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2353 METABOLITE PATTERNS TO DIFFERENTIATE DIRECT FROM INDIRECT HYPOTHYROID EFFECTS. V. Strauss 1 , E. Fabian 1 , M. Herold 2 , H. Kamp 1 , M. Kapp 1 , G. Krennrich 1 , R. Looser 2 , W. Mellert 1 , A. Prokoudine 2 , T. Walk 2 , J. Wiemer 2 and B. van Ravenzwaay 1 . 1 BASF SE, Ludwigshafen, Germany and 2 Metanomics, Berlin, Germany. Sponsor: R. Parod. BASF and metanomics launched a project to predict toxicological risks by measuring metabolite profiles in rat serum during a single repeated dose screening study. For that purpose, a comprehensive database (MetaMapÒ Tox) has been established. About 250 metabolites were measured in serum samples of Wistar rats after administration of about 450 pharmaceutical, chemical and agrochemical compounds for 7, 14 and 28 days. Sets of common metabolite level changes (metabolite patterns) were arranged to characterize several toxicological modes of action (MOAs). Following administration of several compounds known to induce hypothyroidism, metabolite patterns were established to differentiate between a direct effect (thyroperoxidase inhibition) and an indirect effect (increased thyroid hormone conjugation via induction of liver microsomal enzymes) on thyroid hormone homeostasis. These patterns were confirmed by contrast with those seen when L-thyroxine was administered to rats to induce hyperthroidism. When the thyroid is indirectly affected, hormone levels are not consistently changed which can make diagnosis of endocrine disruption more difficult. Consideration of additional metabolite patterns can be used to substantiate the suspicion of an indirect hypothyroid effect. 2354 TCDD, PCB126, AND PCB153 AFFECT HYPOTHALAMIC GNRH AND KISS-1 SIGNALING IN VITRO, BUT NOT IN VIVO. K. Solak, F. Wijnolts, M. van den Berg and M. van Duursen. Toxicology, IRAS, Utrecht University, Utrecht, Netherlands. Dioxins and polychlorinated biphenyls (PCBs) are responsible for causing a variety of adverse effects on development and physiology of the reproductive system. However the molecular mechanisms of the action of dioxin and PCBs on hypothalamic Gonadotropin-releasing hormone (GnRH) and Kisspeptin (Kiss-1), two key regulators of reproduction, still remain unclear. In this study, we investigated the effects of TCDD, PCB126 and PCB153 on the hypothalamus using in vivo exposed adult female rats and a new in vitro immortalized adult hypothalamic rat cell line GnV-3. Unlike the commonly used murine GT1-7 cell line, GnV-3 cells express the aryl hydrocarbon receptor (AhR) similar to the vivo situation. A single oral dose of TCDD (100 μg/kg bw), PCB126 (1000 μg/kg bw) but not PCB 153 (500000 μg/kg bw), resulted in a significant increase in hypothalamic CYP1A1 mRNA level of 400 fold and 212 fold, respectively, in adult female rats after 72 hours. Hypothalamic GnRH and Kisspeptin mRNA expression was not significantly changed. In the GnV-3 cells, a 72-hour exposure to TCDD (10 nM), PCB126 (100 nM) but not PCB 153 (10 μM) caused a significant induction in CYP1A1 mRNA expression. In this model, TCDD, PCB126 and PCB153 exposure resulted in the induction of GnRH mRNA expression and secretion, while Kiss-1 mRNA expression remained unchanged. These in vitro data suggest that dioxins and PCBs may act on the GnRH expression in neuronal cells, but the role of the AhR in GnRH and Kiss-1 signalling needs to be studied further. Also, the effect of dioxins on GnRH signaling was not observed in vivo. The complex interactions of neurotransmitters and steroid hormones within hypothalamus in vivo might influence the effect of dioxin and PCBs on GnRH secretion. The in vivo relevance of the GnV-3 in vitro model is currently being studied using primary rat hypothalamic cultures. 2355 TCDD INDUCES BIOMARKERS FOR ENDOMETRIOSIS IN HUMAN ENDOMETRIUM CARCINOMA CELL LINE. K. van Ede, S. Stelloo, M. van den Berg and M. van Duursen. Toxicology, IRAS, Utrecht University, Utrecht, Netherlands. Endometriosis is a gynaecologic disorder that affects up to 10% of the women in reproductive age. A suggested pathway leading to endometriosis involves overexpression of estrogen receptor (ER)-beta, subsequent suppression of ER-alpha and the progesterone receptor (PR) and upregulation of cyclooxygenase-2 (COX-2) and CYP19. Environmental contaminants like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have often been linked to increased susceptibility to endometriosis. This study investigated the interaction of the aryl hydrocarbon receptor (AhR) with the ER and the PR in the human endometrium carcinoma cell line (ECC-1). ECC-1 cells were exposed to DMSO, TCDD alone or co-exposed to TCDD and estradiol (E2) or progesterone (P4). Gene expression of ER-alpha, ER-beta, PR, COX-2, CYP19 and cytochrome P450 1A1 (CYP1A1) were studied. Single exposure of TCDD resulted in a significant induction of CYP1A1 and COX-2 and downregu- 506 SOT 2011 ANNUAL MEETING lation of PR mRNA levels. Gene expression of CYP19 could not be determined in unexposed ECC-1 cells but was upregulated after exposure to TCDD. These findings correlate with the suggested pathway leading to endometriosis. Opposite, TCDD exposure did not affect gene expression of ER-alpha and caused downregulation of ER-beta mRNA levels. Interestingly, co-exposure of TCDD with P4 or E2 showed similar effects as seen after single exposure, except for ER-alpha and ERbeta. Co-exposure with E2 did not affect ER-alpha and ER-beta expression whereas co-exposure with P4 resulted in upregulation of ER-beta mRNA levels and significant downregulation of ER-alpha. The changes in gene expression in the ECC-1 cell line upon co-exposure of TCDD with E2 or P4 were similar to changes observed in uteri of female Sprague-Dawley rats three days after a single oral dose of TCDD. Taken together, these data suggest that TCDD is able to cause changes in gene expression in endometrium cells that have been associated with endometriosis. However, the role of circulating hormones on TCDD induced effects needs to be studied further. 2356 SODIUM PHENOBARBITAL: ASSESSMENT OF PUBERTAL DEVELOPMENT AND THYROID FUNCTION IN A COMBINED MALE AND FEMALE PUBERTAL ASSAY. M. Blanck, H. Vincent, E. Debruyne, A. Veillon, E. Balme, C. Pallen and C. Langrand-Lerche. Experimental Toxicology, Bayer SAS, Sophia Antipolis, France. Sponsor: E. Debruyne. Sodium Phenobarbital (PB) is a weak thyroid acting agent that enhances thyroid hormone clearance. We investigated the effects of PB on pubertal development and thyroid function in a combined male and female pubertal assay (Tier I test to detect potential endocrine-disrupting chemicals, US guidelines 890.1500 & 890.1450). From 30 time-mated female Sprague-Dawley rats which were received at gestation day 7 or 8, groups of 20 immature littermates per sex were administered 100 mg/kg/day PB or vehicle (corn oil) on PND 22-42 (females) or PND 23-53 (males). Parameters evaluated included body weights, clinical signs, vaginal opening (VO), preputial separation (PS), estrous cycle, hormones levels, gross pathology, organ weights and histopathology. In order to assess the potential effects of anesthesia on hormones levels, blood samples were collected from 10 animals/sex/ group at the abdominal aorta under Isoflurane anesthesia or by decapitation as recommended in the guidelines. Body weights were unaffected by PB treatment. Increased salivation was noted in males and lethargy was observed in both sexes. The age at PS and VO was slightly delayed. A large number of control animals failed to achieve regular cycles during the monitoring period after VO. Therefore it was not possible to assess the effect of PB on estrous cyclicity. TSH levels were slightly higher and testosterone concentrations were lower than controls. T4 levels remained unchanged. Hemolysis was noted in blood samples collected by decapitation. However there were no major differences in hormones levels between sera collected either by decapitation or under Isoflurane anesthesia. The reproductive organ weights were not affected by treatment. Histopathology examination is on-going. In conclusion, this study showed evidence of weak endocrine effects of PB in the male and female pubertal assay. In addition, under the study design conditions, the young age of animals and duration of the study did not allow to assess estrous cyclicity. 2357 ACTIVITY OF LARGE-MOUTH BASS ESTROGEN RECEPTORS IN RESPONSE TO MODEL COMPOUNDS. R. E. Weil 1 , D. S. Barber 2 and N. D. Denslow 2 . 1 Pharmacology, University of Florida, Gainsville, FL and 2 Physiological Sciences, University of Florida, Gainesville, FL. Estrogenic compounds found in the aquatic environment have been shown to disrupt normal endocrine function in fish by interacting with their hormone receptors. Estrogen is involved in a wide array of physiological processes, including the synthesis of vitellogenin (vtg), the egg yolk precursor protein. In largemouth bass (LMB) estrogen signaling is mediated via three known estrogen receptors (ERα, ERβb and ERβa). Studies have shown that the ligand-activated transcriptional activity of ERs is dependent on the estrogen response element (ERE) sequence in the promoters responsive genes. The first aim of this study was to use transfection assays to determine 1) if increasing the number of tandem EREs (from two to three) in the promoter of a reporter gene increases transcriptional response of each of the ERs to estrogen, and 2) to test the ability of the three LMB ERs to respond to 4,4’,4’’-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) a mammalian ERα specific agonist, 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), a mammalian ERβ specific agonist, bisphenol A (BPA), pp’-DDE, dieldrin (model environmental estrogens), and ICI182,780. The second aim is to determine the effects of these compounds on vtg synthesis using an in vitro assay. The results indicate that three tandem EREs in the promoter region of the reporter gene leads to a higher E2-me-
diated transcriptional response of all three ERs as compared to the two tandem EREs. PPT is not a specific agonist for the LMB ERα, as it also activates ERβ, and DPN was shown to activate the ERβs as well as the ERα. As expected, pp’-DDE and BPA were weak agonists of all three receptors. Dieldrin appears to be a more specific agonist of ERα, as it is not very efficacious in activating either ERβb or ERβa. The three LMB ERs showed different sensitivities to ICI 182,780, but at high concentrations (>5μM) it was able to completely inhibit the E2-mediated activation of all three ERs. Tissue slices from LMB livers will be used to test the effects of the above mentioned compounds on vtg synthesis. 2358 IMPACT OF OSRI ON ANIMAL USE AND SCREENING BURDEN FOR TIER I EDSP COMPLIANCE. S. C. Gehen 1 and W. R. Jones 2 . 1 Dow AgroSciences, LLC, Indianapolis, IN and 2 CropLife America, Washington, DC. In response to provisions of the Food Quality Protection Act (FQPA), EPA developed the endocrine disruptor screening program (EDSP) with the intent to identify chemicals that might interact with estrogen, androgen, or thyroid systems. In late 2009, EDSP was implemented with receipt of testing orders for the chemicals on the first screening list, the majority being pesticide active ingredients. According to FQPA language and EPA policy, registrants can utilize existing toxicology information- or other scientifically relevant information (OSRI) - in lieu of generating new data for some or all tier I assays. This policy is especially noteworthy for pesticides where existing legislation mandates a comprehensive registration package of toxicology studies, several which assess endocrine-sensitive parameters. To evaluate the impact of OSRI on animal use and overall burden of endocrine screening, a retrospective analysis of registrant and EPA responses was conducted. Of the 58 individual pesticide registrants and consortia receiving testing orders, about 10% opted to voluntary cancel their respective EPA registration. Of those remaining, the degree to which registrants utilized OSRI was variable with 34% submitting OSRI for all 11 tier I assays, 47% for a sub-set of tier I assays, and 9% choosing to conduct all 11 assays. Registrants cited or submitted OSRI for a total of 211 (61%) in vivo EDSP studies; these responses ranged from 76% citing OSRI for the male pubertal assay to just 47% for the fish short-term reproduction assay. Of the first 5 test order responses published by EPA, registrants cited OSRI for 14 out of a possible 30 in vivo assays; however, none of these data-sets were considered sufficient by EPA to satisfy the test order, thus indicating that new in vivo studies would be required. Understanding the agency’s rationale for accepting or rejecting data submitted as OSRI will be increasingly important as this rationale directly affects animal use and the overall resource burden of the EDSP program. 2359 ORAL EXPOSURE TO BISPHENOL A IMPACTS ELECTROCARDIOGRAPHIC PARAMETERS IN CD-1 MICE. C. B. Lo, T. B. McCutchan, E. L. Kendig and S. M. Belcher. Pharmacology, University of Cincinnati, Cincinnati, OH. Bisphenol A (BPA) is an estrogenic endocrine disrupting chemical that is prevalent in the environment. Humans are exposed to significant amounts of BPA from the consumption of contaminated foods, beverages and other poorly defined routes. Our research has demonstrated that BPA can affect the cardiovascular system by altering intracellular Ca2+ handling in myocytes causing altered EC coupling and arrhythmias. The aim of this study was to determine whether oral exposure to estradiol or BPA can influence normal electrical function and rhythm of the heart in live CD1 mice. Male and female CD-1 mice were randomly paired following a two week pre-treatment period during which time animals were exposed to control diet or diet containing BPA (0.03, 0.3, 3, 30, and 300 ppm) or 17α-ethinyl estradiol (EE; 0.0001, 0.001, and 0.01 ppm). Treatments were continued through the life of breeders (F0) and offspring (F1). Electrocardiogram (ECG) data was collected and analyzed from conscious and unrestrained mice at different time points prior to mating, during pregnancy, and during offspring development. Because levels of endogenous estrogen vary during the estrous cycle, the stage of estrous at time of recording was determined. No significant differences in heart rate or other ECG parameters were observed during estrous in the control group. Dietary exposure to BPA (0.03 ppm and 0.3 ppm) and EE (0.01 ppm) caused significant effects on cardiovascular function during diestrus and estrus in CD-1 mice. The most efficacious dose of BPA was 0.3 ppm, while no effects have been observed at 30.0 ppm BPA. In F0 females 0.03 ppm BPA significantly increased heart rate and heart rate variability was suppressed in males. In the offspring (F0), BPA (0.03 ppm and 0.3 ppm) and EE caused significant effects on cardiovascular function during diestrus and estrus. For these endpoints the most efficacious dose of BPA was 0.3 ppm, with no effects observed at 30.0 ppm BPA. 2360 INTEGRATING HUMAN AND TOXICOLOGICAL EVIDENCE TO UNDERSTAND PCB EFFECTS ON THE DEVELOPING BRAIN. F. Parham 1 , A. Wise 2 , D. A. Axelrad 3 , K. Z. Guyton 3 , C. J. Portier 4 , L. Zeise 5 , R. T. Zoeller 6 and T. J. Woodruff 2 . 1 National Institute for Environmental Health Science, Research Triangle Park, NC, 2 University of California, San Francisco, CA, 3 U.S. EPA, Washington, DC, 4 Centers for Disease Control and Prevention, Atlanta, GA, 5 California EPA, Oakland, CA and 6 University of Massachusetts, Amherst, MA. We reviewed the relationships between chemical exposure, early biological disturbances, and subsequent overt health effects for thyroid hormone disruptions in a case study approach. Thyroid hormones (TH; thyroxine, T4 and triiodothyrine, T3) are essential for normal brain development and for normal physiological controls in adults. Mechanistic, laboratory animal, and human studies indicate that TH disruption during the prenatal period can cause permanent cognitive and neurobehavioral deficits. The quantitative relationships between TH disruption due to chemical exposures and overt disease were analyzed for polychlorinated biphenyls (PCBs). PCBs were chosen because sufficient animal and human data exist to model and compare body burdens, TH disruption and health decrements. We modeled three relationships following a review of 13 epidemiologic studies, applying meta-analysis where appropriate: 1) chemical exposures and TH changes; 2) pregnancy TH changes and neurodevelopmental outcomes of children; and 3) prenatal PCB exposures and neurodevelopmental outcomes of children. Using data from four chronic PCB studies in rats conducted by the National Toxicology Program, we developed a low-dose linear model of PCB body burdens and T4 (free and total) decrements, accounting for 35 PCB congeners. A human extrapolation of the animal findings generally under-predicted the dose-response estimated from human studies. This quantitative analysis can inform approaches for evaluating human health consequences of exposures to multiple chemicals that exert thyroid toxicity. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views and/or policies of the US EPA. 2361 GENISTEIN NEGATES THE INHIBITORY EFFECTS OF LETROZOLE ON AROMATASE RELATED TO MALIGNANT, BUT NOT HEALTHY BREAST TISSUE. M. van Duursen 1 , E. de Morree 1 , S. Nijmeijer 1 , P. de Jong 2 and M. van den Berg 1 . 1 Institute for Risk Assessment Sciences, Utrecht University, Utrecht, Netherlands and 2 Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, Netherlands. Aromatase (cytochrome P450 19, CYP19) catalyzes the conversion of androgens into estrogens. Especially in post-menopausal women, estrogen production in breast tissue by CYP19 becomes a major site of hormone production. In healthy breast adipose fibroblasts (BAF), CYP19 expression is low and is mainly driven by promoter I.4. In fibroblasts surrounding a tumor, a promoter switch to PI.3/II takes place and CYP19 expression is elevated 3-4-fold. This makes this enzyme an important target for estrogen-dependent breast cancer treatment by aromatase inhibitors, such as letrozole (LET). Breast cancer treatment often results in sudden onset of menopausal symptoms and many women seek for alternative therapies to treat these symptoms. A commonly used treatment is the soy-isoflavone genistein (GEN). In this study, the potential interaction between LET and GEN on CYP19 was studied. In healthy primary human BAFs, PI.4-driven CYP19 expression was increased 45-fold by its stimulant dexamethasone. Expression of PI.3/II-driven aromatase was low in BAFs and only increased 7-fold by the stimulant PGE2. GEN did not affect CYP19 expression in BAFs. In contrast, in human adrenocorticocarcinoma H295R cells, that express PI.3/II-driven CYP19, GEN concentration-dependently induced aromatase activity (EC50=26 μM) and expression. LET inhibited CYP19 activity in H295R cells with an IC50 value of 0.2 μM. Co-incubation with GEN resulted in a concentration-dependent negation of CYP19 inhibition by LET through increased CYP19 expression. This interaction did not affect the EC50 of genistein, nor did it alter the IC50 of LET. These data indicate that the actions of GEN on CYP19 appear to be restricted to PI.3/II-driven CYP19 that can be found in BAFs surrounding a tumor. Therefore, the use of GEN by women undergoing breast cancer treatment with LET should be considered with care. 2362 EFFECTS OF REDUCED-PHYTOESTROGEN DIETS ON DEVELOPMENT OF CD1 AND C57BL/6N MICE. E. L. Kendig, S. M. Christie, D. R. Buesing, C. K. Cookman, R. B. Gear, C. B. Lo and S. M. Belcher. Pharmacology, University of Cincinnati, Cincinnati, OH. Endocrine disrupting chemicals (EDC) are chemicals that can affect endocrine-dependent development and function. These chemicals are prevalent in the environment and exhibit a variety of biological effects. Because of limited ability to replicate results from some animal studies controversy surrounds the possible harmful SOT 2011 ANNUAL MEETING 507
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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
Page 361 and 362:
peri-pubertal FasL-/- mice show a d
Page 363 and 364:
showed similar levels of apoptosis
Page 365 and 366:
1676 TWO BIOMARKERS FOR EVALUATION
Page 367 and 368:
motifs selected. This system was ap
Page 369 and 370:
1693 VOC SERUM LEVELS IN THE GENERA
Page 371 and 372:
1702 DOES THE CLOCK MAKE THE POISON
Page 373 and 374:
those with high nickel content are
Page 375 and 376:
isk assessment. However, unique cha
Page 377 and 378:
model of APAP metabolism and glutat
Page 379 and 380:
logically & morphologically similar
Page 381 and 382:
posure, blood chemistry was analyze
Page 383 and 384:
elated to oxidative stress by measu
Page 385 and 386:
ostasis), but work is needed to tra
Page 387 and 388:
tokine products during carcinogenes
Page 389 and 390:
ways as chemical stressors and, the
Page 391 and 392:
toxicity of nanomaterials relates s
Page 393 and 394:
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: effect doses obtained with the rat
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 and 538: 2489 COMPARATIVE TOXICITY OF BIODIE
Page 539 and 540: 2497 TRANSCRIPTIONAL REGULATION OF
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 585 and 586:
Page 587 and 588:
Page 589 and 590:
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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