Toxicogenomic study of triazole fungicides and perfluoroalkyl acids in rat livers predicts toxicity and categorizes chemicals based on mechanisms of toxicity.
Toxicogenomic analysis of five environmental chemicals was performed to investigate the ability of genomics to predict toxicity, categorize chemicals, and elucidate mechanisms of toxicity. Three triazole antifungals (myclobutanil, propiconazole, and triadimefon) and two perfluorinated chemicals [perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS)] were administered daily via oral gavage for one, three, or five consecutive days to male Sprague-Dawley rats at single doses of 300, 300, 175, 20, or 10 mg/kg/day, respectively. Clinical chemistry, hematology, and histopathology were measured at all time points. Gene expression profiling of livers from three rats per treatment group at all time points was performed on the CodeLink Uniset Rat I Expression array. Data were analyzed in the context of a large reference toxicogenomic database containing gene expression profiles for over 630 chemicals. Genomic signatures predicting hepatomegaly and hepatic injury preceded those results for all five chemicals, and further analysis segregated chemicals into two distinct classes. The triazoles caused similar gene expression changes as other azole antifungals, particularly the induction of pregnane X receptor (PXR)-regulated xenobiotic metabolism and oxidative stress genes. In contrast, PFOA and PFOS exhibited peroxisome proliferator-activated receptor alpha agonist-like effects on genes associated with fatty acid homeostasis. PFOA and PFOS also resulted in downregulation of cholesterol biosynthesis genes, matching an in vivo decrease in serum cholesterol, and perturbation of thyroid hormone metabolism genes matched by serum thyroid hormone depletion in vivo. The concordance of in vivo observations and gene expression findings demonstrated the ability of genomics to accurately categorize chemicals, identify toxic mechanisms of action, and predict subsequent pathological responses.
Martin
Matthew T
MT
National Center for Computational Toxicology, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Brennan
Richard J
RJ
Hu
Wenyue
W
Ayanoglu
Eser
E
Lau
Christopher
C
Ren
Hongzu
H
Wood
Carmen R
CR
Corton
J Christopher
JC
Kavlock
Robert J
RJ
Dix
David J
DJ
D000818:Animals; D015415:Biomarkers; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D005466:Fluorocarbons / Q000493:pharmacokinetics / Q000633:toxicity*; D005659:Fungicides, Industrial / Q000633:toxicity*; D006728:Hormones / Q000097:blood; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000097:blood; D013963:Thyroid Hormones / Q000097:blood; D014230:Triazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D015430:Weight Gain / Q000187:drug effects
D015415:Biomarkers; D005466:Fluorocarbons; D005659:Fungicides, Industrial; D006728:Hormones; D013963:Thyroid Hormones; D014230:Triazoles; D013739:Testosterone