Publications by authors named "Ronald Herbert"

44 Publications

Cobalt-induced oxidative stress contributes to alveolar/bronchiolar carcinogenesis in B6C3F1/N mice.

Arch Toxicol 2021 Oct 1;95(10):3171-3190. Epub 2021 Sep 1.

Comparative and Molecular Pathogenesis Branch, DNTP, NIEHS, 111 T.W. Alexander Drive, Research Triangle Park, NC, 27709, USA.

Rodent alveolar/bronchiolar carcinomas (ABC) that arise either spontaneously or due to chemical exposure are similar to a subtype of lung adenocarcinomas in humans. B6C3F1/N mice and F344/NTac rats exposed to cobalt metal dust (CMD) by inhalation developed ABCs in a dose dependent manner. In CMD-exposed mice, the incidence of Kras mutations in ABCs was 67% with 80% of those being G to T transversions on codon 12 suggesting a role of oxidative stress in the pathogenesis. In vitro studies, such as DMPO (5,5-dimethyl-1-pyrroline N-oxide) immune-spin trapping assay, and dihydroethidium (DHE) fluorescence assay on A549 and BEAS-2B cells demonstrated increased oxidative stress due to cobalt exposure. In addition, significantly increased 8-oxo-dG adducts were demonstrated by immunohistochemistry in lungs from mice exposed to CMD for 90 days. Furthermore, transcriptomic analysis on ABCs arising spontaneously or due to chronic CMD-exposure demonstrated significant alterations in canonical pathways related to MAPK signaling (IL-8, ErbB, Integrin, and PAK pathway) and oxidative stress (PI3K/AKT and Melatonin pathway) in ABCs from CMD-exposed mice. Oxidative stress can stimulate PI3K/AKT and MAPK signaling pathways. Nox4 was significantly upregulated only in CMD-exposed ABCs and NOX4 activation of PI3K/AKT can lead to increased ROS levels in human cancer cells. The gene encoding Ereg was markedly up-regulated in CMD-exposed mice. Oncogenic KRAS mutations have been shown to induce EREG overexpression. Collectively, all these data suggest that oxidative stress plays a significant role in CMD-induced pulmonary carcinogenesis in rodents and these findings may also be relevant in the context of human lung cancers.
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http://dx.doi.org/10.1007/s00204-021-03146-5DOI Listing
October 2021

The Role of IgM Antibodies in T Cell Lymphoma Protection in a Novel Model Resembling Anaplastic Large Cell Lymphoma.

J Immunol 2021 05 21;206(10):2468-2477. Epub 2021 Apr 21.

Somatic Hypermutation Group, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC

MRL/lpr mice typically succumb to immune complex-mediated nephritis within the first year of life. However, MRL/lpr mice that only secrete IgM Abs because of activation-induced deaminase deficiency (AIDMRL/lpr mice) experienced a dramatic increase in survival. Further crossing of these mice to those incapable of making secretory IgM (μS mice) generated mice lacking any secreted Abs but with normal B cell receptors. Both strains revealed no kidney pathology, yet Ab-deficient mice still experienced high mortality. In this article, we report Ab-deficient MRL/lpr mice progressed to high-grade T cell lymphoma that can be reversed with injection of autoreactive IgM Abs or following adoptive transfer of IgM-secreting MRL/lpr B cells. Anti-nuclear Abs, particularly anti-dsDNA IgM Abs, exhibited tumor-killing activities against a murine T cell lymphoma cell line. Passive transfers of autoreactive IgM Abs into p53-deficient mice increased survival by delaying onset of T cell lymphoma. The lymphoma originated from a double-negative aberrant T cell population seen in MRL/lpr mice and most closely resembled human anaplastic large cell lymphoma. Combined, these results strongly implicate autoreactive IgM Abs in protection against T cell lymphoma.
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http://dx.doi.org/10.4049/jimmunol.2001279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113120PMC
May 2021

The mutational signature profile of known and suspected human carcinogens in mice.

Nat Genet 2020 11 28;52(11):1189-1197. Epub 2020 Sep 28.

Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

Epidemiological studies have identified many environmental agents that appear to significantly increase cancer risk in human populations. By analyzing tumor genomes from mice chronically exposed to 1 of 20 known or suspected human carcinogens, we reveal that most agents do not generate distinct mutational signatures or increase mutation burden, with most mutations, including driver mutations, resulting from tissue-specific endogenous processes. We identify signatures resulting from exposure to cobalt and vinylidene chloride and link distinct human signatures (SBS19 and SBS42) with 1,2,3-trichloropropane, a haloalkane and pollutant of drinking water, and find these and other signatures in human tumor genomes. We define the cross-species genomic landscape of tumors induced by an important compendium of agents with relevance to human health.
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http://dx.doi.org/10.1038/s41588-020-0692-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610456PMC
November 2020

Nonproliferative and Proliferative Lesions of the Rat and Mouse Hematolymphoid System.

Toxicol Pathol 2019 08;47(6):665-783

CM Keenan ToxPath Consulting, Doylestown, PA, USA.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.
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http://dx.doi.org/10.1177/0192623319867053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752743PMC
August 2019

Do GISTs Occur in Rats and Mice? Immunohistochemical Characterization of Gastrointestinal Tumors Diagnosed as Smooth Muscle Tumors in The National Toxicology Program.

Toxicol Pathol 2019 07 7;47(5):577-584. Epub 2019 May 7.

2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA.

The majority of the tumors in the gastrointestinal (GI) tract of rats and mice, with spindle cell morphology, are diagnosed as smooth muscle tumors (SMTs). Similarly, several decades ago human GI tumors with spindle cell morphology were also diagnosed as SMTs. However, later investigations identified most of these tumors in humans as gastrointestinal stromal tumors (GISTs). The GISTs are considered to arise from the interstitial cells of Cajal located throughout the GI tract. Positive immunohistochemical staining with CKIT antibody is a well-accepted diagnostic marker for GISTs in humans. Since there is a considerable overlap between the histomorphology of SMTs and GISTs, it is not possible to distinguish them on hematoxylin and eosin stained sections. As a result, GISTs are not routinely diagnosed in toxicological studies. The current study was designed to evaluate the tumors diagnosed as leiomyoma or leiomyosarcoma in the National Toxicology Program's 2-year bioassays using CKIT, smooth muscle actin, and desmin immunohistochemistry. The results demonstrate that most of the mouse SMTs diagnosed as leiomyoma or leiomyosarcoma are likely GISTs, whereas in rats the tumors are likely SMTs and not GISTs.
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http://dx.doi.org/10.1177/0192623319845838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836069PMC
July 2019

Immunohistochemistry in Investigative and Toxicologic Pathology.

Toxicol Pathol 2018 07 2;46(5):488-510. Epub 2018 Jul 2.

2 The Division of National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

Immunohistochemistry (IHC) is a valuable tool in pathology. This review provides a brief description of the technical aspects of IHC and a detailed discussion on the variables that affect the results, interpretation, and reproducibility of IHC results. Lists of antibodies that have and have not worked in IHC on various mouse and rat tissues in our laboratory are provided as a guidance for selection of antibodies. An approach to IHC method optimization is presented. Finally, the critical information that should be included as a part of peer-reviewed manuscript is also discussed.
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http://dx.doi.org/10.1177/0192623318776907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033701PMC
July 2018

Whole exome sequencing in the rat.

BMC Genomics 2018 Jun 20;19(1):487. Epub 2018 Jun 20.

Biomolecular Screening Branch, National Institute of Environmental Health Sciences, 111 T.W. Alexander Dr. Research Triangle Park, Durham, NC, USA.

Background: The rat genome was sequenced in 2004 with the aim to improve human health altered by disease and environmental influences through gene discovery and animal model validation. Here, we report development and testing of a probe set for whole exome sequencing (WES) to detect sequence variants in exons and UTRs of the rat genome. Using an in-silico approach, we designed probes targeting the rat exome and compared captured mutations in cancer-related genes from four chemically induced rat tumor cell lines (C6, FAT7, DSL-6A/C1, NBTII) to validated cancer genes in the human database, Catalogue of Somatic Mutations in Cancer (COSMIC) as well as normal rat DNA. Paired, fresh frozen (FF) and formalin-fixed, paraffin-embedded (FFPE) liver tissue from naive rats were sequenced to confirm known dbSNP variants and identify any additional variants.

Results: Informatics analysis of available gene annotation from rat RGSC6.0/rn6 RefSeq and Ensembl transcripts provided 223,636 unique exons representing a total of 26,365 unique genes and untranslated regions. Using this annotation and the Rn6 reference genome, an in-silico probe design generated 826,878 probe sequences of which 94.2% were uniquely aligned to the rat genome without mismatches. Further informatics analysis revealed 25,249 genes (95.8%) covered by at least one probe and 23,603 genes (93.5%) had every exon covered by one or more probes. We report high performance metrics from exome sequencing of our probe set and Sanger validation of annotated, highly relevant, cancer gene mutations as cataloged in the human COSMIC database, in addition to several exonic variants in cancer-related genes.

Conclusions: An in-silico probe set was designed to enrich the rat exome from isolated DNA. The platform was tested on rat tumor cell lines and normal FF and FFPE liver tissue. The method effectively captured target exome regions in the test DNA samples with exceptional sensitivity and specificity to obtain reliable sequencing data representing variants that are likely chemically induced somatic mutations. Genomic discovery conducted by means of high throughput WES queries should benefit investigators in discovering rat genomic variants in disease etiology and in furthering human translational research.
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http://dx.doi.org/10.1186/s12864-018-4858-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011395PMC
June 2018

Uterine Paramesonephric Cysts in Sprague-Dawley Rats from National Toxicology Program Studies.

Toxicol Pathol 2018 06 29;46(4):421-430. Epub 2018 Apr 29.

1 Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

Congenital uterine wall cysts arising from paramesonephric (Müllerian) and mesonephric (Wolffian) ducts are typically incidental findings in most species. We used immunohistochemistry to characterize and determine the origin of uterine cysts in Sprague-Dawley (SD) rats from multigeneration studies conducted by the National Toxicology Program. Subserosal uterine cysts were observed in 20 of the 2,400 SD rats evaluated in five studies, and 10 cysts were characterized for this study. Single cysts were unilocular, fluid-filled, and occurred throughout the uterus. Microscopically, all cysts had a well-developed smooth muscle wall, lined by flattened to cuboidal, sometimes ciliated, epithelium that stained intensely positive for cytokeratin 18 and paired box protein 8 (PAX8). Most cyst epithelia displayed weak to moderate positivity for progesterone receptor (PR) and/or estrogen receptor α (ER-α), as well as were negative for GATA binding protein 3 (GATA3). Cyst lumens contained basophilic flocculent material. The cysts appeared to be developmental anomalies arising from paramesonephric tissue based on positive PAX8 and ER-α and/or PR staining. Additionally, 70% of the cysts lacked GATA3 expression. Taken together, the subserosal uterine cysts observed in adult rats in these studies most likely arose from the paramesonephric duct.
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http://dx.doi.org/10.1177/0192623318772487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999558PMC
June 2018

Comparative pulmonary toxicity of inhaled metalworking fluids in rats and mice.

Toxicol Ind Health 2017 May 23;33(5):385-405. Epub 2016 Jun 23.

1 Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

Metalworking fluids (MWFs) are complex formulations designed for effective lubricating, cooling, and cleaning tools and parts during machining operations. Adverse health effects such as respiratory symptoms, dermatitis, and cancer have been reported in workers exposed to MWFs. Several constituents of MWFs have been implicated in toxicity and have been removed from the formulations over the years. However, animal studies with newer MWFs demonstrate that they continue to pose a health risk. This investigation examines the hypothesis that unrecognized health hazards exist in currently marketed MWF formulations that are presumed to be safe based on hazard assessments of individual ingredients. In vivo 13-week inhalation studies were designed to characterize and compare the potential toxicity of four MWFs: Trim VX, Cimstar 3800, Trim SC210, and Syntilo 1023. Male and female Wistar Han rats or Fischer 344N/Tac rats and B6C3F1/N mice were exposed to MWFs via whole-body inhalation at concentrations of 0, 25, 50, 100, 200, or 400 mg/m for 13 weeks, after which, survival, body and organ weights, hematology and clinical chemistry, histopathology, and genotoxicity were assessed following exposure. Although high concentrations were used, survival was not affected and toxicity was primarily within the respiratory tract of male and female rats and mice. Minor variances in toxicity were attributed to differences among species as well as in the chemical components of each MWF. Pulmonary fibrosis was present only in rats and mice exposed to Trim VX. These data confirm that newer MWFs have the potential to cause respiratory toxicity in workers who are repeatedly exposed via inhalation.
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http://dx.doi.org/10.1177/0748233716653912DOI Listing
May 2017

Recommendations from the INHAND Apoptosis/Necrosis Working Group.

Toxicol Pathol 2016 Feb 14;44(2):173-88. Epub 2016 Feb 14.

Envigo, East Millstone, New Jersey, USA.

Historically, there has been confusion relating to the diagnostic nomenclature for individual cell death. Toxicologic pathologists have generally used the terms "single cell necrosis" and "apoptosis" interchangeably. Increased research on the mechanisms of cell death in recent years has led to the understanding that apoptosis and necrosis involve different cellular pathways and that these differences can have important implications when considering overall mechanisms of toxicity, and, for these reasons, the separate terms of apoptosis and necrosis should be used whenever differentiation is possible. However, it is also recognized that differentiation of the precise pathway of cell death may not be important, necessary, or possible in routine toxicity studies and so a more general term to indicate cell death is warranted in these situations. Morphological distinction between these two forms of cell death can sometimes be straightforward but can also be challenging. This article provides a brief discussion of the cellular mechanisms and morphological features of apoptosis and necrosis as well as guidance on when the pathologist should use these terms. It provides recommended nomenclature along with diagnostic criteria (in hematoxylin and eosin [H&E]-stained sections) for the most common forms of cell death (apoptosis and necrosis). This document is intended to serve as current guidance for the nomenclature of cell death for the International Harmonization of Nomenclature and Diagnostic Criteria Organ Working Groups and the toxicologic pathology community at large. The specific recommendations are:Use necrosis and apoptosis as separate diagnostic terms.Use modifiers to denote the distribution of necrosis (e.g., necrosis, single cell; necrosis, focal; necrosis, diffuse; etc.).Use the combined term apoptosis/single cell necrosis whenThere is no requirement or need to split the processes, orWhen the nature of cell death cannot be determined with certainty, orWhen both processes are present together. The diagnosis should be based primarily on the morphological features in H&E-stained sections. When needed, additional, special techniques to identify and characterize apoptosis can also be used.
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http://dx.doi.org/10.1177/0192623315625859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785073PMC
February 2016

Hormone Receptor Expression in Spontaneous Uterine Adenocarcinoma in Fischer 344 Rats.

Toxicol Pathol 2015 Aug 7;43(6):865-71. Epub 2015 Jul 7.

Department of Pathology/Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA

Most uterine cancers, the most common gynecological malignancies in women in developed countries, are hormone-dependent endometrial adenocarcinomas (EACs) that express estrogen and progesterone receptors. Although rat strains exist with a high spontaneous incidence of EAC, the Fischer 344 (F344) strain, previously one of the most commonly used strains in carcinogenicity testing, is not a high-incidence strain. To better understand the biology of this neoplasm, we assessed estrogen receptor α (ER), progesterone receptor (PR), and Ki-67 expression using immunohistochemistry in spontaneous EAC in 18 F344 rats used as control animals in 2-year National Toxicology Program bioassays. Of the 18 tumors, 9 were well-differentiated and 9 were poorly differentiated. Most tumors, 7/18, were ER+PR+, as observed in women. Of the remainder, 6/18 were ER+PR-, 2/18 were ER-PR+, and 3/18 were ER-PR-. Well-differentiated tumors were ER+ (8/9) more often than poorly differentiated tumors (5/9). The percentage of ER+ tumors (72%) in rats was similar to that seen in women, but rats less frequently had PR+ (50%) tumors than women. The heterogeneous estrogen and progesterone receptor immunophenotypes observed in F344 rats in this study highlight the importance of evaluating hormone receptor expression in animal models used for chemical evaluations.
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http://dx.doi.org/10.1177/0192623315591839DOI Listing
August 2015

Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal.

Toxicol Pathol 2015 Aug 9;43(6):872-82. Epub 2015 Jun 9.

Cellular and Molecular Pathology Branch, Division of the National Toxicology Program (NTP), National Institute of Environmental Health Science (NIEHS), Research Triangle Park, North Carolina, USA Experimental Pathology Laboratories, Inc., Durham, North Carolina, USA

Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kirsten rat sarcoma oncogene homolog (Kras), epidermal growth factor receptor (Egfr), and tumor protein 53 (Tp53) mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD)-induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominant in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assay indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents.
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http://dx.doi.org/10.1177/0192623315581192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526332PMC
August 2015

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) progress to date and future plans.

J Toxicol Pathol 2015 Jan 10;28(1):51-3. Epub 2014 Nov 10.

Department of Pathology II, Kansai Medical University, Hirakata, Osaka, Japan.

The INHAND Proposal (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) has been operational since 2005. A Global Editorial Steering Committee (GESC) manages the overall objectives of the project and the development of harmonized terminology for each organ system is the responsibility of the Organ Working Groups (OWG), drawing upon experts from North America, Europe and Japan.Great progress has been made with 9 systems published to date - Respiratory, Hepatobiliary, Urinary, Central/Peripheral Nervous Systems, Male Reproductive and Mammary, Zymbals, Clitoral and Preputial Glands in Toxicologic Pathology and the Integument and Soft Tissue and Female Reproductive System in the Journal of Toxicologic Pathology as supplements and on a web site - www.goreni.org. INHAND nomenclature guides offer diagnostic criteria and guidelines for recording lesions observed in rodent toxicity and carcinogenicity studies. The guides provide representative photo-micrographs of morphologic changes, information regarding pathogenesis, and key references. During 2012, INHAND GESC representatives attended meetings with representatives of the FDA Center for Drug Evaluation and Research (CDER), Clinical Data Interchange Standards Consortium (CDISC), and the National Cancer Institute (NCI) Enterprise Vocabulary Services (EVS) to begin incorporation of INHAND terminology as preferred terminology for SEND (Standard for Exchange of Nonclinical Data) submissions to the FDA. The interest in utilizing the INHAND nomenclature, based on input from industry and government toxicologists as well as information technology specialists, suggests that there will be wide acceptance of this nomenclature. The purpose of this publication is to provide an update on the progress of INHAND.
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http://dx.doi.org/10.1293/tox.2014-0049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337500PMC
January 2015

Comparative toxicity and carcinogenicity of soluble and insoluble cobalt compounds.

Toxicology 2015 Jul 17;333:195-205. Epub 2015 Apr 17.

Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

Occupational exposure to cobalt is of widespread concern due to its use in a variety of industrial processes and the occurrence of occupational disease. Due to the lack of toxicity and carcinogenicity data following exposure to cobalt, and questions regarding bioavailability following exposure to different forms of cobalt, the NTP conducted two chronic inhalation exposure studies in rats and mice, one on soluble cobalt sulfate heptahydrate, and a more recent study on insoluble cobalt metal. Herein, we compare and contrast the toxicity profiles following whole-body inhalation exposures to these two forms of cobalt. In general, both forms were genotoxic in the Salmonella T98 strain in the absence of effects on micronuclei. The major sites of toxicity and carcinogenicity in both chronic inhalation studies were the respiratory tract in rats and mice, and the adrenal gland in rats. In addition, there were distinct sites of toxicity and carcinogenicity noted following exposure to cobalt metal. In rats, carcinogenicity was observed in the blood, and pancreas, and toxicity was observed in the testes of rats and mice. Taken together, these findings suggest that both forms of cobalt, soluble and insoluble, appear to be multi-site rodent carcinogens following inhalation exposure.
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http://dx.doi.org/10.1016/j.tox.2015.04.008DOI Listing
July 2015

Biomarkers of oxidative stress study VI. Endogenous plasma antioxidants fail as useful biomarkers of endotoxin-induced oxidative stress.

Free Radic Biol Med 2015 Apr 19;81:100-6. Epub 2015 Jan 19.

National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.

This is the newest report in a series of publications aiming to identify a blood-based antioxidant biomarker that could serve as an in vivo indicator of oxidative stress. The goal of the study was to test whether acutely exposing Göttingen mini pigs to the endotoxin lipopolysaccharide (LPS) results in a loss of antioxidants from plasma. We set as a criterion that a significant effect should be measured in plasma and seen at both doses and at more than one time point. Animals were injected with two doses of LPS at 2.5 and 5 µg/kg iv. Control plasma was collected from each animal before the LPS injection. After the LPS injection, plasma samples were collected at 2, 16, 48, and 72 h. Compared with the controls at the same time point, statistically significant losses were not found for either dose at multiple time points in any of the following potential markers: ascorbic acid, tocopherols (α, δ, γ), ratios of GSH/GSSG and cysteine/cystine, mixed disulfides, and total antioxidant capacity. However, uric acid, total GSH, and total Cys were significantly increased, probably because LPS had a harmful effect on the liver. The leakage of substances from damaged cells into the plasma may have increased plasma antioxidant concentrations, making changes difficult to interpret. Although this study used a mini-pig animal model of LPS-induced oxidative stress, it confirmed our previous findings in different rat models that measurement of antioxidants in plasma is not useful for the assessment of oxidative damage in vivo.
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http://dx.doi.org/10.1016/j.freeradbiomed.2015.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467900PMC
April 2015

Nonproliferative and proliferative lesions of the rat and mouse female reproductive system.

J Toxicol Pathol 2014 ;27(3-4 Suppl):1S-107S

National Institute of Health Sciences, Tokyo, Japan.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the female reproductive tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. There is also a section on normal cyclical changes observed in the ovary, uterus, cervix and vagina to compare normal physiological changes with pathological lesions. A widely accepted and utilized international harmonization of nomenclature for female reproductive tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.
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http://dx.doi.org/10.1293/tox.27.1SDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253081PMC
December 2014

Histopathological and Immunohistochemical Characterization of Methyl Eugenol-induced Nonneoplastic and Neoplastic Neuroendocrine Cell Lesions in Glandular Stomach of Rats.

Toxicol Pathol 2015 Jul 1;43(5):681-93. Epub 2014 Dec 1.

Cellular and Molecular Pathology Branch, Division of National Toxicology Program, Research Triangle Park, North Carolina, USA

Methyl eugenol induces neuroendocrine (NE) cell hyperplasia and tumors in F344/N rat stomach. Detailed histopathological and immunohistochemical (IHC) characterization of these tumors has not been previously reported. The objective of this study was to fill that data gap. Archived slides and paraffin blocks were retrieved from the National Toxicology Program Archives. NE hyperplasias and tumors were stained with chromogranin A, synaptophysin, amylase, gastrin, H(+)/K(+) adenosine triphosphatase (ATPase), pepsinogen, somatostatin, and cytokeratin 18 (CK18) antibodies. Many of the rats had gastric mucosal atrophy, due to loss of chief and parietal cells. The hyperplasias and tumors were confined to fundic stomach, and females were more affected than the males. Hyperplasia of NE cells was not observed in the pyloric region. Approximately one-third of the females with malignant NE tumors had areas of pancreatic acinar differentiation. The rate of metastasis was 21%, with liver being the most common site of metastasis. Immunohistochemically, the hyperplasias and tumors stained consistently with chromogranin A and synaptophysin. Neoplastic cells were also positive for amylase and CK18 and negative for gastrin, somatostatin, H(+)/K(+) ATPase, and pepsinogen. Metastatic neoplasms histologically similar to the primary neoplasm stained positively for chromogranin A and synaptophysin. Based on the histopathological and IHC features, the neoplasms appear to arise from enterochromaffin-like cells.
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http://dx.doi.org/10.1177/0192623314560030DOI Listing
July 2015

The National Toxicology Program Web-based nonneoplastic lesion atlas: a global toxicology and pathology resource.

Toxicol Pathol 2014 ;42(2):458-60

1Division of the National Toxicology Program, National Institute of Environmental Health Sciences, North Carolina, USA.

Toxicologists and pathologists worldwide will benefit from a new, website-based, and completely searchable Nonneoplastic Lesion Atlas just released by the U.S. National Toxicology Program (NTP). The atlas is a much-needed resource with thousands of high-quality, zoomable images and diagnostic guidelines for each rodent lesion. Liver, gallbladder, nervous system, bone marrow, lower urinary tract and skin lesion images, and diagnostic strategies are available now. More organ and biological systems will be added with a total of 22 chapters planned for the completed project. The atlas will be used by the NTP and its many pathology partners to standardize lesion diagnosis, terminology, and the way lesions are recorded. The goal is to improve our understanding of nonneoplastic lesions and the consistency and accuracy of their diagnosis between pathologists and laboratories. The atlas is also a useful training tool for pathology residents and can be used to bolster any organization's own lesion databases. Researchers have free access to this online resource at www.ntp.niehs.nih.gov/nonneoplastic.
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http://dx.doi.org/10.1177/0192623313517304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880752PMC
September 2014

Mechanistic insights from the NTP studies of chromium.

Toxicol Pathol 2013 Feb 18;41(2):326-42. Epub 2013 Jan 18.

Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.

Hexavalent chromium (Cr(VI)) is a contaminant of water and soil and is a human lung carcinogen. Trivalent chromium (Cr(III)), a proposed essential element, is ingested by humans in the diet and in dietary supplements such as chromium picolinate (CP). The National Toxicology Program (NTP) demonstrated that Cr(VI) is also carcinogenic in rodents when administered in drinking water as sodium dichromate dihydrate (SDD), inducing neoplasms of the oral cavity and small intestine in rats and mice, respectively. In contrast, there was no definitive evidence of toxicity or carcinogenicity following exposure to Cr(III) administered in feed as CP monohydrate (CPM). Cr(VI) readily enters cells via nonspecific anion channels, in contrast to Cr(III), which cannot easily pass through the cell membrane. Extracellular reduction of Cr(VI) to Cr(III), which occurs primarily in the stomach, is considered a mechanism of detoxification, while intracellular reduction is thought to be a mechanism of genotoxicity and carcinogenicity. Tissue distribution studies in additional groups of male rats and female mice demonstrated higher Cr concentrations in tissues following exposure to Cr(VI) compared to controls and Cr(III) exposure at a similar external dose, indicating that some of the Cr(VI) escaped gastric reduction and was distributed systemically. The multiple potential pathways of Cr-induced genotoxicity will be discussed.
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http://dx.doi.org/10.1177/0192623312469856DOI Listing
February 2013

Pyrogallol-associated dermal toxicity and carcinogenicity in F344/N rats and B6C3F1/N mice.

Cutan Ocul Toxicol 2013 Sep 11;32(3):234-40. Epub 2012 Dec 11.

National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.

Pyrogallol (CAS No. 87-66-1), a benzenetriol used historically as a hair dye and currently in a number of industrial applications, was nominated to the National Toxicology Program (NTP) for testing based on the lack of toxicity and carcinogenicity data. Three-month and two-year toxicity studies to determine the toxicity and carcinogenicity of pyrogallol when applied to naïve skin (i.e. dermal administration) were conducted in both sexes of F344/N rats and B6C3F1/N mice. In the three-month studies, adult rodents were administered pyrogallol in 95% ethanol five days per week for 3 months at doses of up to 150 mg/kg body weight (rats) or 600 mg/kg (mice). Based on the subchronic studies, the doses for the two-year studies in rats and mice were 5, 20 and 75 mg/kg of pyrogallol. All mice and most rats survived until the end of the three-month study and body weights were comparable to controls. During the two-year study, survival of dosed rats and male mice was comparable to controls; however survival of 75 mg/kg female mice significantly decreased compared to controls. The incidences of microscopic non-neoplastic lesions at the site of application were significantly higher in all dosed groups of rats and mice and in both the 3-months and two-year studies. In the two-year study, hyperplasia, hyperkeratosis and inflammation tended to be more severe in mice than in rats, and in the mice they tended to be more severe in females than in males. The incidence of squamous cell carcinoma at the site of application (SOA) in 75 mg/kg female mice and SOA squamous cell papillomas in 75 mg/kg male mice were greater than controls. Pyrogallol was carcinogenic in female mice and may have caused tumors in male mice.
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http://dx.doi.org/10.3109/15569527.2012.746358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637858PMC
September 2013

International harmonization of toxicologic pathology nomenclature: an overview and review of basic principles.

Toxicol Pathol 2012 Jun;40(4 Suppl):7S-13S

EPL Northwest, Seattle, Washington 98119, USA.

The International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice is a global project that is publishing criteria for both proliferative and nonproliferative changes in laboratory animals. This paper presents a set of general suggestions for terminology across systems. These suggestions include the use of diagnostic versus descriptive terms, modifiers, combination terms, and grading systems; and the use of thresholds, synonyms, and terminology for some processes that are common to several organ systems. The purpose of this paper is to help the reader understand some of the basic principles underlying the International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice process.
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http://dx.doi.org/10.1177/0192623312438738DOI Listing
June 2012

Histopathological evaluation of the nervous system in National Toxicology Program rodent studies: a modified approach.

Toxicol Pathol 2011 Apr 23;39(3):463-70. Epub 2011 Mar 23.

National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.

This article outlines the changes and underlying rationale for modifications to the histopathological evaluation of the nervous system during toxicology and carcinogenesis studies conducted by the National Toxicology Program (NTP). In the past, routine evaluation of the nervous system was mostly limited to three sections of brain, and occasionally the spinal cord and peripheral nerves. Factors such as the increasing occurrence of human neurological diseases and associated economical cost burden, the role of unidentified environmental stressors in neurodegenerative disorders, multiple therapeutic drug-induced neuropathies noted in human clinical trials, and the exponential use of environmental chemicals with unknown neurotoxic potential necessitate a more extensive evaluation of the nervous system. The NTP has modified its protocol to include examination of key anatomic subsites related to neurodegenerative diseases such as Parkinson's disease. Modifications include four additional sections of the brain. Increasing the number of brain sections permits examination of a greater number of specific anatomic subsites with unique vulnerability. In addition, the spinal cord, peripheral nerves, trigeminal ganglion, and intestinal autonomic ganglia will be evaluated as needed. It is expected that this modified approach will increase the sensitivity of detecting neurotoxicants and neurocarcinogens important in human neurologic and neurodegenerative disorders.
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http://dx.doi.org/10.1177/0192623311401044DOI Listing
April 2011

Effects of the PPARα Agonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism.

PPAR Res 2010 4;2010. Epub 2010 Oct 4.

National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Drive, Research Triangle Park, NC 27709, USA.

Gemfibrozil is a widely prescribed hypolipidemic agent in humans and a peroxisome proliferator and liver carcinogen in rats. Three-month feed studies of gemfibrozil were conducted by the National Toxicology Program (NTP) in male Harlan Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters, primarily to examine mechanisms of hepatocarcinogenicity. There was morphologic evidence of peroxisome proliferation in rats and mice. Increased hepatocyte proliferation was observed in rats, primarily at the earliest time point. Increases in peroxisomal enzyme activities were greatest in rats, intermediate in mice, and least in hamsters. These studies demonstrate that rats are most responsive while hamsters are least responsive. These events are causally related to hepatotoxicity and hepatocarcinogenicity of gemfibrozil in rodents via peroxisome proliferator activated receptor-α (PPARα) activation; however, there is widespread evidence that activation of PPARα in humans results in expression of genes involved in lipid metabolism, but not in hepatocellular proliferation.
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http://dx.doi.org/10.1155/2010/681963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952818PMC
July 2011

Mass in the lateral cervical-thoracic region in a male Wistar rat. Adenocarcinoma of the mammary gland.

Lab Anim (NY) 2009 Sep;38(9):288-91

International Institute of Biotechnology and Toxicology, Kancheepuram District, Tamil Nadu, India.

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http://dx.doi.org/10.1038/laban0909-288DOI Listing
September 2009

Hexavalent chromium is carcinogenic to F344/N rats and B6C3F1 mice after chronic oral exposure.

Environ Health Perspect 2009 May 31;117(5):716-22. Epub 2008 Dec 31.

National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709 , USA.

Background: Hexavalent chromium [Cr(VI)] is a human carcinogen after inhalation exposure. Humans also ingest Cr(VI) from contaminated drinking water and soil; however, limited data exist on the oral toxicity and carcinogenicity of Cr(VI).

Objective: We characterized the chronic oral toxicity and carcinogenicity of Cr(VI) in rodents.

Methods: The National Toxicology Program (NTP) conducted 2-year drinking water studies of Cr(VI) (as sodium dichromate dihydrate) in male and female F344/N rats and B6C3F1 mice.

Results: Cr(VI) exposure resulted in increased incidences of rare neoplasms of the squamous epithelium that lines the oral cavity (oral mucosa and tongue) in male and female rats, and of the epithelium lining the small intestine in male and female mice. Cr(VI) exposure did not affect survival but resulted in reduced mean body weights and water consumption, due at least in part to poor palatability of the dosed water. Cr(VI) exposure resulted in transient microcytic hypochromic anemia in rats and microcytosis in mice. Nonneoplastic lesions included diffuse epithelial hyperplasia in the duodenum and jejunum of mice and histiocytic cell infiltration in the duodenum, liver, and mesenteric and pancreatic lymph nodes of rats and mice.

Conclusions: Cr(VI) was carcinogenic after administration in drinking water to male and female rats and mice.
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http://dx.doi.org/10.1289/ehp.0800208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2685832PMC
May 2009

Glis3 is associated with primary cilia and Wwtr1/TAZ and implicated in polycystic kidney disease.

Mol Cell Biol 2009 May 9;29(10):2556-69. Epub 2009 Mar 9.

LRB, Cell Biology Section, Division of Intramural Research, National Institutes of Health, Research Triangle Park, NC 27709, USA.

In this study, we describe the generation and partial characterization of Krüppel-like zinc finger protein Glis3 mutant (Glis3(zf/zf)) mice. These mice display abnormalities very similar to those of patients with neonatal diabetes and hypothyroidism syndrome, including the development of diabetes and polycystic kidney disease. We demonstrate that Glis3 localizes to the primary cilium, suggesting that Glis3 is part of a cilium-associated signaling pathway. Although Glis3(zf/zf) mice form normal primary cilia, renal cysts contain relatively fewer cells with a primary cilium. We further show that Glis3 interacts with the transcriptional modulator Wwtr1/TAZ, which itself has been implicated in glomerulocystic kidney disease. Wwtr1 recognizes a P/LPXY motif in the C terminus of Glis3 and enhances Glis3-mediated transcriptional activation, indicating that Wwtr1 functions as a coactivator of Glis3. Mutations in the P/LPXY motif abrogate the interaction with Wwtr1 and the transcriptional activity of Glis3, indicating that this motif is part of the transcription activation domain of Glis3. Our study demonstrates that dysfunction of Glis3 leads to the development of cystic renal disease, suggesting that Glis3 plays a critical role in maintaining normal renal functions. We propose that localization to the primary cilium and interaction with Wwtr1 are key elements of the Glis3 signaling pathway.
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http://dx.doi.org/10.1128/MCB.01620-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682055PMC
May 2009

Evaluation of dichloroacetic acid for carcinogenicity in genetically modified Tg.AC hemizygous and p53 haploinsufficient mice.

Toxicol Sci 2009 Jan 30;107(1):19-26. Epub 2008 Oct 30.

Environmental Diseases and Medicine Program, Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709, USA.

There has been considerable interest in the use of genetically modified mice for detecting potential environmental carcinogens. For this reason, the National Toxicology Program has been evaluating Tg.AC hemizygous and p53 haploinsufficient mice as models to detect potential carcinogens. It was reasoned that these mouse models might also prove more effective than standard rodent models in evaluating the numerous disinfection byproducts that are found in low concentrations in drinking water. Dichloroacetic acid (DCA) is one of the most frequently found disinfection byproducts and DCA has been consistently shown to cause hepatocellular tumors in rats and mice in standard rodent studies. Tg.AC hemizygous and p53 haploinsufficient mice were exposed in the drinking water to DCA for up to 41 weeks. In a second study Tg.AC mice were subjected to dermal DCA exposure for up to 39 weeks. Increased incidences and severity of cytoplasmic vacuolization of hepatocytes were seen in the p53 mice, but there was no evidence of carcinogenic activity at exposures of up to 2000 mg/l in the drinking water. Increased incidences and severity of cytoplasmic vacuolization of hepatocytes were seen in the drinking water study with Tg.AC mice and a modest non-dose-related increase in pulmonary adenomas was observed in males exposed to 1000 mg/l in the drinking water. Dermal exposure up to 500 mg/kg for 39 weeks resulted in increased dermal papillomas at the site of application in Tg.AC mice. No significant increase in papillomas under the same study conditions was seen in the 26-week study. For DCA under these study conditions, the p53 and Tg.AC mice appear less sensitive to hepatocarcinogenesis than standard rodent models. These results suggest caution for the use of Tg.AC and p53 mice to screen unknown chemicals in drinking water for potential carcinogenicity.
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http://dx.doi.org/10.1093/toxsci/kfn228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2638641PMC
January 2009

Influence of Helicobacter hepaticus infection on the chronic toxicity and carcinogenicity of triethanolamine in B6C3F1 mice.

Toxicol Pathol 2008 Oct 23;36(6):783-94. Epub 2008 Sep 23.

National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.

Helicobacter hepaticus (H. hepaticus) infection causes hepatitis and increased hepatocellular neoplasms in male mice; although females are also infected, liver lesions are not typically expressed. In the 1990s, B6C3F1 mice from some chronic National Toxicology Program (NTP) studies were found to be infected with H. hepaticus. In these studies, there was hepatitis in many of the males, and there were more hepatocellular neoplasms in control males compared to studies with uninfected mice. In one of these studies, increased hepatocellular neoplasms at the high doses in male and female mice exposed topically to triethanolamine (TEA) provided the only evidence of carcinogenic activity. This study was repeated in mice free of H. hepaticus.However, the NTP mouse production colony and the diet differed between studies; these differences were the result of NTP programmatic decisions. In repeat study males, although control incidences were similar between studies, exposure did not result in increased hepatocellular neoplasms. In repeat study females, the control incidence of hepatocellular neoplasms was half that observed in the initial study, and these neoplasms were increased over controls at all doses. These data suggest that in the initial study, H. hepaticusinfluenced the induction of hepatocellular neoplasms in males, but not in females.
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http://dx.doi.org/10.1177/0192623308322312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719836PMC
October 2008

Brain lesion in a Wistar rat. Encephalitozoonosis.

Lab Anim (NY) 2008 Sep;37(9):401-4

Department of Pathology, International Institute of Biotechnology and Toxicology, Padappai 601301, Kancheepuram District, Tamil Nadu, India.

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http://dx.doi.org/10.1038/laban0908-401DOI Listing
September 2008
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