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2493 ATMOSPHERIC AEROSOLS FORMED FROM BIOGENIC AND ANTHROPOGENIC PRECURSOR REACTIONS AND COAL COMBUSTION EMISSIONS SHOW MILD VASCULAR TOXICITY COMPARED WITH MOTOR VEHICLE EXHAUST. J. McDonald 1 , M. Doyle-Eisele 1 , A. Lund 1 , M. Campen 3 , E. Knipping 2 and A. Rohr 2 . 1 Lovelace, Albuqueruque, NM, 2 Electric Power Research Institute, Palo Alto, CA and 3 University of New Mexico, Albuquerque, NM. Comparative biological response to inhalation of atmospheres of secondary organic aerosol (SOA), motor vehicle exhaust (MVe), and simulated downwind coal atmospheres (SDCA) was evaluated. SOA was derived from the oxidation of α-pinene (biogenic) and toluene (anthropogenic). The reaction conditions included the addition of nitrogen oxides and with/without sulfur dioxide. The addition of SO2 resulted in the additional presence of organosulfate compounds in the α-pinene (biogenic) but not the toluene atmosphere. MVe was created through a combination of gasoline + diesel exhaust, mixed in proportions to achieve the desired particulate concentration (1:5 proportion of gasoline:diesel particulate matter). SDCA was created through combustion of coal and subsequent addition of addition sulfate and inorganic gases that were projected to be present in air downwind from coal combustion facilities. All exposures were conducted at particle concentrations of 300 μg m-3. Apolipoprotein E knockout (ApoE-/-) mice were exposed for 6 h/d x 7 days. Pulmonary inflammation was assayed by analysis of cell counts/differentials in lavage. Aortas were assayed for transcriptional alterations of endothelin-1 (ET-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-2 (TIMP-2), and heme oxygenase-1 (HO-1). Pulmonary inflammation was absent in all atmospheres. Transcriptional alterations in the aorta were highest in the MVe atmosphere. Only mild responses were observed in SOA, with comparable responses from α-pinene and toluene precursors. Minimal to no vascular response was observed from the SDCA. Research supported by the Electric Power Research Institute. 2494 UNIQUE ASSOCIATIONS OF PM2.5 –INDUCED CHANGES IN HEART RATE VARIABILITY IN SPONTANEOUSLY HYPERTENSIVE RATS WITH WIND DIRECTION AND SPECIFIC SOURCES IN STEUBENVILLE, OH. J. G. Wagner 1 , A. Kamal 2 , M. Morishita 2 , B. Mukherjee 2 , G. J. Keeler 2 , J. R. Harkema 1 and A. C. Rohr 3 . 1 Michigan State University, East Lansing, MI, 2 University of Michigan, Ann Arbor, MI and 3 Electrical Power Research Institute, Palo Alto, CA. Short-term increases in fine particulate matter (PM2.5) are associated with acute cardiovascular morbidity and mortality, including stroke and myocardial infarction. The specific components in PM2.5 responsible for these adverse responses are unknown. We exposed spontaneously hypertensive (SH) rats to concentrated air particulates (CAPs) in Steubenville, OH, and measured changes in heart rate (HR) and variability (HRV) as physiological markers of cardiovascular stress. Eight male SH rats were exposed to either Filtered Air (FA) or fine CAPs, 7:30AM- 3:30PM for 13 consecutive days and ECG recordings were used to derive HR and HRV indices of SDNN and rMSSD. High-resolution, 30-minute data streams of HRV and CAPs metrics were analyzed with a mixed models design, and positive matrix factorization (PMF) was applied to 30-minute trace element data to identify pollution sources. CAPs exposure (mean 719 μg/m3), induced bi-directional changes in HR and HRV that were associated with specific trace elements and with the predominant wind directions at our exposure sites, from NE or SW directions. Elevated HR was observed during SW winds and associated with Mo, La, Ce, PM mass, NOx and V. Decreased HR was seen when winds were from the NE, and were associated with S, Se, Rb, Pb, Mn and Zn. Source factors linked to HR changes were metal processing with SW winds, and incineration, lead, and steel and iron processing NE winds. CAPs-exposed rats had significant decreases in SDNN regardless of wind direction, and that was associated with the incinerator factor with NE winds and with metals processing from the SW. Modest changes were detected RMSSD only from the SW, with association with Mo. V and SO2, but without significant associations with a source factor. These data demonstrate unique wind- and sourcespecific dependence of urban PM2.5 exposure on acute cardiovascular and autonomic responses. 534 SOT 2011 ANNUAL MEETING 2495 INHALATION OF ULTRAFINE PARTICULATE MATTER INDUCES INFLAMMATORY GENE EXPRESSION IN STRIATUM THROUGH NRF-2 AND NF-κB PATHWAYS IN RATS EXPOSED IN MEXICO CITY. R. Guerra-Garcia 1 , E. Vera-Aguilar 2 , G. Gookin 3 , M. Uribe-Ramirez 1 , A. Campbell 4 , J. Camacho 2 , M. Kleinman 3 and A. De Vizcaya-Ruiz 1 . 1 Department of Toxicology, Cinvestav, Mexico City, Mexico, 2 Department Pharmacology, Cinvestav, Mexico City, Mexico, 3 Division of Occupational and Environmental Medicine, Department of Medicine, University of Irvine, Irvine, CA and 4 Department of Pharmacological Sciences, Western University of Health Sciences, Pomona, CA. Air pollution particulate matter (PM) consist of transition metals and organic compounds (PAH), which can reach the brain and aggravate events linked to the pathology of brain stroke, Alzheimer’s, and Parkinson’s diseases. Brain inflammation in apolipoprotein E knockout (Apo E -/- ) and ovalbumin sensitized mice after exposure to different PM fractions derived from a heavily polluted site in California, USA, while loss of striatal neurons was observed in PM-exposed Apo E - /- mice in a study in New York (NYC). To further investigate the toxicity of PM on central nervous system, Sprague-Dawley male rats were exposed to filtered air or coarse, fine (fine+ultrafine) or ultrafine concentrated PM from Mexico City for 8 weeks, using a particle concentrator system during the warm-dry season of 2009. Olfactory bulb, frontal cortex, striatum and hippocampus, structures linked with neurodegenerative diseases, were harvested after exposure to assess gene expression of proinflammatory cytokines: IL-1β and TNFα using real-time PCR. Activation of nuclear transcription factors NF-κB and Nrf-2, related with inflammatory and antioxidant responses, respectively, was measured by gel shift mobility assay. IL-1β and TNFα increased 2 and 3-fold versus filtered air, respectively, and activation of NfκB and Nrf-2 was observed in striatum of the animals exposed to ultrafine PM. Thus the exposure to ultrafine PM enhances oxidative stress in the brain, which possibly leads to an inflammatory response. These molecular processes might help to explain the linkage between higher incidences of neurodegenerative diseases and exposures to elevated levels of ambient ultrafine PM. (Financement: CONACyT #57752 and UCLA-Fogarty Program). 2496 NRF2 IN TOXICOLOGY: FROM MONOFUNCTIONAL INDUCERS TO THE NEXT GENERATION OF THERAPY. C. D. Klaassen. Pharmacology, University Kansas Medical Center, Kansas City, KS. In the late 1980s, Paul Talalay pioneered the idea that some inducers had little effect on phase-I enzymes but induced phase-II enzymes. In retrospect, this concept of monofunctional inducers explained many confounding results in toxicology, such as the protective effect of butylated hydroxyanisole against acetaminophen hepatotoxicity and the observation that oltipraz diminished aflatoxin-induced carcinogenicity. In 1990, Cecil Pickett’s group reported that induction of glutathione S-transferases (GSTs) was dependent on an antioxidant response element (ARE) found in genes, and in 1997 Yamamoto and colleagues discovered that Nrf2 was the transcription factor necessary for the induction. Thus, many monofunctional inducers are now referred to as Nrf2 activators, which induce genes containing AREs. Our work on Nrf2 began in the late 1980s when Jie Liu came to my laboratory from China with several compounds extracted from Chinese herbal medicines. He tested 16 of these chemicals for hepatoprotective effects and determined one chemical, oleanolic acid, was the most effective. In fact, oleanolic acid protected against nine different hepatotoxicants with seemingly different pathways of producing toxicity. Michael Sporn and his group synthesized many derivatives of oleanolic acid, and eventually 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO- Im) emerged as the most potent derivative. We now know that Nrf2 activators increase not only the GSTs and other phase-II enzymes, but also glutathione synthesis enzymes, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, microsomal epoxide hydrolase, and various enzymes that detoxify reactive oxygen species, all of which cumulatively produce robust anti-oxidant and anti-inflammatory effects. Thus, it is not surprising that activators of the Nrf2 pathway, like oleanolic acid, can protect against the toxicity of many chemicals. It is interesting to note that another derivative of oleanolic acid (CDDO-Me, bardoxolone methyl) is in Phase 2 clinical trials as an activator of the Nrf2 pathway for the treatment of chronic kidney disease in diabetic patients. (NIH DK-081461)
2497 TRANSCRIPTIONAL REGULATION OF THE HUMAN FERRITIN GENE THROUGH AN ANTI-OXIDANT RESPONSIVE ELEMENT BY CORE HISTONE MODIFICATIONS. B. Huang, K. Iwasaki and Y. Tsuji. Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC. Sponsor: J. Ninomiya-Tsuji. Oxidative stress is implicated in various diseases such as cancer and neurodegeneration; therefore, gaining insight into the molecular mechanism through which antioxidant detoxification genes are regulated is important to understand the pathogenesis and prevention of oxidative stress-related diseases. Ferritin, the major iron storage protein that sequesters intracellular excess iron to prevent production of reactive oxygen species, is transcriptionally regulated via an ARE (anti-oxidant responsive element) under oxidative stress. We recently observed that Nrf2 and ATF1 bind to the ferritin ARE. Single knockdown of ATF1 or Nrf2 showed only partial effect, whereas ATF1 and Nrf2 double-knockdown in K562 human erythroleukemic cells showed a complete inhibition of ferritin mRNA induction following hemin treatment. Hemin-mediated transcriptional activation of the ferritin gene was associated with p38 MAPK phosphorylation along with ATF1 phosphorylation at Ser-63, in which SB203580, a p38 inhibitor, inhibited all these events. Concomitantly, both recruitment of protein arginine methyltransferase 1 (PRMT1) and its target methylation of histone H4 Arg-3 around the ferritin ARE were increased after hemin treatment. PRMT1 expression activated ARE-dependent ferritin transcription, and AMI-1, a PRMT inhibitor, inhibited hemin-mediated ferritin transcription. These results suggest that hemin-mediated ferritin transcription through the ARE is regulated by p38-mediated ATF1 Ser-63 phosphorylation along with PRMT1-mediated histone H4 Arg-3 methylation. Furthermore, ChIP assays demonstrated that acetylation of histone H3 Lys-9 and - 14, and recruitment of histone acetyltransferases p300 and CBP around the ferritin ARE were induced following hemin treatment. We are currently investigating whether phosphorylation of ATF1 at Ser-63 and recruitment of PRMT1 orchestrate ferritin ARE activation by recruiting chromatin remodeling proteins such as p300 and CBP and subsequent histone acetylation. 2498 ACTIVATION OF NRF2 BY INTRINSIC AND EXTRINSIC LIGANDS. A. Chia, R. Megherbi, I. Copple, N. R. Kitteringham, L. E. Randle, C. E. Goldring and K. Park. Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, Merseyside, United Kingdom. Sponsor: D. Mendrick. Nrf2 is a key activator of cytoprotective genes in mammalian cells. Cysteine residues in the inhibitor of Nrf2, Keap1, are targets for electrophilic and oxidative modifications, which may result in uncoupling of Keap1 to Nrf2 resulting in Nrf2 stabilization. The work of a number of groups, including our own, has shown that patterns of cysteine adduction in Keap1 in vitro and in living cells are electrophiledependent. The aim of the present work was to assess the relevance of covalent modification of cysteines in Keap1 in the activation of Nrf2-dependent genes through the use of a model compound, DNCB, which targets only one cysteine in Keap1 expressed in cells, i.e. C257. LC-MS/MS analysis was performed on Keap1 intracellularly modified by DNCB and its analogues (dinitrohalobenzenes), which retain similar chemistry to DNCB, deplete glutathione with similar potencies, but differ in their overall reactivity with intracellular protein targets. We detected modification of intracellular Keap1 by all of these chemicals only at C257, and found that this remarkable cysteine residue selectivity occurs despite the fact that all of the cysteines of Keap1 are potentially available for modification by other sulfhydryl-reactive chemical probes. Pre-treatment of Keap1-expressing cells with buthionine sulfoximine (an inhibitor of glutathione synthesis), resulted in a reduced ability of DNCB to adduct C257. Nevertheless, mutation of this cysteine did not affect the ability of DNCB to induce Nrf2 accumulation and Nrf2-dependent gene transcription. The hypothesis that reversible and/or irreversible oxidation of other cysteine residues in Keap1 may provide a signal for activation of the Nrf2 pathway is currently being pursued. In summary, covalent binding to specific reactive cysteine residues in Keap1 may not necessarily be the sole trigger for activation of Nrf2-dependent cell defence, rather that other forms of modification of Keap1, and possibly other proteins in this pathway, may also serve as sensors, to enable the system to be chemically highly versatile. 2499 KEAP1-KNOCKDOWN AND HEPATOCYTE-SPECIFIC SIRT1 DELETION CONFER RESISTANCE TO FASTING- INDUCED DOWN-REGULATION OF NRF2-TARGET GENE EXPRESSION. S. Kulkarni1 , J. Xu1 , W. Wei1 , X. Li2 , M. Yamamoto3 and A. Slitt1 . 1Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, 2National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC and 3Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan. Food deprivation (fasting) causes a coordinated whole body response to enhance gluconeogenesis. Fasting increases serum glucagon levels; this activates the protein kinase A (PKA)/cAMP signal transduction pathway and enhances liver glucose production. Fasting and caloric restriction also increase Sirtuin 1 (Sirt1) activity, which also enhances gluconeogenesis. Both pathways enhance the expression and activity of the transcriptional co-activator Pgc-1α. Nuclear factor-E2 related factor 2 (Nrf2, Nfe2l2) is a transcription factor, well known to be responsive to cellular oxidative stress, but may be also sensitive to cellular nutrient status. First, C57Bl/6 (lean) and ob/ob (obese) mice were food withheld (fasted) for 30 hours and Nrf2 target gene (e.g. Nqo-1, gclc, gclm, gsta-1, Mrp2) expression was quantified. Fasting for 30 hours decreased Nrf2 target gene expression in liver by 40-75% compared to fed C57BL/6 and ob/ob mice. Second, increased constitutive expression of Nrf2 diminished the fasting effects on Nrf2 target genes (lower fold decrease), as observed in Keap1-KD fasted mice compared to C57Bl/6 fasted controls. Third, Liver-specific deletion of Sirt1 (Sirt1LKO), a deacetylase known to be activated upon nutrient deprivation, also diminished the fold decrease in expression of Nrf2 target genes upon fasting. In general, the obese, Keap1-KD, and Sirt1LKO mice were resistant to fasting-induced changes in Nrf2 target gene expression, as observed by the attenuated expression of Pgc-1α in these livers. The above data directs towards a novel role for nutrient status affecting Nrf2 activity, the antioxidant response, and potential novel interplay between Sirt1 and the antioxidant response (NIH 3R01ES016042). 2500 A BIOCHEMICAL AND PROTEOMIC ANALYSIS OF THE EFFECT OF NRF2 GENE DELETION ON ACUTE ACETAMINOPHEN-INDUCED HEPATOTOXICITY. C. E. Goldring, L. E. Randle, R. L. Sison, N. R. Kitteringham, D. Denk, R. E. Jenkins, J. Walsh, B. Lane, A. Kipar and K. Park. Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, Merseyside, United Kingdom. Sponsor: D. Mendrick. The Keap1-Nrf2-ARE signalling pathway has emerged as a key protective mechanism in the response to chemical stress. To date, a number of studies have investigated Nrf2-dependent changes at the RNA level, however these may not necessarily be translated into changes at the protein level and function. We have now sought to determine the role of Nrf2 in the early mechanisms of adaptation to acute DILI through a shotgun proteomics approach and targeted metabolite analysis, in a murine model of acetaminophen (APAP)-induced hepatotoxicity. Clinical chemistry and histopathology confirmed the increased sensitivity of Nrf2-null mice towards APAP-induced liver damage. Metabolomic analysis of the glutathione system indicated adaptation to Nrf2 deletion through an enhancement of cellular defence through conservation and/or increase of intermediates in this pathway, in an apparent attempt to maintain redox homeostasis. Proteomic analysis revealed Nrf2-mediated efforts by the liver to maintain energy production. Following acute APAPmediated injury, it appears that an early Nrf2-mediated attempt is made to source alternative substrates for the citric acid cycle by upregulating enzymes within the hepatoproteome. Liver carboxylesterase 31 and propionyl-coA carboxylase were identified as novel Nrf2-dependent, APAP-responsive proteins. Several other APAP-sensitive proteins were also identified, and these may warrant further investigation into their suitability as biomarkers of APAP intoxication. In summary, we have demonstrated novel APAP-mediated, Nrf2-dependent changes in the liver proteome and metabolome that provides new areas of study for delineating the molecular events that are implicated in this important form of liver toxicity. 2501 PROFILING ENVIRONMENTAL CHEMICALS IN THE ANTIOXIDANT RESPONSE ELEMENT PATHWAY USING QUANTITATIVE HIGH-THROUGHPUT SCREENING (QHTS). S. J. Shukla 1 , R. Huang 1 , S. O. Simmons 2 , R. R. Tice 3 , K. L. Witt 3 and M. Xia 1 . 1 NIH Chemical Genomics Center, Rockville, MD, 2 U.S. EPA, Research Triangle Park, NC and 3 National Toxicology Program, Research Triangle Park, NC. The antioxidant response element (ARE) signaling pathway plays an important role in the amelioration of oxidative stress, which can contribute to a number of diseases, including cancer. We screened 1408 NTP-provided substances in 1536-well SOT 2011 ANNUAL MEETING 535
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The Toxicologist Supplement to Toxi
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The Toxicologist Supplement to Toxi
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1 BIODEGRADABLE MATERIALS FOR TISSU
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that genetic toxicology data are ge
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well-orchestrated lung inflammation
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scribed in the literature. We have
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years ago). We will illustrate how
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involved in the biodegradation proc
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stem cells but rather a treatment i
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additional compound showed agreemen
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82 COMPARISON OF 3H-THYMIDINE INCOR
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irritants. While in practice these
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alleles are especially vulnerable t
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109 CD4+ T CELL INTRINSIC TNF RECEP
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118 TO STUDY THE SIGNAL TRANSDUCTIO
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PAHs, such as dioxins, are prevalen
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containing substituents and/or hydr
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146 COMPUTATIONAL MODELING FOR QT P
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suggest that the combination of too
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164 TRANSLOCATOR PROTEIN (18 KDA) (
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function as a metal binding protein
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laboratory has demonstrated that NR
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known. The aim of this study was to
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from 5 to 28 days in duration) in e
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positive cells, caspase-3 activatio
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creased level in the 46 kDa preproe
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invasiveness at concentrations repr
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thracene (DMBA,50 μg in acetone, a
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247 CO-CARCINOGENESIS OF N, N- DIET
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sponds to the endosomal dsRNA that
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ODD in both WT (maximum 177% of con
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Lastly, using p53siRNA cells, p53 w
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its receptor Mpl to exert its funct
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294 LOW LEVEL OF LEAD CAN INDUCE PH
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lunar surface presented potential h
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lar about cellular export mechanism
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DNA in the kidney medulla, grandula
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5.00 and 7.50 mg/kg/day by oral gav
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events and carcinogenesis. Here we
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tinization of cells of the hair fol
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358 CHARACTERIZATION OF GENOME-WIDE
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RNAi were also performed to identif
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376 A FUNCTIONAL CROSSTALK BETWEEN
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UGT1A gene induction, while this re
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tivity, specifically peroxisome pro
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and cytotoxic effects; however, its
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histone deacetylase that is necessa
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ment. Paradoxically, buthionine sul
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drug leflunomide and its major (A77
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442 GENE EXPRESSION AND MORPHOLOGIC
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451 INHIBITION OF THE MITOCHONDRIAL
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460 SULFORAPHANE PREVENTS ACETAMINO
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drophilic/lipophilic balance. Other
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pharmacokinetic and toxicological p
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489 USE OF ‘OMICS DATA TO IMPROVE
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498 APPLICATION OF AGE-SPECIFIC ADJ
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507 A DOSE VOLUME TOLERABILITY STUD
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involved the use of an acute inflam
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sorption in the gastrointestinal (G
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(ABC) transporters actively transpo
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545 BEHAVIORAL EFFECTS OF REPIN IN
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a blood pressure phenotype that res
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and inhalation exposure system that
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and lethality associated with these
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position, on vascular reactivity an
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therefore more accurate and reprodu
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commercial chrysotile product that
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elative to their controls. ST-depre
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ats. The majority of the studies fo
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in the China Jintan Child Cohort St
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corneum thickness, cellular epiderm
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645 EVALUATION OF THE IN VITRO EPIS
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654 TCDD ADSORBED ONTO NATURAL AND
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tion revealed no test article-relat
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671 INFLAMMATION AND TISSUE DAMAGE
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model, ethanol was found to inhibit
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689 ENHANCED SUPPRESSIVE FUNCTION O
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NAC + LPS yielded different levels
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707 LIFE-STAGE PBPK MODELS FOR MULT
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downstream of the apical endpoint o
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726 UPDATED ALUMINUM PHARMACOKINETI
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global parameter sensitivity analys
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and renal inflammation induced by 2
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754 PLASMA, URINE, AND TISSUE CONCE
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cently characterized transporter OA
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exposure system was developed from
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lood cell mass and decrease in urin
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practical alternatives to MC in non
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imals dosed with 167 mg/kg THU alon
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and organ weights, clinical signs a
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yet is induced in most bladder and
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830 RISK ASSESSMENT OF THE SPILL: C
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knowledgebase creation. Results are
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852 UNDERSTANDING STRUCTURAL AND PH
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for integrating epidemiology and an
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motor activity, including age of th
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y partial purification of urine (fr
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pacity for self-renewal and may dif
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sue. The depth of our analysis led
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910 IMPLEMENTING CALIFORNIA’S GRE
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concentrations in six tissues and b
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934 THE FDA’S LIVER TOXICITY KNOW
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943 GENOME-WIDE DNA METHYLATION DIF
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membrane localization and subsequen
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trols, respectively. Subtoxic and t
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survival using both smoking regimes
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as non-, weak, moderate, or strong
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988 NNK-INDUCED CYTOKINE ALTERATION
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group (one-way ANOVA, p90 % viabili
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ered as an organ involved in xenobi
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Transport of CPZ across the Caco-2
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estrous cycle and sexual behavior d
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mRNA expression levels. Collectivel
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1043 THE EFFECTS OF ENDOCRINE DISRU
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1052 MONO-2-ETHYLHEXYL PHTHALATE IN
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Results: MC was variable within and
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UtSMCs. Phosphorylation of FoxO1 wa
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nonpregnant and pregnant diabetic m
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1089 PFOA-INDUCED LIVER EFFECTS IN
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events in the liver. AZD9056 was ev
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The peppermint oil caused a concent
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OA did not affect food consumption.
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1126 PERSISTENT DEVELOPMENTAL ARYLH
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1135 BACH2 BINDING TO Prdm1 AS A ME
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The purpose of this project was to
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one marrow. Since Chk1 is an attrac
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1163 THE MRNA AND MIRNA PROFILE OF
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have now compared the IC50 values b
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1181 ELUCIDATION OF FACTORS DETERMI
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enced by pre-exposure to cigarette
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if abnormal PF was associated with
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weight (P=0.016) and small for gest
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portant cause of death, compared to
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posure groups. However, the differe
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Naphthalene is routinely analyzed i
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1245 SEASONAL CHARACTERIZATION OF H
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1255 URINARY T, T MUCONIC ACID LEVE
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modating a reliable data evaluation
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enzoquinone generate ROS and arylat
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teins (e.g. C3, 4, and 5, APOB, VDB
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1293 TRANSFORMING GROWTH FACTOR BET
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mation was decreased to the same le
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1312 EVALUATION OF THE SENSITIVITY
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luted OFR and CRL. Culture media ex
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urinary TCPy levels, blood and brai
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activity. The dose-response curves
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mice, each with 4 dose groups. One
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exposure to both ATR and DACT has a
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third tetratricopeptide repeats (TP
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7d. 28d after TMT injury there was
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subunits. Each cell type was treate
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1394 COMPARATIVE EFFECTS OF METHYLM
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1403 GENOTOXICITY AND PRE-NEOPLASTI
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vated only in high-dose-treated ani
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1421 DOSE-RESPONSE OF NAPHTHALENE-I
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cisplatin; 1.2-, 1.9- and 2.9-fold
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Day 11 and started to recover on Da
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1448 DEVELOPMENT OF A METHOD FOR QU
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1457 GLOBAL GENE PROFILING REVEALS
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cluding mouse and human macrophage,
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model of lung inflammation and host
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1484 NANOTOXICOLOGY AND NANOHEALTH
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throughput in vitro approach was us
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1502 IMMUNOLOGICAL ASPECTS OF AN AN
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(CIA) and the Streptococcal cell wa
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sitizers were 100% concordant among
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1530 MINIMAL RISK LEVELS FOR STYREN
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ical groups in the field of regulat
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vitro with this potentially insect-
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their performance on toxicological
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need for a better understanding of
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1577 AN IN VITRO MODEL SYSTEM FOR A
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gene expression post-transcriptiona
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1595 GENE EXPRESSION PROFILE OF RAT
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to confirm a hepatotoxic property o
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1613 AN INVESTIGATION OF THE CLEARA
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its nuclear translocation was reduc
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were collected from TK animals at d
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egulated targets were selected for
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U/L after tetracycline. Minocycline
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peri-pubertal FasL-/- mice show a d
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showed similar levels of apoptosis
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1676 TWO BIOMARKERS FOR EVALUATION
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motifs selected. This system was ap
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1693 VOC SERUM LEVELS IN THE GENERA
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1702 DOES THE CLOCK MAKE THE POISON
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those with high nickel content are
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isk assessment. However, unique cha
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model of APAP metabolism and glutat
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logically & morphologically similar
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posure, blood chemistry was analyze
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elated to oxidative stress by measu
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ostasis), but work is needed to tra
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tokine products during carcinogenes
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ways as chemical stressors and, the
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toxicity of nanomaterials relates s
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1815 MEASURING COMPOUND SELECTIVITY
Page 395 and 396:
1825 EFFECTS OF METABOLISM BY INTES
Page 397 and 398:
cyanoacetic acid increased 2-3 fold
Page 399 and 400:
1845 IS THE PROMISCUITY OF THE ARYL
Page 401 and 402:
crorarray analysis. RT-PCR results
Page 403 and 404:
are a family of phase-II biotransfo
Page 405 and 406:
ous labs. As a result of positive s
Page 407 and 408:
down the doses may produce more tox
Page 409 and 410:
spectively. Below 100 mg/l of gemfi
Page 411 and 412:
1900 GENERATION OF PRECISION CUT LI
Page 413 and 414:
iomarkers or observation of lesions
Page 415 and 416:
creased reticulocytes and lymphocyt
Page 417 and 418:
statistically significant interacti
Page 419 and 420:
monize sample preparation and analy
Page 421 and 422:
NPC and sinonasal cancer in neighbo
Page 423 and 424:
showed incidences of lung and nasal
Page 425 and 426:
utylbenzenes, exhibited most simila
Page 427 and 428:
1975 DIFFERENTIAL MODULATION OF CYP
Page 429 and 430:
organic As to MMA(V) and a lower ca
Page 431 and 432:
ole in invasion and metastasis of c
Page 433 and 434:
3T3-L1 cells to low-levels of arsen
Page 435 and 436:
2011 IDENTIFICATION OF A NOVEL VX M
Page 437 and 438:
This work was supported by Cooperat
Page 439 and 440:
2029 EFFICACY OF ENDOTRACHEAL ADMIN
Page 441 and 442:
Diazepam injections and its combina
Page 443 and 444:
2047 ESTERASE ACTIVITIES AND HEMOST
Page 445 and 446:
nanoparticle-induced toxicity progr
Page 447 and 448:
house, were iv infused into rats ov
Page 449 and 450:
een explored. This study investigat
Page 451 and 452:
croscopic analysis revealed that on
Page 453 and 454:
egg yolk collected from turtles inh
Page 455 and 456:
consistency of results in both expe
Page 457 and 458:
2111 CYTOCHROME P450 3A5 GENOTYPE I
Page 459 and 460:
esidues of organophosphates or thei
Page 461 and 462:
manganism. Recent work from our lab
Page 463 and 464:
Aβ1-40 in CSF and hippocampus in P
Page 465 and 466:
2147 CATALASE MANIPULATIONS MODIFY
Page 467 and 468:
ation based on real-world exposure
Page 469 and 470:
NPs. Aggregation of citrate-stabili
Page 471 and 472:
2175 THE ROLE OF SURFACE CHEMISTRY
Page 473 and 474:
seen rapid uptake in biological ima
Page 475 and 476:
effect on uterine weight or vaginal
Page 477 and 478:
dicating widespread exposure. While
Page 479 and 480:
components into the liver parenchym
Page 481 and 482:
2223 ISOLATION AND DETECTION OF RIC
Page 483 and 484:
stored (-20 celsius degree). The co
Page 485 and 486:
2241 DDA, A BIOMARKER FOR ENVIRONME
Page 487 and 488: 2249 INTERACTION BETWEEN DIETARY SE
Page 489 and 490: 2258 PHARMACOKINETICS, EXCRETION BA
Page 491 and 492: 2267 SENSITIVE AND SPECIFIC FLUORES
Page 493 and 494: 2276 METABOLISM AND DISPOSITION OF
Page 495 and 496: ment of hypertension in companion a
Page 497 and 498: for the propyl series can be used f
Page 499 and 500: 2304 IN VITRO EXPOSURE AND EVALUATI
Page 501 and 502: 2313 THE SYNERGISTIC EFFECT OF SODI
Page 503 and 504: genes that play a crucial role in M
Page 505 and 506: 2330 THE ROLE OF TRANSFORMING GROWT
Page 507 and 508: ined following up to 96 h continuou
Page 509 and 510: effect doses obtained with the rat
Page 511 and 512: diated transcriptional response of
Page 513 and 514: docrine disruptor activities of EDC
Page 515 and 516: individuals. Week 6 results were qu
Page 517 and 518: functionality of photosystem II and
Page 519 and 520: wild mice (Mus musculus) from areas
Page 521 and 522: 2406 TOXICITY AND BIOACCUMULATION O
Page 523 and 524: Isocitric acid is the acid in the h
Page 525 and 526: 2425 EFFECTS OF FUMONISINS IN ETHAN
Page 527 and 528: centration(μg/g) were: 5.1-95.3; 2
Page 529 and 530: 2445 AUTOPHAGY IN DEVELOPMENT: A LI
Page 531 and 532: sures to inhaled Mn in dust. Nevert
Page 533 and 534: 2466 CRITICAL EVALUATION OF ANIMAL
Page 535 and 536: elationships predict that resting r
Page 537: 2489 COMPARATIVE TOXICITY OF BIODIE
Page 541 and 542: 2506 TOXICOLOGICAL CONSIDERATIONS O
Page 543 and 544: launched with the aim of developing
Page 545 and 546: forms mRNA expression levels were a
Page 547 and 548: 2534 CUTANEOUS WOUND HEALING IN THE
Page 549 and 550: wells (0, 1, 5, 10, 25, 50, 100, an
Page 551 and 552: 2553 AN ORGANOTYPIC MICROLIVER PLAT
Page 553 and 554: serum-free media. At 24 hrs, the gr
Page 555 and 556: 2572 INCREASED ARSENIC BIOACCESSIBI
Page 557 and 558: nology to develop improved methods.
Page 559 and 560: tuna, swordfish, or mako shark (3.5
Page 561 and 562: nificantly reduce circulating thyro
Page 563 and 564: grouped into 9 observation periods
Page 565 and 566: histopathological or biochemical ev
Page 567 and 568: exhibited a hyperactive phenotype,
Page 569 and 570: the search of effective drugs for e
Page 571 and 572: 2644 COVALENT BINDING OF 14 C 2-MET
Page 573 and 574: aries targeting all transcription f
Page 575 and 576: (p 9 weeks) and CSC phenotype acqui
Page 577 and 578: 2673 IMMUNE-MEDIATED VASCULAR INJUR
Page 579 and 580: for risk identification and charact
Page 581 and 582: to control toxicant delivery in tob
Page 583 and 584: Author Index (Continued) The numera
Page 589 and 590:
Author Index (Continued) The numera
Page 591 and 592:
Page 593 and 594:
Page 595 and 596:
Page 597 and 598:
Page 599 and 600:
Page 601 and 602:
Page 603 and 604:
Page 605 and 606:
Page 607 and 608:
Page 609 and 610:
Page 611 and 612:
Keyword Index (Continued) Arsenite
Page 613 and 614:
Keyword Index (Continued) Covalent
Page 615 and 616:
Keyword Index (Continued) flow cyto
Page 617 and 618:
Keyword Index (Continued) innate im
Page 619 and 620:
Keyword Index (Continued) nanoparti
Page 621 and 622:
Keyword Index (Continued) preservat
Page 623 and 624:
Keyword Index (Continued) Thrombocy
Page 625 and 626:
Toxicological Sciences The Official
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