Dataset Information

Predicting the Acute Liver Toxicity of Aflatoxin B1 in Rats and Humans by an In Vitro-In Silico Testing Strategy.

ABSTRACT: SCOPE:High-level exposure to aflatoxin B1 (AFB1) is known to cause acute liver damage and fatality in animals and humans. The intakes actually causing this acute toxicity have so far been estimated based on AFB1 levels in contaminated foods or biomarkers in serum. The aim of the present study is to predict the doses causing acute liver toxicity of AFB1 in rats and humans by an in vitro-in silico testing strategy. METHODS AND RESULTS:Physiologically based kinetic (PBK) models for AFB1 in rats and humans are developed. The models are used to translate in vitro concentration-response curves for cytotoxicity in primary rat and human hepatocytes to in vivo dose-response curves using reverse dosimetry. From these data, the dose levels at which toxicity would be expected are obtained and compared to toxic dose levels from available rat and human case studies on AFB1 toxicity. The results show that the in vitro-in silico testing strategy can predict dose levels causing acute toxicity of AFB1 in rats and human. CONCLUSIONS:Quantitative in vitro in vivo extrapolation (QIVIVE) using PBK modeling-based reverse dosimetry can predict AFB1 doses that cause acute liver toxicity in rats and human.

SUBMITTER: Gilbert-Sandoval I

PROVIDER: S-EPMC7379280 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Predicting the Acute Liver Toxicity of Aflatoxin B1 in Rats and Humans by an In Vitro-In Silico Testing Strategy.

Gilbert-Sandoval Ixchel I Wesseling Sebastiaan S Rietjens Ivonne M C M IMCM

Molecular nutrition & food research 20200602 13

<h4>Scope</h4>High-level exposure to aflatoxin B1 (AFB1) is known to cause acute liver damage and fatality in animals and humans. The intakes actually causing this acute toxicity have so far been estimated based on AFB1 levels in contaminated foods or biomarkers in serum. The aim of the present study is to predict the doses causing acute liver toxicity of AFB1 in rats and humans by an in vitro-in silico testing strategy.<h4>Methods and results</h4>Physiologically based kinetic (PBK) models for A ...[more]

PMID: 32421213

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Project description:Archival tissues from laboratory studies represent a unique opportunity to explore the relationship between genomic changes and agent-induced disease. In this study, we evaluated the applicability of qPCR for detecting genomic changes in formalin-fixed, paraffin-embedded (FFPE) tissues by determining if a subset of 14 genes from a 90-gene signature derived from microarray data and associated with eventual tumor development could be detected in archival liver, kidney, and lung of rats exposed to aflatoxin B1 (AFB1) for 90 days in feed at 1 ppm. These tissues originated from the same rats used in the microarray study. The 14 genes evaluated were Adam8, Cdh13, Ddit4l, Mybl2, Akr7a3, Akr7a2, Fhit, Wwox, Abcb1b, Abcc3, Cxcl1, Gsta5, Grin2c, and the C8orf46 homologue. The qPCR FFPE liver results were compared to the original liver microarray data and to qPCR results using RNA from fresh frozen liver. Archival liver paraffin blocks yielded 30 to 50 ?g of degraded RNA that ranged in size from 0.1 to 4 kB. qPCR results from FFPE and fresh frozen liver samples were positively correlated (p ? 0.05) by regression analysis and showed good agreement in direction and proportion of change with microarray data for 11 of 14 genes. All 14 transcripts could be amplified from FFPE kidney RNA except the glutamate receptor gene Grin2c; however, only Abcb1b was significantly upregulated from control. Abundant constitutive transcripts, S18 and ?-actin, could be amplified from lung FFPE samples, but the narrow RNA size range (25-500 bp length) prevented consistent detection of target transcripts. Overall, a discrete gene signature derived from prior transcript profiling and representing cell cycle progression, DNA damage response, and xenosensor and detoxication pathways was successfully applied to archival liver and kidney by qPCR and indicated that gene expression changes in response to subchronic AFB1 exposure occurred predominantly in the liver, the primary target for AFB1-induced tumors. We conclude that an evaluation of gene signatures in archival tissues can be an important toxicological tool for evaluating critical molecular events associated with chemical exposures.

Dataset Information

Predicting the Acute Liver Toxicity of Aflatoxin B1 in Rats and Humans by an In Vitro-In Silico Testing Strategy.

Publications

Predicting the Acute Liver Toxicity of Aflatoxin B1 in Rats and Humans by an In Vitro-In Silico Testing Strategy.

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