Douglas C Wolf

Publications (111) View all

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  Available from: Douglas C Wolf

  Article: Transcriptional Modulation of the ERK1/2 MAPK and NF-κB Pathways in Human Urothelial Cells After Trivalent Arsenical Exposure: Implications for Urinary Bladder Cancer.

  Kathryn A Bailey, Kathleen Wallace, Lisa Smeester, Sheau-Fung Thai, Douglas C Wolf, Stephen W Edwards, Rebecca C Fry
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  ABSTRACT: Chronic exposure to drinking water contaminated with inorganic arsenic (iAs) is associated with an increased risk of urinary bladder (UB) cancers in humans. The exact role of specific iAs metabolite(s) in As-mediated carcinogenesis remains largely unknown. Experimental evidence suggests that trivalent arsenicals, namely arsenite (iAs(III)) and two of its metabolites, monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)), are possible proximate UB carcinogens. Here, we used a transcriptomics approach to examine perturbed molecular pathways in a human urothelial cell line (UROtsa) after short-term exposure to iAs(III), MMA(III) and DMA(III). Molecular pathways containing genes that encode proteins implicated in UB cancer development were perturbed by both MMA(III) and DMA(III). These pathways included those of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK 1/2 MAPK) and nuclear factor kappa beta (NF-κB). Together, these results may inform the current understanding of effects in the UB induced by acute As exposure and the relationship of these effects with As-mediated carcinogenesis.
  Journal of cancer research updates. 08/2012; 1:57-68.
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  Article: Identification and characterization of adverse effects in 21st century toxicology.

  Douglas A Keller, Daland R Juberg, Natasha Catlin, William H Farland, Frederick G Hess, Douglas C Wolf, Nancy G Doerrer
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  ABSTRACT: The practice of toxicology is changing rapidly, as demonstrated by the response to the 2007 NRC report on "Toxicity Testing in the 21(st) Century." New assays are being developed to replace animal testing; yet the use of data from these assays in decision making is not clear. A Health and Environmental Sciences Institute committee held a May 2011 workshop to discuss approaches to identifying adverse effects in the context of the NRC report. Scientists from industry, government, academia, and NGOs discussed two case studies and explored how information from new, high data content assays developed for screening can be used to differentiate adverse effects from adaptive responses. The terms "adverse effect" and "adaptive response" were defined, as well as two new terms, the relevant pathways of toxicological concern (RPTCs) and relevant responses for regulation (RRRs). RPTCs are biochemical pathways associated with adverse events and need to be elucidated before they are used in regulatory decision making. RRRs are endpoints that are the basis for risk assessment and may or may not be at the level of pathways. Workshop participants discussed the criteria for determining whether, at the RPTC level, an effect is potentially adverse or potentially indicative of adaptability, and how the use of prototypical, data-rich compounds could lead to a greater understanding of RPTCs and their use as RRRs. Also discussed was the use of RPTCs in a weight-of-evidence approach to risk assessment. Inclusion of data at this level could decrease uncertainty in risk assessments but will require the use of detailed dosimetry and consideration of exposure context and the time and dose continuum to yield scientifically based decisions. The results of this project point to the need for an extensive effort to characterize RPTCs and their use in risk assessment to make the vision of the 2007 NRC report a reality.
  Toxicological Sciences 01/2012; 126(2):291-7. · 4.65 Impact Factor
• Chapter: Toxicogenomics and the Regulatory Framework

  Kathryn Gallagher, Federico M. Goodsaid, David J. Dix, Susan Y. Euling, Melissa Kramer, Nancy E. McCarroll, Julian R. Preston, Philip G. Sayre, Banalata Sen, Douglas C. Wolf, William H. Benson
  07/2011: pages 293 - 321; , ISBN: 9781118001042
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  Article: Transcriptional profile of diuron-induced toxicity on the urinary bladder of male Wistar rats to inform mode of action.

  Shadia M Ihlaseh, Kathryn A Bailey, Susan D Hester, Carlton Jones, Hongzu Ren, Ana Paula F Cardoso, Maria Luiza C S Oliveira, Douglas C Wolf, João Lauro V de Camargo
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  ABSTRACT: Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a substituted urea herbicide that induces rat urinary bladder urothelial tumors at high dietary levels (2500 ppm). The specific mode of action and molecular alterations triggered by diuron, however, have not been clarified. The present study evaluated the dose-dependent effects of mucosal alterations and transcriptional changes in the urinary bladder of rats exposed to diuron. Six-week-old male Wistar rats were treated with 0, 60, 125, 1250, and 2500 ppm of diuron in the diet for 20 weeks. Histologic examination showed urothelial hyperplasia present in rats treated with either 1250 or 2500 ppm of diuron but not 60 or 125 ppm. Comprehensive gene expression analyses of urothelial cell RNA were conducted using Affymetrix microarrays. The numbers of differentially expressed transcripts between each treatment group and control increased with diuron dose. Based on similar histology and gene expression responses, the treatment groups were regrouped into a high-dose (1250 and 2500 ppm) and low-dose group (60 and 125 ppm). These data suggest that persistent exposure to high dietary concentrations of diuron induces oxidative stress, increases cellular metabolism, and enhances cell death that is associated with sustained urothelial hyperplasia.
  Toxicological Sciences 05/2011; 122(2):330-8. · 4.65 Impact Factor
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  Article: Pathology peer review.

  Gary A Boorman, Douglas C Wolf, Sabine Francke-Carroll, Robert R Maronpot
  Toxicologic Pathology 12/2010; 38(7):1009-10. · 1.91 Impact Factor