formation by ochratoxin A in rodents

Functional proteomics reveals hepatotoxicity and the molecular mechanisms of different forms of chromium delivered by skin administration

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