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2134 MANGANESE AND VANADIUM EXPOSURE INDUCES SEVERE NEUROTOXIC RESPONSE IN OLFACTORY SYSTEM OF AN ANIMAL MODEL: POTENTIAL RELEVANCE TO OLFACTORY DYSFUNCTION AND PARKINSON’S DISEASE (PD). H. Afeseh Ngwa, A. Kanthasamy, V. Anantharam and A. G. Kanthasamy. Iowa State University, Ames, IA. Chronic environmental exposure to heavy metals through occupational and industrial sources has been suggested in the etiopathogenesis of neurodegenerative conditions like PD. Metal exposure often occurs with multiple rather than individual components, warranting an understanding of the neurotoxic effects of metal mixtures. Vanadium pentoxide (V2O5) typically presents along with manganese (Mn) especially in welding rods. Mechanisms of V2O5/Mn interaction and resulting consequences of neurotoxicity are unknown. Using cell culture models, we have recently shown that the V2O5/Mn metal mixture is a more potent neurotoxicant than V2O5 or Mn alone. In this study, we examined the neurotoxic effects of Mn, V2O5 and Mn - V2O5 co-exposure in an animal model. C57 black mice were intranasally exposed to 252μg MnCl2 alone, 182μg V2O5 alone, or MnCl2-V2O5 in combination three times a week for up to one month. The delivered metal levels are relevant to the exposure limits found in many workplace settings. Following exposure, behavioral, neurochemical, and histological studies were performed. Our results revealed dramatic decreases in olfactory bulb weights and levels of tyrosine hydroxylase, dopamine and DOPAC in the treatment groups as compared to control. Interestingly, increased levels α-synuclein in the substantia nigra of treated animals were observed. We also observed accompanying locomotor deficits and olfactory dysfunction with the co-treatment group producing the most severe deficits. Taken together with recent observations of anosmia in PD patients, our results suggest that exposure to Mn and V2O5 can adversely affect the olfactory and nigral systems, with accompanying behavioral deficits. These results also indicate that mixtures of Mn and vanadium might have more serious neurotoxic implications in environmentally linked PD like conditions than that of individual metals (NIH grant ES10586). 2135 CHRONIC MANGANESE ALTERS THYROID AND ESTROGEN LEVELS IN RATS BLOOD. O. Soldin 1 and M. Aschner 2 . 1 Departments of Oncology, Medicine, Physiology and Biophysics, Obstetrics and Gynegology, Georgetown University, Washington, DC and 2 Departments of Pediatrics and Pharmacology, Vanderbilt University, Nashville, TN. Manganese (Mn) is an essential trace nutrient that is potentially toxic at high levels of exposure. As a constituent of numerous enzymes and a cofactor, manganese plays an important role in a number of physiologic processes in mammals. Exposure to high Mn levels can result in manganism characterized by motor deficits and damage to nuclei of the basal ganglia and dopaminergic deficits. Dopamine is a known inhibitory modulator of thyroid stimulating hormone (TSH) secretion. The involvement of dopamine and dopaminergic receptors in neurodevelopment, as well as TSH modulation, led us to hypothesize that excessive manganese exposure may lead to the disruption of normal thyroidal processes and thyroid hormone synthesis. Four groups of rats were treated for 14 weeks. The control group received normal dietary levels of Mn. A second group received a 10-fold excess of Mn daily. In addition two other groups received an iron (Fe) deficient diet (6 mg/kg/day) in the presence of normal or excess of Mn. Serum thyroxine (T4), triiodothyronine (T3) and a panel of 14 steroids were measured using liquid chromatography tandem mass spectrometry (LC/MS/MS) at the end of exposures. Mn exposure resulted in a decrease in T4 and T3 when rats were fed iron deficient diets. Similar results were obtained for Cortisol, DHEAS and progesterone. These results suggest that chronic Mn exposure may alter thyroid and steroid hormone levels, which may have critical implications for normal growth and differentiation and fetal neurodevelopment during pregnancy. Supported by DoD W81XWH-05-0239, NIEHS 10563, the Flight Attendants Medical Research Institute and the Georgetown Bioanalytical Core Laboratory. 2136 PEPTIDOME AND PROTEOME IN MURINE CHOROID PLEXUS-CEREBROSPINAL FLUID SYSTEM: EFFECT OF CHRONIC MANGANESE (MN) EXPOSURE. G. J. Li 1 , K. H. Wei 2 , H. M. Jing 1 , F. Yang 2 , C. Y. Zhao 1 , L. Ma 1 , T. Zhang 2 , X. Y. Zhang 2 , J. Z. Liu 1 , L. P. Liu 1 and W. Zheng 3 . 1 Beijing Center for Preventive Medicine, Beijing, China, 2 Beijing Proteome Research Center, Beijing, China and 3 Purdue University, West Lafayette, IN. Occupational Mn exposure is known to cause Parkinsonism; yet the mechanism is unclear. The choroids plexus (CP)-cerebrospinal fluid (CSF) system maintains the homeostasis of brain’s milieu including Mn. This study was designed to explore the 458 SOT 2011 ANNUAL MEETING normal peptidome and proteome in the CP, and the change of proteome in the CP- CSF system after Mn exposure. Rats (1.5 mn) were divided into 3 groups; each received daily ip injections of either MnCl2 (6 mg Mn/kg) or saline (as controls) for 30, 90 days, or 90 days followed by additional 30-day convalescence. The CP and CSF were collected and analyzed. The results showed: (1) 163 peptides in the normal CP were identified by using matrix-assisted laser desorption/ionization TOF/TOF mass spectrometry and nano-LC-MS/MS. (2) A total of 231 non-redundant proteins were identified in the CP by two ways of 1-DE combining with LC-Q-TOF-MS and 1-DE combining with LC-IT-MS. Further analysis by Gene Ontology (GO) annotation revealed that the proteins responsible for binding, transport and structural integrity accounted for 67% of all the identified proteins in the CP. (3) In the CP of Mn-treated rats, a total of 448 protein spots were isolated by 2D-PAGE, and 69 protein spots were significantly different from the controls by using PDQuest 8.0.1 software for quantitative analyses (changes more than 10 folds). (4) Moreover, a group of 32 differentially expressed proteins in the CP of Mn-exposed rats were identified by Nano-LC-MS/MS, of which 27 were up-regulated (e.g. mitochondrial aconitase, nucleobindin-1 precursor), and five were down-regulated (e.g. transthyretin). Based on the GO, these proteins involve largely in the functions of binding, catalysis and transportation. An in-depth study of Mn-related peptidome and proteome in the CSF is currently in progress. (PRC Beijing City Personnel Grant 2007-62; US NIH/NIEHS ES017055) 2137 REDUCED COPPER CLEARANCE BY THE BLOOD-CSF BARRIER FOLLOWING IN VIVO MANGANESE AND THE ROLE OF CU TRANSPORTER ATP7A. X. Fu, Y. Zhang, W. Jiang, A. D. Monnot and W. Zheng. School of Health Sciences, Purdue University, West Lafayette, IN. Previous animal and human studies by this lab showed a significant increase of Cu in blood, saliva and brain following Mn exposure. However, the mechanism is unknown. ATP7A functions to translocate Cu from the cytosol to cellular membrane. This study was designed to test the hypothesis that Mn exposure interfered the intracellular trafficking of ATP7A in the choroid plexus (CP) where the blood-CSF barrier (BCB) resides. Rats received i.p. injection of 6 mg Mn/kg as MnCl2 or saline, 5 d/week for 4 weeks. The ICP-MS analyses revealed a significant increase of Mn and Cu levels in serum, cerebrospinal fluid (CSF), CP, hippocampus, and frontal cortex, when compared with controls. An in situ ventriculo-cisternal perfusion study by infusing the mixture of [64]Cu and a space marker [14]C-sucrose showed that Mn exposure did not affect the CSF clearance of [14]C-sucrose, but it significantly increased, about 2.6 folds, [64]Cu radioactivity in the CSF as compared to controls, suggesting a reduced Cu clearance by the BCB. The mRNA expression of ATP7A in choroidal epithelial Z310 cells was significantly higher in Mn-treated (100 μM for 48 hr) groups than in controls. Confocal imaging studies also exhibited an increased fluorescent signal in choroidal epithelial Z310 cells after Mn treatment. Additionally, the confocal technique was used to study the intracellular trafficking of ATP7A in freshly isolated CP tissues from in vivo Mn exposed rats. An evident intracellular migration of ATP7A from the sub-nucleus region to the apical membrane in the choroidal epithelia, which are in the direct contact with the CSF, was observed. Collectively, these data suggest that Mn exposure results in the overload of intracellular Cu with an ensuing increase of ATP7A level in the BCB. A subsequent translocation of ATP7A towards the apical microvilli facing the CSF may expel Cu into the CSF and reduce Cu clearance from this central milieu. Consequently, an increased Cu in the CNS may account for Mn-induced neurotoxicity. (Supported by NIH/RO1-ES008146) 2138 INCREASED BETA-AMYLOID DEPOSITION IN TRANSGENIC APP MICE FOLLOWING CHRONIC LEAD (PB) EXPOSURE. W. Zheng 1 , H. Gu 2 , X. Wei 2 , A. D. Monnot 1 and Y. Du 1, 2 . 1 School of Health Sciences, Purdue University West Lafayette, IN and 2 Neurology, Indiana University School of Medicine, Indianapolis, IN. Pb is an environmental toxicant that may contribute to the etiology of Alzheimer’s disease. Our early studies suggest that Pb exposure reduces the clearance of betaamyloid (Aβ) from the cerebrospinal fluid (CSF) by acting on Aβ removal system in the choroid plexus (CP). This study tested the hypothesis that a reduced Aβ clearance following Pb exposure increased Aβ levels in the CSF, leading to amyloid plaque formation in brain tissues. APP transgenic mice were used for their ability to overexpress human amyloid precursor protein (APP) with an age-related deposition of neuritic plaques beginning at 3 mn of age. Following acute Pb exposure (27 mg Pb/kg, ip, 24 h) in 2-mn-old mice, ELISA revealed a significantly higher level of
Aβ1-40 in CSF and hippocampus in Pb-treated mice than in controls (p
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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
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1825 EFFECTS OF METABOLISM BY INTES
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cyanoacetic acid increased 2-3 fold
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1845 IS THE PROMISCUITY OF THE ARYL
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crorarray analysis. RT-PCR results
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are a family of phase-II biotransfo
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ous labs. As a result of positive s
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down the doses may produce more tox
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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
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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
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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
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Page 457 and 458: 2111 CYTOCHROME P450 3A5 GENOTYPE I
Page 459 and 460: esidues of organophosphates or thei
Page 461: manganism. Recent work from our lab
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
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docrine disruptor activities of EDC
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individuals. Week 6 results were qu
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functionality of photosystem II and
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wild mice (Mus musculus) from areas
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2406 TOXICITY AND BIOACCUMULATION O
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Isocitric acid is the acid in the h
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2425 EFFECTS OF FUMONISINS IN ETHAN
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centration(μg/g) were: 5.1-95.3; 2
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2445 AUTOPHAGY IN DEVELOPMENT: A LI
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sures to inhaled Mn in dust. Nevert
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2466 CRITICAL EVALUATION OF ANIMAL
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elationships predict that resting r
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2489 COMPARATIVE TOXICITY OF BIODIE
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2497 TRANSCRIPTIONAL REGULATION OF
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2506 TOXICOLOGICAL CONSIDERATIONS O
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launched with the aim of developing
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forms mRNA expression levels were a
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2534 CUTANEOUS WOUND HEALING IN THE
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wells (0, 1, 5, 10, 25, 50, 100, an
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2553 AN ORGANOTYPIC MICROLIVER PLAT
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serum-free media. At 24 hrs, the gr
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2572 INCREASED ARSENIC BIOACCESSIBI
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nology to develop improved methods.
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tuna, swordfish, or mako shark (3.5
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nificantly reduce circulating thyro
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grouped into 9 observation periods
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histopathological or biochemical ev
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exhibited a hyperactive phenotype,
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the search of effective drugs for e
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2644 COVALENT BINDING OF 14 C 2-MET
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aries targeting all transcription f
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(p 9 weeks) and CSC phenotype acqui
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2673 IMMUNE-MEDIATED VASCULAR INJUR
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for risk identification and charact
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to control toxicant delivery in tob
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Author Index (Continued) The numera
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Keyword Index (Continued) Arsenite
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Keyword Index (Continued) Covalent
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Keyword Index (Continued) flow cyto
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Keyword Index (Continued) innate im
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Keyword Index (Continued) nanoparti
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Keyword Index (Continued) preservat
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Keyword Index (Continued) Thrombocy
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Toxicological Sciences The Official
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