Unknown,Transcriptomics,Genomics,Proteomics

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The glucosinolate metabolite 1-methoxy-3-indolylmethyl alcohol induces a gene expression profile in mouse liver similar to the expression signature caused by known genotoxic hepatocarcinogens

ABSTRACT: Breakdown products of some glucosinolates M-bM-^@M-^S defense chemicals of Brassicales M-bM-^@M-^S induce detoxifying enzymes and demonstrate preventive activities against chemically induced tumorigenesis in animal models. However, other breakdown products are genotoxic. 1-Methoxy-3-indolylmethyl alcohol (1-MIM-OH) is mutagenic in bacterial and mammalian cells upon activation by sulphotransferases and forms DNA adducts in mouse tissues. This effect was enhanced in mice transgenic for human sulphotransferases 1A1/2 (FVB/N-hSULT1A1/2). In this study we explored gene expression changes induced by 1-MIM-OH in mouse liver. FVB/N-hSULT1A1/2 mice were orally treated with 1-MIM-OH for 21 or 90 days, leading to high levels of hepatic 1-MIM-DNA adducts. Genome-wide expression analyzes in this tissue demonstrated no influence on detoxifying enzymes, but up-regulation of many mediators of the tumour suppressor p53 and down-regulation of Fhit and other long genes. In conclusion, 1-MIM-OH did not induce protective enzymes, but formed high levels of DNA adducts, which were recognized by affected cells as reflected by p53 activation. While this p53 response might aim to protection, it was unable to prevent the accumulation of DNA adducts. However, various epdemiological studies reported inverse associations between the intake of cruciferous vegetables and cancer. This association might be due to the presence of other glucosinolates with tumour-preventing influences possibly outweighing adverse effects of some metabolites. Nevertheless, 1-MIM-OH is a genotoxic substance inducing a gene expression profile similar to the expression signature caused by known genotoxic hepatocarcinogens. Male FVB/N-SULT1A1/2 mice were orally treated with 1-MIM-OH, trice per week, 26 mg/kg body mass per treatment. Control animals only received the vehicle (glyceryl trioctanoate) over the same period. Animals were killed after 10 and 40 treatments (over a period of 21 and 90 d, respectively), always 24 h after the last treatment (6 treated and 6 control mice, respectively). Organs were weighed, shock-frozen in liquid nitrogen and stored for a few days at -80M-BM-0C until further processing. Liver organs were ground in a Tissuelyser ball mill (Qiagen, Hilden, Germany) under cooling with liquid nitrogen. The frozen liver tissue was crushed and total RNA was isolated using the RNeasy Mini Kit (Qiagen, Hilden, Germany) according to the manufacturerM-bM-^@M-^Ys instructions. For genome-wide microarray analysis quality of RNA was controlled using the BioAnalyzer (Agilent, Santa Clara, CA, USA). Affymetrix GeneChip hybridization (GeneChip MouseGenome 430 2.0) was performed with 1 M-BM-5g total RNA according to the manufacturerM-bM-^@M-^Ys recommendations. RNA from six individual animals per group (21-day and 90-day treatments with 1-MIM-OH or the vehicle only) was analyzed. For the analysis one hybridized GeneChip (mouse 6 [treated for 21 days with 1-MIM-OH]) was excluded due to hybridization artefacts.

ORGANISM(S): Mus musculus

SUBMITTER: Anke Ehlers

PROVIDER: E-GEOD-61494 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The glucosinolate metabolite 1-methoxy-3-indolylmethyl alcohol induces a gene expression profile in mouse liver similar to the expression signature caused by known genotoxic hepatocarcinogens.

Ehlers Anke A Florian Simone S Schumacher Fabian F Meinl Walter W Lenze Dido D Hummel Michael M Heise Tanja T Seidel Albrecht A Glatt Hansruedi H Lampen Alfonso A

Molecular nutrition & food research 20150209 4

<h4>Scope</h4>Breakdown products of certain glucosinolates induce detoxifying enzymes and demonstrate preventive activities against chemically induced tumourigenesis in animal models. However, other breakdown products are genotoxic. 1-Methoxy-3-indolylmethyl alcohol (1-MIM-OH) is mutagenic in bacterial and mammalian cells upon activation by sulphotransferases and forms DNA adducts in mouse tissues. This effect is enhanced in mice transgenic for human sulphotransferases 1A1/2 (FVB/N-hSULT1A1/2). ...[more]

PMID: 25559983

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Project description:MicroRNAs (miRNAs) are small regulatory RNA molecules that modulate the activity of specific mRNA targets and play important roles in a wide range of physiologic and pathologic processes. We hypothesized that miRNAs might be involved in the progression of CKD. In our previous studies we found chronic renal damages developed progressively in rats with 5/6 nephrectomy. L-mimosine(L-Mim) intervention from wk 5 to wk 12 improved renal function and resulted in additional accumulation of HIF-1 M-NM-1 and -2 M-NM-1 at wk 12. In the current study we found miR-29c was up-regulated in the L-Mim treated group compared with the control using Agilent miRNA microarrays. Of the microRNAs and proteins that exhibited reciprocal changes in expression following the L-Mim treatment, miR-29c and tropomyosin 1M-NM-1 (TPM1), which is involved in stress fiber function, met the sequence criteria for microRNA-target interaction, were later confirmed by 3'-untranslated region reporter analysis. TGFM-NM-21 treatment (3 ng/ml, 24 hours) decreased miR-29c expression and up-regulated protein expression of TPM1 in human renal epithelial cells. Overexpression of miR-29c significantly attenuated TGF-M-NM-21 induced increase in TPM1 in vitro. Moreover, intrarenal expression of miR-29c was decreased in IgAN patients with moderate to severe tubulointerstital fibrosis (TIF), compared with IgAN patients without TIF, and intrarenal protein expression of TMP1 was significantly increased in IgAN patients with TIF. The results suggest that intrarenal expression of miR-29c was down-regulated while its predicted target, TPM1 was up-regulated in the progression of CKD. Short term stabilizing of HIF up-regulates miR-29c and attenuates CKD in the remnant kidney model. Four weeks after 5/6 nephrectomy, rats were treated with intraperitoneal injections of vehicle or L-mimosine (L-Mim, Calbiochem), a prolyl 4-hydroxylase inhibitor (PHD), at a dosage of 50 mg/kg every other day. At the end of wk 12 after 5/6 nephrectomy, all rats (n=4, for each group) were sacrificed and blood samples were collected via cardiac puncture. Renal tissue were harvested, one piece of which was fixed in neutral formalin and then embedded in paraffin. The remaining kidney tissue was dissected in ice-cold PBS to, remove medulla, and then snap-frozen in liquid nitrogen before transferring to storage at -80M-BM-0C until further analysis.

Dataset Information

The glucosinolate metabolite 1-methoxy-3-indolylmethyl alcohol induces a gene expression profile in mouse liver similar to the expression signature caused by known genotoxic hepatocarcinogens

Publications

The glucosinolate metabolite 1-methoxy-3-indolylmethyl alcohol induces a gene expression profile in mouse liver similar to the expression signature caused by known genotoxic hepatocarcinogens.

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