Abstract:
:The InnoMed PredTox consortium was formed to evaluate whether conventional preclinical safety assessment can be significantly enhanced by incorporation of molecular profiling ("omics") technologies. In short-term toxicological studies in rats, transcriptomics, proteomics and metabolomics data were collected and analyzed in relation to routine clinical chemistry and histopathology. Four of the sixteen hepato- and/or nephrotoxicants given to rats for 1, 3, or 14days at two dose levels induced similar histopathological effects. These were characterized by bile duct necrosis and hyperplasia and/or increased bilirubin and cholestasis, in addition to hepatocyte necrosis and regeneration, hepatocyte hypertrophy, and hepatic inflammation. Combined analysis of liver transcriptomics data from these studies revealed common gene expression changes which allowed the development of a potential sequence of events on a mechanistic level in accordance with classical endpoint observations. This included genes implicated in early stress responses, regenerative processes, inflammation with inflammatory cell immigration, fibrotic processes, and cholestasis encompassing deregulation of certain membrane transporters. Furthermore, a preliminary classification analysis using transcriptomics data suggested that prediction of cholestasis may be possible based on gene expression changes seen at earlier time-points. Targeted bile acid analysis, based on LC-MS metabonomics data demonstrating increased levels of conjugated or unconjugated bile acids in response to individual compounds, did not provide earlier detection of toxicity as compared to conventional parameters, but may allow distinction of different types of hepatobiliary toxicity. Overall, liver transcriptomics data delivered mechanistic and molecular details in addition to the classical endpoint observations which were further enhanced by targeted bile acid analysis using LC/MS metabonomics.
journal_name
Toxicol Appl Pharmacoljournal_title
Toxicology and applied pharmacologyauthors
Ellinger-Ziegelbauer H,Adler M,Amberg A,Brandenburg A,Callanan JJ,Connor S,Fountoulakis M,Gmuender H,Gruhler A,Hewitt P,Hodson M,Matheis KA,McCarthy D,Raschke M,Riefke B,Schmitt CS,Sieber M,Sposny A,Suter L,Sweatmandoi
10.1016/j.taap.2010.09.022subject
Has Abstractpub_date
2011-04-15 00:00:00pages
97-111issue
2eissn
0041-008Xissn
1096-0333pii
S0041-008X(10)00364-9journal_volume
252pub_type
杂志文章abstract::The prediction and understanding of acetaminophen (APAP)-induced liver injury (APAP-ILI) and the response to therapeutic interventions is complex. This is due in part to sensitivity and specificity limitations of currently used assessment techniques. Here we sought to determine the utility of integrating translational...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2017.07.019
更新日期:2017-10-01 00:00:00
abstract::Many herbal medicines and dietary supplements sold as aids to improve memory or treat neurodegenerative diseases or have other favorable effects on the CNS contain a catechol or similar 1,2-dihydroxy aromatic moiety in their structure. As an approach to isolate and examine the neuroprotective properties of catechols, ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2007.12.001
更新日期:2008-04-15 00:00:00
abstract::The effect of captopril, an angiotensin-converting enzyme inhibitor, on the progression of chronic renal disease was studied in rats subjected to partial nephrectomy. Following ablation of approximately 70% of their renal mass, rats were divided into three treatment groups: group I received a placebo treatment; group ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(85)90397-7
更新日期:1985-09-30 00:00:00
abstract::To study the effect of cadmium exposure on maternal and fetal zinc metabolism, rats were exposed to 0, 5, 50, or 100 ppm Cd in the drinking water on Days 6 through 20 of pregnancy. In comparison to controls, fetal and maternal weights were slightly reduced in the 50- and 100-ppm groups, but not the 5-ppm group. Multip...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(90)90048-y
更新日期:1990-03-01 00:00:00
abstract::We expressed rat Na(v)1.6 sodium channels in combination with the rat beta(1) and beta(2) auxiliary subunits in Xenopus laevis oocytes and evaluated the effects of the pyrethroid insecticides S-bioallethrin, deltamethrin, and tefluthrin on expressed sodium currents using the two-electrode voltage clamp technique. S-Bi...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2010.07.001
更新日期:2010-09-15 00:00:00
abstract::The comparative antiestrogenic effects of progesterone and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on cytosolic and nuclear estrogen (ERc and ERn, respectively) and progesterone (PRc and PRn, respectively) receptor levels were determined in female Long Evans rats. Estradiol treatment typically increases ER and PR l...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(88)90177-9
更新日期:1988-03-15 00:00:00
abstract::Chemicals from anthropogenic and natural origins enter animal feed, human food and water either as undesirable contaminants or as part of the components of a diet. Over the last five decades, considerable efforts and progress to develop methodologies to protect humans and animals against potential risks associated wit...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.taap.2012.03.013
更新日期:2013-08-01 00:00:00
abstract::Tattooing is a popular cosmetic practice involving more than 45 million US citizens. Since the toxicology of tattoo inks and pigments used to formulate tattoo inks has not been reported, we studied the immunological impact of tattooing and determined recovery time from this trauma. SKH-1 hairless mice were tattooed us...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2005.04.003
更新日期:2005-12-01 00:00:00
abstract::The influence of carbon monoxide (CO) on the development of systemic hypertension was studied in Dahl rats selectively bred for susceptibility (DS) and resistance (DR) to NaCl-induced hypertension. This study was designed to examine the interactions among rat line (DS or DR), NaCl content of diet, and exposure to CO. ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(84)90003-6
更新日期:1984-11-01 00:00:00
abstract::Published toxicology data on chitosan nanoparticles (NP) often lack direct correlation to the in situ size and surface characteristics of the nanoparticles, and the repeated NP assaults as experienced in chronic use. The aim of this paper was to breach these gaps. Chitosan nanoparticles synthesized by spinning disc pr...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2012.04.037
更新日期:2012-08-01 00:00:00
abstract::Fischer 344 rats and B6C3F1 mice of both sexes were exposed to 400 ppm perchloroethylene (PER) by inhalation, 6 hr/day for 14, 21, or 28 days or to 200 ppm for 28 days. Increased numbers of peroxisomes were seen under the electron microscope and increased peroxisomal cyanide-insensitive palmitoyl CoA oxidation was mea...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(88)90232-3
更新日期:1988-01-01 00:00:00
abstract::Diurnal patterns of feeding, drinking, locomotor activity, and rearing in male Fischer-344 rats were examined for 2 weeks after a single oral dose of trimethyltin chloride (TMT) at 0, 3, 5, or 7 mg/kg. Body weights and feeding and drinking efficiency ratios (ratios of amount of food or water consumed per unit effort) ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(85)90375-8
更新日期:1985-06-15 00:00:00
abstract::1p4studied the effect of L-2-chloropropionic acid (L-CPA)-induced (250 mg/kg/po/day for 3 days) neurotoxicity, which results in an almost total destruction of cerebellar granule cells over 5 days, on forebrain and cerebellar neurochemistry. There was a reduction in cerebellar aspartate and glutamate concentrations of ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1996.0006
更新日期:1996-01-01 00:00:00
abstract::Exposure of rodents to benzo[a]pyrene (BaP) associated with particles has previously been shown to result in increased retention of BaP and metabolites in lungs. To determine if DNA damage might be enhanced, DNA adducts were measured in lungs of F344 rats following inhalation of pure BaP aerosols or BaP absorbed on ca...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(89)90334-7
更新日期:1989-02-01 00:00:00
abstract::CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone) is the major active agent of the alkaloid derivative of Camptotheca acuminata, with multiple pharmacological activities, including anticancer effects and promotion of apoptosis. The mechanism by which CIL-102 inhibits growth remains poorly understood in hum...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2012.05.025
更新日期:2012-08-15 00:00:00
abstract::Ethanol induces cumulative liver damage including steatosis, steatohepatitis and cirrhosis. The aim of this study is to investigate the global intrahepatic gene expression profile in the mouse liver treated with ethanol. A single oral dose of 0.5 or 5 g/kg ethanol was administered to male ICR mice, and liver samples w...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2007.06.018
更新日期:2007-09-15 00:00:00
abstract::The pharmacokinetics of 1,1,1-trichloroethane (TRI) was studied in male Sprague-Dawley rats in order to characterize and quantify TRI uptake and elimination oby direct measurements of the inhaled and exhaled compound. Fifty or 500 ppm TRI was inhaled for 2 hr through a one-way breathing valve by unanesthetized rats of...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(89)90168-3
更新日期:1989-05-01 00:00:00
abstract::Decreased daily sperm production (DSP) and cauda epididymal sperm number (CESN) are some of the most sensitive effects of in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. The reduction in CESN cannot be fully accounted for by decreased spermatogenesis. To explain the decrease in CESN it wa...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1996.0207
更新日期:1996-09-01 00:00:00
abstract::This study was undertaken to determine the ability of a series of 19 compounds representing different chemical classes of carcinogens to induce lung tumors in strain A/J mice after either ip or po administration. Aflatoxin B1, dibutylnitrosamine, 1,2-dimethylhydrazine, and methylnitrosourea induced a significant incre...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(86)90433-3
更新日期:1986-01-01 00:00:00
abstract::Inhalation of nitrogen dioxide (NO2) produces injury to the epithelium of terminal airways and the alveoli proximal to the airways. Techniques were devised to isolate alveolar tissue from this region for morphometric studies to define the extent of alveolar septal injury caused by NO2. One-day-old and six-week-old rat...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(86)90321-2
更新日期:1986-03-30 00:00:00
abstract::Assessment of toxic or mutagenic risks associated with phosphorothioate oligonucleotides (PTO) is important. In vitro and in vivo data have shown that PTOs are nontoxic and nonmutagenic. However, these studies do not address interactions between PTOs and other compounds. The sulfur on PTOs may provide a novel reactive...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1995.1126
更新日期:1995-07-01 00:00:00
abstract::The vitamin E analogue alpha-tocopheryl succinate (alpha-TOS) is an efficient anti-cancer drug. Improved efficacy was achieved through the synthesis of alpha-tocopheryl maleamide (alpha-TAM), an esterase-resistant analogue of alpha-tocopheryl maleate. In vitro tests demonstrated significantly higher cytotoxicity of al...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2009.01.027
更新日期:2009-06-15 00:00:00
abstract::The subcellular location of aluminium is unknown, probably because of difficulties in investigating aluminium biochemistry and the use of varied experimental approaches of uncertain sensitivity. We have studied levels of uptake and the localization of gallium and of aluminium in cultured human neuroblastoma cells trea...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1998.8489
更新日期:1998-09-01 00:00:00
abstract::This study was designed to determine whether an optimized in vitro lymphocyte blastogenesis assay for identification of strong contact sensitizers would also detect sensitization to the weaker, clinically relevant allergen nickel sulfate (NiSO4). Though NiSO4 is effective in eliciting allergic skin reactions in patien...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(90)90286-4
更新日期:1990-06-01 00:00:00
abstract::We have previously shown that ricin, a toxic lectin from the castor bean, increases cardiac output and blood flow to the heart in rabbits in the early stage of its intoxication and causes hemorrhage and necrosis in the heart following a lethal dose. To investigate possible alterations in coronary arteries following ri...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1994.1224
更新日期:1994-11-01 00:00:00
abstract::Three major enzyme systems have been shown to metabolize epoxidized xenobiotics in vertebrate tissues, and this study demonstrates that these enzyme systems can be differentially induced. The cytosolic epoxide hydrolase activity was routinely monitored with trans-beta-ethylstyrene oxide, the microsomal epoxide hydrola...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(83)90342-3
更新日期:1983-11-01 00:00:00
abstract::For many decades it has been thought that oxygen analogs (oxons) of organophosphorus insecticides phosphorylate the catalytic site of acetylcholinesterase by a mechanism that follows simple Michaelis-Menten kinetics. More recently, the interactions of at least some oxons have been shown to be far more complex and like...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2007.03.013
更新日期:2007-06-01 00:00:00
abstract::The discovery of the cadmium (Cd)-binding protein from horse kidney in 1957 marked the birth of research on this low-molecular weight, cysteine-rich protein called metallothionein (MT) in Cd toxicology. MT plays minimal roles in the gastrointestinal absorption of Cd, but MT plays important roles in Cd retention in tis...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.taap.2009.03.026
更新日期:2009-08-01 00:00:00
abstract::Although the mechanisms responsible for chemically induced oxidative stress are under intense investigation, little is known about the effects of prooxidant chemicals on the expression of drug-metabolizing enzymes. We examined the effects of diquat (0.1 mmol/kg, ip) and ciprofibrate (0.025% w/w, diet), chemicals which...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1995.1171
更新日期:1995-09-01 00:00:00
abstract::Patulin is a mycotoxin mainly found in apple and apple products. In addition to being toxic for animals, mutagenic, carcinogenic and teratogenic, patulin induces intestinal injuries, including epithelial cell degeneration, inflammation, ulceration, and hemorrhages. In a study of the cellular mechanisms associated with...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.2002.9417
更新日期:2002-06-15 00:00:00