@article{tully_bao_goetz_blystone_ren_schmid_strader_wood_best_narotsk_et al._2006, title={Gene expression profiling in liver and testis of rats to characterize the toxicity of triazole fungicides}, volume={215}, ISSN={["1096-0333"]}, DOI={10.1016/j.taap.2006.02.015}, abstractNote={Four triazole fungicides were studied using toxicogenomic techniques to identify potential mechanisms of action. Adult male Sprague-Dawley rats were dosed for 14 days by gavage with fluconazole, myclobutanil, propiconazole, or triadimefon. Following exposure, serum was collected for hormone measurements, and liver and testes were collected for histology, enzyme biochemistry, or gene expression profiling. Body and testis weights were unaffected, but liver weights were significantly increased by all four triazoles, and hepatocytes exhibited centrilobular hypertrophy. Myclobutanil exposure increased serum testosterone and decreased sperm motility, but no treatment-related testis histopathology was observed. We hypothesized that gene expression profiles would identify potential mechanisms of toxicity and used DNA microarrays and quantitative real-time PCR (qPCR) to generate profiles. Triazole fungicides are designed to inhibit fungal cytochrome P450 (CYP) 51 enzyme but can also modulate the expression and function of mammalian CYP genes and enzymes. Triazoles affected the expression of numerous CYP genes in rat liver and testis, including multiple Cyp2c and Cyp3a isoforms as well as other xenobiotic metabolizing enzyme (XME) and transporter genes. For some genes, such as Ces2 and Udpgtr2, all four triazoles had similar effects on expression, suggesting possible common mechanisms of action. Many of these CYP, XME and transporter genes are regulated by xeno-sensing nuclear receptors, and hierarchical clustering of CAR/PXR-regulated genes demonstrated the similarities of toxicogenomic responses in liver between all four triazoles and in testis between myclobutanil and triadimefon. Triazoles also affected expression of multiple genes involved in steroid hormone metabolism in the two tissues. Thus, gene expression profiles helped identify possible toxicological mechanisms of the triazole fungicides.}, number={3}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={Tully, Douglas B. and Bao, Wenjun and Goetz, Amber K. and Blystone, Chad R. and Ren, Hongzu and Schmid, Judith E. and Strader, Lillian F. and Wood, Carmen R. and Best, Deborah S. and Narotsk, Michael G. and et al.}, year={2006}, month={Sep}, pages={260–273} }
 @article{goetz_bao_ren_schmid_tully_wood_rockett_narotsky_sun_lambert_et al._2006, title={Gene expression profiling in the liver of CD-1 mice to characterize the hepatotoxicity of triazole fungicides}, volume={215}, ISSN={["1096-0333"]}, DOI={10.1016/j.taap.2006.02.016}, abstractNote={Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and hypotheses on potential mechanisms of action for this class of chemicals. Adult male CD-1 mice were exposed daily for 14 days to fluconazole, myclobutanil, propiconazole, or triadimefon at three dose levels by oral gavage. Doses were based on previous studies that resulted in liver hypertrophy or hepatotoxicity. All four triazoles caused hepatocyte hypertrophy, and all except triadimefon increased relative liver/body weight ratios at the middle and high dose levels. CYP enzyme activities were also induced by all four triazoles at the middle and high doses as measured by the dealkylations of four alkoxyresorufins, although some differences in substrate specificity were observed. Consistent with this common histopathology and biochemistry, several CYP and xenobiotic metabolizing enzyme (XME) genes were differentially expressed in response to all four (Cyp2d26 and Cyp3a11), or three of the four (Cyp2c40, Cyp2c55, Ces2, Slco1a4) triazoles. Differential expression of numerous other CYP and XME genes discriminated between the various triazoles, consistent with differences in CYP enzyme activities, and indicative of possible differences in mechanisms of hepatotoxicity or dose response. Multiple isoforms of Cyp1a, 2b, 2c, 3a, and other CYP and XME genes regulated by the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were differentially expressed following triazole exposure. Based on these results, we expanded on our original hypothesis that triazole hepatotoxicity was mediated by CYP induction, to include additional XME genes, many of which are modulated by CAR and PXR.}, number={3}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={Goetz, Amber K. and Bao, Wenjun and Ren, Hongzu and Schmid, Judith E. and Tully, Douglas B. and Wood, Carmen and Rockett, John C. and Narotsky, Michael G. and Sun, Guobin and Lambert, Guy R. and et al.}, year={2006}, month={Sep}, pages={274–284} }
 @article{crosby_morgan_gaskill_wolf_deangelo_2000, title={Origin and distribution of potassium bromate-induced testicular and peritoneal mesotheliomas in rats}, volume={28}, ISSN={["0192-6233"]}, DOI={10.1177/019262330002800205}, abstractNote={ Tissue sections were examined from a 2-year bioassay of male Fischer 344 rats treated with potassium bromate administered in drinking water. All animals exhibiting peritoneal mesotheliomas also had mesotheliomas of the tunica vaginalis testis mesorchium (the reverse was not true), and the correlation of these 2 types of mesotheliomas was highly significant (r2 = 0.98). Mapping of the tunica vaginalis tumors at all time points and at all bromate concentrations revealed a pattern of increasing incidence of tumor formation on the mesothelium of the tunica vaginalis testis as a function of proximity to the mesorchial ligament. Thus, the mesorchium appears to be the major mesothelial target site for potassium bromate-mediated carcinogenesis. The frequency of occurrence of mesotheliomas by location was tunica vaginalis testis (25%), mesosplenium (20%), mesentery (10%), mesojejunum/mesocolon (8%), bladder (6.5%), mesogastrium (13%), liver serosa (5%), and kidney, small intestine, and rectum (1% each). A complete cross-section of the rat testis was prepared and used to construct a complete map of the mesothelium. Any attempt to determine the role of local dose and tissue susceptibility for the purpose of interspecies risk extrapolation must take into account the complex anatomy and physiology of this region of the visceral and testicular suspensory apparatus. Improved histologic approaches are needed for adequate assessment of this delicate suspensory system. }, number={2}, journal={TOXICOLOGIC PATHOLOGY}, author={Crosby, LM and Morgan, KT and Gaskill, B and Wolf, DC and DeAngelo, AB}, year={2000}, pages={253–266} }