Toxicogenomic Study of Triazole Fungicides and Perfluoroalkyl Acids in Rat Livers Predicts Toxicity and Categorizes Chemicals Based on Mechanisms of Toxicity

Abstract

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.

Effects of fluorotelomer alcohol 8:2 FTOH on steroidogenesis in H295R cells: Targeting the cAMP signalling cascade

“…Previous studies reported that certain PFCs, such as PFOA, PFDA, and PFDoA decreased serum testosterone level in rats under toxicological dosages (Bookstaff et al, 1990;Martin et al, 2007;Shi et al, 2007Shi et al, , 2009). The serum PFCs concentrations (5 μg/mL to 260 μg/mL) measured in those dosed animals were in the same range as the concentrations of FTOHs applied to H295R cells in this study Martin et al, 2007). It has been shown that exposure to 6:2 FTOH or 8:2 FTOH significantly disrupted plasma concentrations of sex steroids in zebrafish with a LOEC of 30 μg/L for both chemicals (Liu et al, 2009a,b).…”

“…After culture for 24 h, cells were exposed to 0, 7.4, 22.2 or 66.6 μM 8:2 FTOH dissolved in dimethyl sulfoxide (DMSO; Sigma) for 24 h. Control treatments received 0.1% DMSO (v/v). The exposure concentrations were chose based on the information from previous studies Martin et al, 2007).…”

“…Recently, some PFCs have been shown to have potential endocrinedisruptive activities in vertebrates. For example, perfluorooctanoic acid (PFOA) lowered concentrations of testosterone and cholesterol in serum in rats (Biegel et al, 2001;Martin et al, 2007), and modified the mRNA expression of genes associated with cholesterol biosynthesis and steroid metabolism in fetal mouse liver (Rosen et al, 2007). Exposure to perfluorodecanoic acid (PFDA) decreased circulating concentrations of testosterone and dihydrotestosterone in male rats (Bookstaff et al, 1990).…”

Waterborne exposure to PFOS causes disruption of the hypothalamus–pituitary–thyroid axis in zebrafish larvae

“…In mammals, Dio1 gene expression has also been shown to respond to changes in circulating levels of THs (Burmeister et al, 1997). Martin et al (2007) showed that PFOS caused significant Dio1 repression, concordant with significant total T 3 decreases in rats. In fish, Wei et al (2008) found that exposure of rare minnows (Gobiocypris rarus) to perfluorooctanoic acid (PFOA) significantly suppressed the gene expression of Dio2.…”

Prognostic Model for Corrosion-Inhibition of Mild Steel in Hydrochloric Acid by Crushed Leaves of Voacanga Africana

“…Benzimidazole and triazole derivatives are well known corrosion inhibitors that showed more than 97% of inhibition against acid corrosion of mild steel [4], but they are also known for their toxicity [5,6,7]. Notably, the toxic nature of the known effective inhibitors of arsenate-and chromate-based has necessitated the search for an alternative inhibitor that would not only be efficacious but environmentally friendly.…”