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1988 AUTOPHAGY: A CELLULAR PROCESS STRONGLY ASSOCIATED WITH ARSENITE-INDUCED IMMUNOTOXICITY IN HUMAN LYMPHOBLASTOID CELL LINES. A. M. Bolt, R. M. Douglas and W. T. Klimecki. Pharmacology and Toxicology, University of Arizona, Tucson, AZ. Inorganic arsenic is a global environmental toxicant that is associated with a diverse array of complex diseases, making it challenging to identify the mechanism underlying arsenic-induced cytotoxicity. A mounting body of literature from epidemiological and in vitro / in vivo studies has demonstrated that arsenic is a potent immunotoxicant, but the mechanism driving arsenic-induced immunotoxicity is not well established. We have previously demonstrated that in human lymphoblastoid cell lines (LCL), arsenic-induced cell death is strongly associated with the induction of autophagy. In this study we utilized genome-wide gene expression analysis and functional assays to characterize arsenic-induced immunotoxicity in seven LCL that were exposed to an environmentally relevant, minimally cytotoxic, concentration of sodium arsenite (0.75 uM) over an eight-day time course. Arsenite exposure resulted in inhibition of cell proliferation and the induction of autophagy (measured by expansion of acidic vesicles) over the eight-day exposure duration. Interestingly, there was a strong correlation between the extent to which arsenite exposure inhibited cell proliferation and the fold induction in autophagy in the different LCL analyzed. Gene expression analysis revealed that arsenite exposure globally increased lysosomal gene expression, which was associated with increased functional activity of the lysosome protease, cathepsin D. The lysosomal gene master regulator, transcription factor EB (TFEB) was also up regulated in arsenite exposed samples in a time-dependent manner, which could explain the concordant lysosomal gene expression. The arsenic-induced expansion of the lysosomal compartment in LCL represents a novel target that may offer mechanistic insight into the immunotoxic effects of arsenic. (Funded by ES 006694, ES 16652, and ES 04940) 1989 DEVELOPMENTAL IMMUNOTOXICITY OF LOW DOSE ARSENIC EXPOSURE. C. Kozul-Horvath 1 , J. W. Hamilton 2 and R. Enelow 1 . 1 Immunology, Dartmouth Medical School, Lebanon, NH and 2 Bay Paul Center for Comparative Molecular Biology & Evolution, Marine Biological Laboratory, Woods Hole, MA. Arsenic (As) exposure is a significant worldwide environmental health concern and chronic exposure via contaminated drinking water has been associated with an increased incidence of a number of diseases. We previously reported that As exposure has significant effects on immune responses to influenza infection in adult mice. In order to identify critical windows of developmental As exposure and specifically, the potential immunotoxic effects of such exposures at the current EPA standard of 10 ppb, C57B6 pups were exposed to 10 ppb As, either in utero or during the postnatal weaning period (via the dam). We observed that following in utero As exposure there was a decrease in productive matings. However birth outcomes, such as litter weight, size, and gestational length were unaffected. Following birth, the pups in both models of exposure had significant growth defects, which resolved following cessation of exposure. Additionally we observed significant As-associated alterations in immune cell populations within the lung and spleen, including T cells (CD4+ and CD8+) and B cells. These results suggest that low level As exposure via the mother can induce significant alterations in the growth of offspring and the development of the immune system, which may contribute to enhanced disease risk. (NIH-NIEHS SRP P42 ES007373) 1990 ARSENIC ALTERS PURINERGIC TYPE 2 (P2) RECEPTOR Ca 2+ SIGNALING ASSOCIATED WITH INNATE IMMUNITY IN HUMAN AIRWAY EPITHELIAL CELLS. C. L. Sherwood 1, 2, 5 , R. Lantz 2, 4, 5 , J. L. Burgess 4, 6 and S. Boitano 1, 3, 4 . 1 Respiratory Center, Arizona Health Sciences Center, Tucson, AZ, 2 Cell Biology and Anatomy, Arizona Health Sciences Center, Tucson, AZ, 3 Physiology, Arizona Health Sciences Center, Tucson, AZ, 4 SWEHSC, Arizona Health Sciences Center, Tucson, AZ, 5 Bio5 Institute, Arizona Health Sciences Center, Tucson, AZ and 6 College of Public Health, Arizona Health Sciences Center, Tucson, AZ. Arsenic is a natural contaminant of drinking water supplies worldwide. Consumption of arsenic-tainted water has been correlated with malignant and nonmalignant lung diseases. Despite strong links with respiratory illness, underlying mechanisms of arsenic-induced disease remain unclear. Recent research on chronic lung disease has uncovered a key role for paracrine ATP signaling. We hypothesized that arsenic may elicit some of its detrimental effects on the airway through limitation of innate immune function, and specifically, through alteration of paracrine ATP and intracellular Ca 2+ signaling in the airway epithelium. We examined the ef- 426 SOT 2011 ANNUAL MEETING fects of acute (24 hr) exposure with environmentally relevant levels of arsenic (i.e., < 4 μM (~300 μg/L) as Na-arsenite) on wound-induced Ca 2+ signaling pathways in an immortalized human bronchial epithelial cell line (16HBE14o-). We found arsenic reduces ATP-induced Ca 2+ signaling in a dose-dependent manner and results in a reshaping of the Ca 2+ signaling response upon wounding. We next examined arsenic effects on two ATP-mediated pathways for Ca 2+ signaling: the metabotropic P2Y and ionotropic P2X receptors. Arsenic inhibited P2Y response to ATP; this included a transcriptional reduction of P2Y 2 following sub-micromolar (0.8 μM) or micromolar (3.9 μM) additions of arsenic. Arsenic induced a dose-dependent inhibition of P2X response to ATP; this included a transcriptional reduction of P2X 4 only at micromolar (3.9 μM) levels. Ingested arsenic rapidly reaches the airway epithelium where ATP signaling is essential in innate immune functions (e.g., ciliary beat, salt and water transport, bactericide production, and wound repair). Arsenicinduced compromise of such airway defense mechanisms may be an underlying contributor to chronic lung disease. 1991 SODIUM ARSENITE AND HYPERTHERMIA ALTER EXPRESSION OF XPA, XPC, AND MSH2 IN RESPONSE TO CISPLATIN-INDUCED DNA DAMAGE AND INCREASE ACCUMULATION OF PLATINUM IN OVARIAN CANCER. C. S. Muenyi 1 , V. A. States 1 , J. H. Masters 1 , T. Fan 1, 2 , W. Helm 1, 3 and J. States 1 . 1 Pharmacology & Toxicology, University of Louisville, Louisville, KY, 2 Chemistry, Univesity of Louisville, Louisville, KY and 3 Obstetrics, Gynecology & Women’s Health, Univesity of Louisville, Louisville, KY. Ovarian cancer (OC) is the leading cause of gynecologic cancer death in the USA. Recurrence rates are high after front-line therapy and most patients eventually die from platinum-resistant disease. Cisplatin resistance is associated with increased nucleotide excision repair (NER), decreased mismatch repair (MMR) and decreased platinum uptake. We hypothesize that sodium arsenite (NaAsO2) and hyperthermia will sensitize OC to cisplatin by altering DNA repair and increasing platinum accumulation. A2780 and A2780/CP70 OC cells were treated with cisplatin ± NaAsO2 at 37 or 39 oC for 1 h. Co-treatment with NaAsO2 and hyperthermia sensitized these cells to cisplatin. NaAsO2 ± hyperthermia decreased cisplatin-induced XPC, an NER protein. NaAsO2 and hyperthermia additively increased platinum accumulation in these cells. Nude mice were injected with A2780/CP70 cells to create intraperitoneal (IP) tumors. Expression of key NER (ERCC1, XPC and XPA) and MMR proteins (MSH2) were analyzed by western blot in metastatic tumors isolated from mice after hyperthermic IP chemotherapy (HIPEC). XPA induction by cisplatin was suppressed by hyperthermia (43 oC). NaAsO2 suppressed XPC induction by cisplatin. Hyperthermia ± NaAsO2 decreased cisplatin-induced XPC 24 h after perfusion. MSH2 levels were higher in tumors perfused with NaAsO2 plus cisplatin. NaAsO2 significantly increased initial accumulation of platinum in tumors, but had no effect on Pt retention. Hyperthermia had no effect on tumor Pt levels. Platinum and arsenic generally accumulated in systemic tissues during HIPEC and decreased 24 h after perfusion. Conclusion: NaAsO2 and hyperthermia have the potential to sensitize OC to cisplatin by inhibiting NER and increasing MMR and platinum accumulation. Supported in part by NIH grants P30ES014443 and R01ES011314; and NSF-EPSCoR grant EPS-0447479. 1992 EPITHELIA MALIGNANTLY TRANSFORMED BY ARSENIC OR CADMIUM DRIVES NEARBY NORMAL STEM CELLS TOWARDS A MALIGNANT PHENOTYPE. Y. Xu, E. Tokar and M. Waalkes. National Toxicology Program, NIEHS, Research Triangle Park, NC. Stem cells (SCs) likely play a key role in carcinogenesis and can be committed to differentiation pathways by various factors. We find that arsenic malignantly transforms the normal human prostate epithelial cell line (RWPE-1) into a malignant phenotype involving survival selection of SCs and overproduction of cancer SCs (CSCs). Cadmium (Cd) can also malignantly transform the same cells through mechanisms likely different from arsenic. Whether and how a malignant epithelium might affect nearby normal SCs is poorly defined. Thus, we studied the potential effects of neighboring arsenic- and Cd-transformed malignant prostate epithelia on the normal prostate SC line, WPE-stem cells, which was previously isolated from RWPE-1 cells. These SCs were exposed via transwells, which do not allow cell lines direct contact but allow soluble factors to interact between cells, to malignant transformants from chronic arsenic-exposed RWPE-1 cells (CAsE-PE cells) or to chronic Cd-exposed RWPE-1 cells (CTPE cells) or to normal RWPE-1 cells, all of which are isogenic. Matrix metalloproteinases (MMPs) play a crucial
ole in invasion and metastasis of cancer cells and are markers of malignant transformation by arsenic or Cd. In SCs trans-cultured with CAsE-PE or CTPE cells, MMP transcript increased after only 1 week of trans-culture, and secreted MMP-2 and MMP-9 activity increased after 2 weeks. PTEN, a tumor suppressor gene with a critical role in SCs differentiation, is often inactivated in malignancies. PTEN transcript was highly suppressed after only 1 week of trans-culture of SCs with either CAsE-PE or CTPE cells. K5 and P63 are markers of prostate basal cells, the absence of which is used for pathological diagnosis of prostate cancer. K5 and P63 were also markedly suppressed by trans-culture of SCs with CAsE-PE or CTPE cells. Therefore, arsenic- and Cd-induced malignantly transformed prostate epithelia impacts nearby normal SCs, apparently driving them towards a malignant phenotype while not actually having physical contact. 1993 OVERABUNDANCE OF PUTATIVE CANCER STEM CELLS IN HUMAN SKIN KERATINOCYTE CELLS MALIGNANTLY TRANSFORMED BY ARSENIC. Y. Sun, E. Tokar and M. Waalkes. National Toxicology Program, NIEHS, Research Triangle Park, NC. Arsenic is a human skin carcinogen. Cancer is probably a disease driven by stem cells (SCs) and SCs are likely a key target during arsenic oncogenesis. In utero arsenic exposure predisposes mice to skin carcinoma formation with an overproduction of cancer SCs (CSCs) and distortion of CSC signaling and population dynamics. Therefore, here we hypothesized that accumulation of CSCs may occur in a human skin keratinocyte line during arsenic-induced malignant transformation in vitro. Thus, the HaCaT cell line, which was malignantly transformed by sodium arsenite (100 nM, 30 weeks; termed As-TM cells) in prior work, was further studied for the quantity and nature of SC/CSCs during transformation. SCs/CSCs were isolated from As-TM cells and control cells by using a positive magnetic bead isolation system that purifies CD34 positive cells. CD34 is a cell surface marker for both human skin SCs and CSCs. Using this system, there were 2.5 times more SCs/CSCs isolated from As-TM cells than from control cells. Holoclones are dense, tightly packed clusters of cells formed in culture by SCs/CSCs and enriched in these same cells. After isolation of SC/CSCs, holoclone production from CSCs isolated from As-TM cells was 2.5-fold higher at 1 week and 3.5-fold higher at 2 weeks than SCs isolated from control cells. SC characteristics and potential malignant phenotype were assessed in SC/CSCs isolated from control and As-TM cells and compared to their parental lines. Transcript level of SC/CSC markers were elevated in both As-TM CSCs and control SCs compared to parental cells, but CSCs from As-TM cells had elevated Oct-4, K5, K15 transcripts, and dramatically stronger staining for p63, Notch1, K19 compared to control SCs. As-TM CSCs also showed markedly elevated MMP-9 secretion and colony formation in agar, both indicators of cancer phenotype, even when compared to total population of As-TM cells. Thus, arsenic-induced malignant phenotype is particularly pronounced in SCs during transformation of human skin cells and occurs concurrently with an overproduction of CSCs. 1994 TRANSFORMATION OF NORMAL HUMAN BREAST EPITHELIAL (MCF-10A) CELLS BY ARSENITE AND CADMIUM INDUCES THE OVER-EXPRESSION OF NEURONAL SPECIFIC ENOLASE (ENOLASE-2). M. Soh, S. H. Garrett, C. Bathula, D. A. Sens, S. Somji and M. Sens. Pathology, University of North Dakota, Grand Forks, ND. Arsenite (As +3 ) and cadmium (Cd +2 ) exposure have been associated with many types of cancers including bladder, skin, liver, prostate and lung, and in case of breast, they have been implicated in estrogen receptor mediated gene transcription, endocrine disruption, DNA damage and altered cell growth. Previous studies from our laboratory haves shown that both As +3 and Cd +2 can directly malignantly transform the non-tumorigenic urothelial cell line UROtsa. The goal of this study was to determine if both these heavy metals could also transform the breast epithelial cell line MCF-10A. For this purpose the MCF-10A cells were exposed to 1 μM As +3 or Cd +2 for a long period of time with the end point being the ability to form colonies in soft agar. It was the demonstrated that long term exposure resulted in selection of cells that were able to form colonies in soft agar. These transformed cells were subjected to microarray analysis and one of the differentially expressed gene that was identified was enolase-2 (ENO-2) which is a glycolytic enzyme that catalyses the conversion of 2-phosphoglycerate to phosphoenol pyruvate. ENO-2 has shown to be over expressed in neuronal and neuro-endocrine tumors. It is also over expressed in certain breast cancers that have a neuro-endocrine differentiation. The next goal of the study was to determine if Cd +2 and As +3 could induce the expression of this enzyme in the MCF-10A cells upon short and long term exposure. The results obtained indicate that both the metals can up-regulate the expression of ENO-2 in a time and dose dependent manner. Although the mechanism involved in the up-regulation of ENO-2 is unknown, our study provides evidence that the increased expression of ENO-2 may have implications in the increased glycolytic capacity of tumors 1995 SPARC GENE EXPRESSION IS REPRESSED IN HUMAN UROTHELIAL CELLS (UROTSA) EXPOSED TO OR MALIGNANTLY TRANSFORMED BY CADMIUM OR ARSENITE. J. L. Larson 1 , S. Somji 2 , D. A. Sens 2 , M. Sens 2 , S. H. Garrett 2 and J. R. Dunlevy 1 . 1 Anatomy and Cell Biology, University of North Dakota, Grand Forks, ND and 2 Pathology, University of North Dakota, Grand Forks, ND. SPARC belongs to a class of extracellular matrix-associated proteins that have counteradhesive properties. The ability of SPARC to modulate cell-cell and cell-matrix interactions provides a strong rationale for studies designed to determine its expression in cancer. The objective of this study was to determine if SPARC expression was altered in cadmium (Cd +2 ) and arsenite (As +3 ) induced bladder cancer and if these alterations were present in archival specimens of human bladder cancer. The expression of SPARC was determined in human parental UROtsa cells, their Cd +2 and As +3 transformed counterparts and derived tumors, and in archival specimens of human bladder cancer using a combination of real time reverse transcriptase polymerase chain reaction, western blotting, immunofluoresence localization and immunohistochemical staining. It was demonstrated that SPARC expression was down-regulated in Cd +2 and As +3 transformed UROtsa cells. In addition, the malignant epithelial component of tumors derived from these cell lines were also down-regulated for SPARC expression, but the stromal cells recruited to these tumors was highly reactive for SPARC. This finding was shown to translate to specimens of human bladder cancer where tumor cells were SPARC negative, but stromal cells were positive. Acute exposure of UROtsa cells to both cadmium and arsenite reduced the expression of SPARC through a mechanism that did not involve changes in DNA methylation or histone acetylation. These studies suggest that environmental exposure to As +3 or Cd +2 can alter cell-cell and cell-matrix interactions in normal urothelial cells through a reduction in the expression of SPARC. The SPARC associated loss of cell-cell and cell-matrix contacts may participate in the multi-step process of bladder carcinogenesis. 1996 DIFFERENCES IN THE EPIGENETIC REGULATION OF METALLOTHIONEIN-3 GENE EXPRESSION BETWEEN PARENTAL AND CADMIUM- OR ARSENITE- TRANSFORMED HUMAN UROTHELIAL CELLS. D. A. Sens, S. H. Garrett, A. Ajjimaporn, M. Sens and S. Somji. Pathology, University of North Dakota, Grand Forks, ND. Cadmium (Cd +2 ) and arsenite (As +3 ) and are human carcinogens and exposure to them has been associated with the development of bladder cancer. Previous work from our laboratory has shown that the UROtsa cell line can be directly malignantly transformed by both Cd +2 and As +3 and that the resulting tumors retain features of urothelial cancer. These transformed cell lines in cell culture do not express metallothionein-3 (MT-3); despite the fact that most human bladder tumors overexpress this gene. However, when they are transplanted as tumors they show strong expression of MT-3. This difference in MT-3 expression suggests that the mechanism of MT-3 gene silencing between the parental and transformed urothelial cells are different. The goal of this study was to determine if epigenetic modifications control urothelial MT-3 gene expression and if regulation is altered by malignant transformation by Cd +2 or As +3 . For this purpose, the parent and the transformed cell lines were exposed to the histone deacetylase inhibitor MS-275 and RNA was isolated and subjected to RT-PCR. The results obtained showed that MS-275 induced MT-3 mRNA expression in both parental UROtsa cells and their transformed counterparts. Chromatin Immunoprecipitation analysis showed that the metal-responsive transcription factor-1 (MTF-1) binding to the metal response elements (MRE) of the MT-3 promoter was restricted in parental cells under basal conditions, but MTF-1 binding to the MREs was unrestricted in the transformed cell lines. Histone acetylation of H4 and trimethylation of H3K4, H3K9 and H3K27 were compared between the parental and transformed cells. These studies showed that there is a fundamental difference in the accessibility of the MRE elements to MTF-1 binding within the MT-3 promoter between the parental UROtsa SOT 2011 ANNUAL MEETING 427
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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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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: organic As to MMA(V) and a lower ca
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 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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