Title
Transcriptomics analysis of interactive effects of benzene, trichloroethylene and methyl mercury within binary and ternary mixtures on the liver and kidney following subchronic exposure in the rat
Author
Hendriksen, P.J.M.
Freidig, A.P.
Jonker, D.
Thissen, U.
Bogaards, J.J.P.
Mumtaz, M.M.
Groten, J.P.
Stierum, R.H.
TNO Kwaliteit van Leven
Publication year
2007
Abstract
The present research aimed to study the interaction of three chemicals, methyl mercury, benzene and trichloroethylene, on mRNA expression alterations in rat liver and kidney measured by microarray analysis. These compounds were selected based on presumed different modes of action. The chemicals were administered daily for 14 days at the Lowest-Observed-Adverse-Effect-Level (LOAEL) or at a two- or threefold lower concentration individually or in binary or ternary mixtures. The compounds had strong antagonistic effects on each other's gene expression changes, which included several genes encoding Phase I and II metabolizing enzymes. On the other hand, the mixtures affected the expression of "novel" genes that were not or little affected by the individual compounds. The three compounds exhibited a synergistic interaction on gene expression changes at the LOAEL in the liver and both at the sub-LOAEL and LOAEL in the kidney. Many of the genes induced by mixtures but not by single compounds, such as Id2, Nr2f6, Tnfrsf1a, Ccng1, Mdm2 and Nfkb1 in the liver, are known to affect cellular proliferation, apoptosis and tissue-specific function. This indicates a shift from compound specific response on exposure to individual compounds to a more generic stress response to mixtures. Most of the effects on cell viability as concluded from transcriptomics were not detected by classical toxicological endpoints illustrating the benefit of increased sensitivity of assessing gene expression profiling. These results emphasize the benefit of applying toxicogenomics in mixture interaction studies, which yields biomarkers for joint toxicity and eventually can result in an interaction model for most known toxicants. © 2007 Elsevier Inc. All rights reserved.
Subject
Biology
Analytical research
Biomedical research
Benzene
Mercury
Microarrays
Mixtures
Toxicogenomics
Trichloroethylene
benzene
biological marker
messenger RNA
methylmercury
trichloroethylene
animal experiment
animal tissue
apoptosis
article
Ccng1 gene
cell proliferation
cell viability
controlled study
gene
gene expression profiling
gene induction
id2 gene
liver toxicity
long term exposure
male
MDM2 gene
microarray analysis
nephrotoxicity
NFKB1 gene
nonhuman
Nr2f6 gene
rat
stress
tissue specificity
tnfrsf1a gene
toxicogenetics
transcriptomics
Animals
Benzene
Cell Survival
Drug Interactions
Drug Synergism
Environmental Pollutants
Gene Expression Profiling
Gene Expression Regulation
Kidney
Liver
Male
Methylmercury Compounds
No-Observed-Adverse-Effect Level
Oligonucleotide Array Sequence Analysis
Rats
Rats, Inbred F344
RNA, Messenger
Toxicity Tests
Trichloroethylene
Rattus
To reference this document use:
http://resolver.tudelft.nl/uuid:3f05455a-9265-43c2-bf67-a75043001d56
DOI
https://doi.org/10.1016/j.taap.2007.08.017
TNO identifier
240386
ISSN
0041-008X
Source
Toxicology and Applied Pharmacology, 225 (2), 171-188
Document type
article