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.
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.
Hendriksen
Peter J M
PJ
TNO Quality of Life, Zeist, The Netherlands. phendriksen@tno.nl
Freidig
Andreas P
AP
Jonker
Diana
D
Thissen
Uwe
U
Bogaards
Jan J P
JJ
Mumtaz
Moiz M
MM
Groten
John P
JP
Stierum
Rob H
RH
D000818:Animals; D001554:Benzene / Q000494:pharmacology / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D004357:Drug Synergism; D004785:Environmental Pollutants / Q000494:pharmacology / Q000633:toxicity*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008767:Methylmercury Compounds / Q000494:pharmacology / Q000633:toxicity*; D019055:No-Observed-Adverse-Effect Level; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D018675:Toxicity Tests; D014241:Trichloroethylene / Q000494:pharmacology / Q000633:toxicity*
D004785:Environmental Pollutants; D008767:Methylmercury Compounds; D012333:RNA, Messenger; D014241:Trichloroethylene; D001554:Benzene