MedWorm: Pathology

Drug delivery systems.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Drug delivery systems.

Toxicol Pathol. 2008;36(1):16-20

Authors: Mathiowitz E

PMID: 18337217 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

MedWorm Sponsored Message: Read news and analysis about clinical lab software and the clinical lab industry at the most widely read lab blog - Lab Soft News.

Liposomal nanomedicines: an emerging field.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Liposomal nanomedicines: an emerging field.

Toxicol Pathol. 2008;36(1):21-9

Authors: Fenske DB, Chonn A, Cullis PR

Liposomal nanoparticles (LNs) encapsulating therapeutic agents, or liposomal nanomedicines (LNMs), represent one of the most advanced classes of drug delivery systems, with several currently on the market and many more in clinical trials. During the past 20 years, a variety of techniques have been developed for encapsulating both conventional drugs and the new genetic drugs (plasmid DNA-containing therapeutic genes, antisense oligonucleotides, and small, interfering RNA [siRNA]) within LNs encompassing a very specific set of properties: a diameter centered on 100 nm, a high drug-to-lipid ratio, excellent retention of the encapsulated drug, and a long (>6 hours) circulation lifetime. Particles with these properties tend to accumulate at sites of disease, such as tumors, where the endothelial layer is "leaky" and allows extravasation of particles with small diameters. Thus, LNs protect the drug during circulation, prevent it from reaching healthy tissues, and permit its accumulation at sites of disease. We will discuss recent advances in this field involving conventional anticancer drugs as well as gene-delivery, immunostimulatory, and gene-silencing applications involving the new genetic drugs. LNMs have the potential to offer new treatments in such areas as cancer therapy, vaccine development, and cholesterol management.

PMID: 18337218 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Cyclodextrins.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Cyclodextrins.

Toxicol Pathol. 2008;36(1):30-42

Authors: Stella VJ, He Q

beta-cyclodextrin (beta-CD) and other cyclodextrins (CDs) have utility for solubilizing and stabilizing drugs; however, some are nephrotoxic when administered parenterally. A number of workers have attempted to identify, prepare, and evaluate various CD derivatives with superior inclusion complexation and maximal in vivo safety for various biomedical uses. A systematic study led to SBE-beta-CD (Captisol), a polyanionic variably substituted sulfobutyl ether of beta-CD, as a non-nephrotoxic derivative and HP-beta-CD, a modified CD developed by Janssen. SBE-beta-CD and HP-beta-CD have undergone extensive safety studies and are currently used in six products approved by the Food and Drug Administration (four for Captisol and two for HP-beta-CD). They are also in use in numerous clinical and preclinical studies. This article will focus on the issues that led to the development of these two CDs, their safety, characterization, and applications, and especially their ability to improve drug delivery. SBE-beta-CD interacts very well with neutral drugs to facilitate solubility and chemical stability, and because of its polyanionic nature, it interacts particularly well with cationic drugs. Complexes between SBE-beta-CD and HP-beta-CD and various drugs have been shown to rapidly dissociate after parenteral drug administration, to have no tissue-irritating effects after intramuscular dosing, and to result in superior oral bioavailability of poorly water-soluble drugs. The pharmacokinetics, tissue distribution, and cellular effects of some representative CDs, including SBE-beta-CD and HP-beta-CD, are reviewed. The safety profiles of CDs are discussed, with emphasis on the biological effects of some CDs on the gastrointestinal tract, kidney, and reproduction and development and the carcinogenic potential of CDs. In addition, human experience with CD derivatives, specifically SBE-beta-CD and HP-beta-CD, indicates that these two CDs are well tolerated in humans and have no adverse effects on the kidneys or other organs following either oral or intravenous administration.

PMID: 18337219 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Drug nanoparticles: formulating poorly water-soluble compounds.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Drug nanoparticles: formulating poorly water-soluble compounds.

Toxicol Pathol. 2008;36(1):43-8

Authors: Merisko-Liversidge EM, Liversidge GG

More than 40% of compounds identified through combinatorial screening programs are poorly soluble in water. These molecules are difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues. Formulating these compounds as pure drug nanoparticles is one of the newer drug-delivery strategies applied to this class of molecules. Nanoparticle dispersions are stable and have a mean diameter of less than 1 micron. The formulations consist of water, drug, and one or more generally regarded as safe excipients. These liquid dispersions exhibit an acceptable shelf-life and can be postprocessed into various types of solid dosage forms. Drug nanoparticles have been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. Suitable formulations for the most commonly used routes of administration can be identified with milligram quantities of drug substance, providing the discovery scientist with an alternate avenue for screening and identifying superior analogs. For the toxicologist, the approach provides a means for dose escalation using a formulation that is commercially viable. In the past few years, formulating poorly water-soluble compounds using a nanoparticulate approach has evolved from a conception to a realization whose versatility and applicability are just beginning to be realized.

PMID: 18337220 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Safety evaluation of ocular drug delivery formulations: techniques and practical considerations.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Safety evaluation of ocular drug delivery formulations: techniques and practical considerations.

Toxicol Pathol. 2008;36(1):49-62

Authors: Short BG

Development of new drug candidates and novel delivery techniques for treatment of ocular diseases has recently accelerated. Treatment of anterior-segment diseases has witnessed advances in prodrug formulations and permeability enhancers. Intravitreal, subconjunctival, and periocular routes of administration and sustained-release formulations of nanoparticles and microparticles, as well as nonbiodegradable and biodegradable implants to deliver drugs to the posterior segment of the eye, are becoming popular therapeutic approaches. Without adequate regulatory guidance for ocular drugs, such routes of administration and novel formulations can pose unique challenges to those involved in designing nonclinical programs, including considering clinical and nonclinical factors and choosing species, strains, and ocular toxicity parameters. Toxicologic pathologists also contribute practical experience to evaluating morphological effects of these novel formulations. Lastly, understanding species' anatomical differences is useful for interpreting toxicological and pathological responses to the eye and is important for human risk assessment of these important new therapies for ocular diseases.

PMID: 18337221 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Medical device regulations and testing for toxicologic pathologists.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Medical device regulations and testing for toxicologic pathologists.

Toxicol Pathol. 2008;36(1):63-9

Authors: Schuh JC

Awareness of the regulatory environment is fundamental to understanding the biological assessment of biomaterials and medical devices. Medical devices are a diverse and heterogeneous group of medical products and technologies defined by the lack of chemical action or requirement for metabolism. Regional activity and the Global Harmonization Task Force are now working on harmonizing the categorization and testing of medical devices. The International Organization for Standardization (ISO) has published 19 standards for biological evaluation. ISO 10993 standards are generally accepted outright or as an alternative to most national regulatory directives or acts, although Japan and the United States require more stringency in some tests. Type of materials, intended use, and risk are the basis for drafting testing programs for biomaterials and medical devices. With growth of the medical device industry and advent of new biomaterials and technologies, the need for toxicologic pathologists in safety (biocompatibility) and efficacy (conditions of use) evaluation of moderate- to high-risk devices is expanding. Preclinical evaluation of biomaterials and medical devices increasingly requires a basic understanding of materials science and bioengineering to facilitate interpretation of complex interface reactions between biomaterials, cellular and secretory factors, and vascular and tissue responses that modulate success or failure of medical devices.

PMID: 18337222 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

MedWorm Sponsored Message: Read news and analysis about clinical lab software and the clinical lab industry at the most widely read lab blog - Lab Soft News.

Biocompatibility: meeting a key functional requirement of next-generation medical devices.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Biocompatibility: meeting a key functional requirement of next-generation medical devices.

Toxicol Pathol. 2008;36(1):70-80

Authors: Helmus MN, Gibbons DF, Cebon D

The array of polymeric, biologic, metallic, and ceramic biomaterials will be reviewed with respect to their biocompatibility, which has traditionally been viewed as a requirement to develop a safe medical device. With the emergence of combination products, a paradigm shift is occurring that now requires biocompatibility to be designed into the device. In fact, next-generation medical devices will require enhanced biocompatibility by using, for example, pharmacological agents, bioactive coatings, nano-textures, or hybrid systems containing cells that control biologic interactions to have desirable biologic outcomes. The concept of biocompatibility is moving from a "do no harm" mission (i.e., nontoxic, nonantigenic, nonmutagenic, etc.) to one of doing "good," that is, encouraging positive healing responses. These new devices will promote the formation of normal healthy tissue as well as the integration of the device into adjacent tissue. In some contexts, biocompatibility can become a disruptive technology that can change therapeutic paradigms (e.g., drug-coated stents). New database tools to access biocompatibility data of the materials of construction in existing medical devices will facilitate the use of existing and new biomaterials for new medical device designs.

PMID: 18337223 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Preparation of medical devices for evaluation.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Preparation of medical devices for evaluation.

Toxicol Pathol. 2008;36(1):81-4

Authors: Rousselle S, Wicks J

Preparing and processing medical device implants for evaluation is a relatively high-risk and high-dollar process in which studies get made and endpoints can be lost with no second chance. It is important to customize every aspect of the preparation process to the type of device and the study endpoints. Some standard and proven approaches for a few types of implants are discussed, addressing fixation, special dissection and extraction techniques, preprocessing imaging, trimming techniques, sample processing, embedding media, and cutting and staining options.

PMID: 18337224 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Medical devices in orthopedic applications.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Medical devices in orthopedic applications.

Toxicol Pathol. 2008;36(1):85-91

Authors: Long PH

Orthopedic medical devices have been extremely successful in restoring mobility, reducing pain, and improving the quality of life for millions of individuals each year. Their success is reflected in the worldwide biomaterials market, in which orthopedic devices dominated sales at approximately $14 billion in 2002. Of this, approximately $12 billion was spent on joint replacements. In spite of their overwhelming benefits and successes, orthopedic medical devices are not without risk of adverse effects. Most adverse joint replacement outcomes are thought to be mediated by degradation products generated by wear and electrochemical corrosion. Infection and flaws in device manufacturing are other noteworthy causes of orthopedic device failure. This article illustrates and discusses the uses, general properties, and limitations (including adverse outcomes) of orthopedic biomaterials, which are fundamental to understanding requirements for improving current orthopedic medical devices.

PMID: 18337225 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Tissue engineering and regenerative medicine: role of toxicologic pathologists for an emerging medical technology.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Tissue engineering and regenerative medicine: role of toxicologic pathologists for an emerging medical technology.

Toxicol Pathol. 2008;36(1):92-6

Authors: Jayo MJ, Watson DD, Wagner BJ, Bertram TA

Tissue Engineering Regenerative Medical (TERM) products are a new technology currently in human clinical testing for a variety of unmet medical needs involving tissue and organ dysfunction and failure. Safety evaluation of TERM products overlaps 3 established product paradigms: pharmaceuticals (biologically active substances), transplantation (cells or tissue), and devices (biomaterials). As TERM products recapitulate organ or tissue structure and function with unique biological activity and characteristics, they require new preclinical paradigms to bring TERM products through to clinical trials. Establishing TERM-product safety programs requires broad-based knowledge of tissue and organ homeostasis, regenerative biology, and translational medicine to design new preclinical paradigms. Therefore, toxicologic pathologists have a compelling scientific role in evaluating TERM products, characterizing tissue responses, and helping distinguish optimal (regeneration) from deficient or incomplete outcomes indicative of substandard functionality (repair). As new-tissue engineering and regenerative medical technologies develop for tissue and organ regeneration, the toxicologic pathologist will be asked to develop novel testing, reevaluate established toxicologic diagnostic criteria, and reinterpret tissue responses that may extend beyond current standards.

PMID: 18337226 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Gene therapy: some history, applications, problems, and prospects.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Gene therapy: some history, applications, problems, and prospects.

Toxicol Pathol. 2008;36(1):97-103

Authors: Cotrim AP, Baum BJ

The concept of transferring genes to tissues for clinical applications has been discussed for nearly half a century, but our ability to manipulate genetic material via recombinant DNA technology has brought this goal to reality. While originally conceived as a way to treat life-threatening disorders (inborn errors, cancers) refractory to conventional treatment, gene therapy now is considered for many non-life-threatening conditions, including those adversely affecting a patient's quality of life. The lack of suitable treatment has become a rational basis for extending the scope of gene therapy. This manuscript reviews the general methods by which genes are transferred as well as diverse examples of clinical applications (acquired tissue damage, upper gastrointestinal tract infection, autoimmune disease, systemic protein deficiency). Despite some well-publicized problems, gene therapy has made substantive progress, including tangible success, albeit much slower than was initially predicted. Although gene therapy is still at a fairly primitive stage, it is firmly science based. There is justifiable optimism that with increased pathobiological understanding and biotechnological improvements, gene therapy will become a standard part of clinical practice within 20 years.

PMID: 18337227 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

MedWorm Sponsored Message: Read news and analysis about clinical lab software and the clinical lab industry at the most widely read lab blog - Lab Soft News.

An approach to achieve long-term expression in skin gene therapy.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

An approach to achieve long-term expression in skin gene therapy.

Toxicol Pathol. 2008;36(1):104-11

Authors: Therrien JP, Pfützner W, Vogel JC

For gene therapy purposes, the skin is an attractive organ to target for systemic delivery of therapeutic proteins to treat systemic diseases, skin diseases, or skin cancer. To achieve long-term stable expression of a therapeutic gene in keratinocytes (KC), we have developed an approach using a bicistronic retroviral vector expressing the desired therapeutic gene linked to a selectable marker (multidrug resistant gene, MDR) that is then introduced into KC and fibroblasts (FB) to create genetically modified human skin equivalent (HSE). After grafting the HSE onto immunocompromised mice, topical colchicine treatment is used to select and enrich for genetically modified keratinocyte stem cells (KSC) that express MDR and are resistant to colchicine's antimitotic effects. Both the apparatus for topical colchicine delivery and the colchicine doses have been optimized for application to human skin. This approach can be validated by systemic delivery of therapeutic factors such as erythropoietin and the antihypertensive atrial natriuretic peptide.

PMID: 18337228 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

The application of fluorescent quantum dots to confocal, multiphoton, and electron microscopic imaging.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

The application of fluorescent quantum dots to confocal, multiphoton, and electron microscopic imaging.

Toxicol Pathol. 2008;36(1):112-6

Authors: Deerinck TJ

Fluorescent quantum dots are emerging as an important tool for imaging cells and tissues, and their unique optical and physical properties have captured the attention of the research community. The most common types of commercially available quantum dots consist of a nanocrystalline semiconductor core composed of cadmium selenide with a zinc sulfide capping layer and an outer polymer layer to facilitate conjugation to targeting biomolecules such as immunoglobulins. They exhibit high fluorescent quantum yields and have large absorption cross-sections, possess excellent photostability, and can be synthesized so that their narrow-band fluorescence emission can occur in a wide spectrum of colors. These properties make them excellent candidates for serving as multiplexing molecular beacons using a variety of imaging modalities including highly correlated microscopies. Whereas much attention has been focused on quantum-dot applications for live-cell imaging, we have sought to characterize and exploit their utility for enabling simultaneous multiprotein immunolabeling in fixed cells and tissues. Considerations for their application to immunolabeling for correlated light and electron microscopic analysis are discussed.

PMID: 18337229 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Applications of laser scanning cytometry in immunohistochemistry and routine histopathology.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Applications of laser scanning cytometry in immunohistochemistry and routine histopathology.

Toxicol Pathol. 2008;36(1):117-32

Authors: Peterson RA, Krull DL, Butler L

Laser scanning cytometry (LSC) is a powerful tool for qualitative and quantitative analysis of tissue sections in preclinical drug development. LSC combines the strengths of flow cytometry with tissue architecture retention. This technology has been used predominantly with immunofluorescent techniques on cell culture and tissue sections, but recently LSC has shown promise in evaluating chromogenic immunohistochemistry (IHC) and histochemical products in paraffin-embedded and/or frozen tissue sections. Inverted light scatter measurements or a combination of inverted scatter and fluorescence allows automated determination of cell/nuclear counts (e.g., proliferation labeling indices), cell area (e.g., cellular hypertrophy), stromal elements, and labeling intensity (e.g., cytoplasmic/organellar proteins) in chromogen-labeled IHC or histochemical stained sections that correlates well with standard manual quantification methods. Segmentation with autofluorescence or dual immunolabeling facilitates capture of labeling data from specific cell populations. LSC evaluation of HE-stained sections is accomplished using autofluorescence/eosin fluorescence and inverse scatter. A standardized fluorescent approach with archivability, a lack of fluorescence quenching (photobleaching), and amenability to evaluation of multiple markers in a section has been demonstrated using Qdot nanocrystals. Examples of LSC use in chromogenic IHC, routine histopathology, and Qdot labeling will be reviewed, and advantages and disadvantages of this technology will be discussed.

PMID: 18337230 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Pharmacodynamic monitoring of molecular-targeted agents in the peripheral blood of leukemia patients using flow cytometry.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Pharmacodynamic monitoring of molecular-targeted agents in the peripheral blood of leukemia patients using flow cytometry.

Toxicol Pathol. 2008;36(1):133-9

Authors: Hedley DW, Chow S, Goolsby C, Shankey TV

The introduction of specific, molecular-targeted drugs is radically changing cancer treatment. Pharmacodynamics, which measures drug effects on the host, is key during early-phase clinical trials of novel agents to determine the relations between drug dose and target inhibition as well as measure the downstream effects of target inhibition on the cancer. In this article, we describe the application of flow cytometry to the pharmacodynamic monitoring of molecular-targeted agents in leukemia patients. The methods are based on current clinical flow-cytometry applications, with the addition of phosphospecific antibodies to measure the activation states of intracellular signaling elements and the introduction of techniques that maintain drug-target equilibrium during sample preparation. Using this approach, we successfully showed dose-dependent inhibition of c-Kit during a phase I clinical trial treating acute leukemia patients with the novel agent sorafenib. Further refinements identify considerable interpatient variation in signaling activity within leukemic blast populations, suggesting that an individualized approach to treatment based on flow cytometric monitoring might be advantageous. Improvements in sample turnaround offer the potential to introduce real-time pharmacodynamic monitoring during early-phase clinical trials.

PMID: 18337231 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Metabolic profiling as a tool for understanding mechanisms of toxicity.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Metabolic profiling as a tool for understanding mechanisms of toxicity.

Toxicol Pathol. 2008;36(1):140-7

Authors: Clarke CJ, Haselden JN

Metabolic profiling (metabolomics/metabonomics) is the measurement in biological systems of the complement of low-molecular-weight metabolites and their intermediates that reflects the dynamic response to genetic modification and physiological, pathophysiological, and/or developmental stimuli. The measurement and interpretation of the endogenous metabolite profile from a biological sample (typically urine, serum, or biological tissue extract) have provided many opportunities to investigate the changes induced by external stimuli (e.g., drug treatment) or enhance our knowledge of inherent biological variation within subpopulations. This article will focus on the basic principles of metabolic profiling and how the tools (nuclear magnetic resonance [NMR], liquid chromatography-mass spectrometry [LC-MS]) can be applied in toxicology and pathology. Metabolic profiling can complement conventional methodologies and other "omics" technologies in investigating preclinical drug development issues. Case studies will illustrate the value of metabolic profiling in improving our understanding of phospholipidosis and peroxisome proliferation. A key message will be that metabolic profiling offers huge potential to highlight biomarkers and mechanisms in support of toxicology and pathology investigations in preclinical drug development.

PMID: 18337232 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

MedWorm Sponsored Message: Read news and analysis about clinical lab software and the clinical lab industry at the most widely read lab blog - Lab Soft News.

A new medium-term rat colorectal bioassay applying neoplastic lesions as end points for detection of carcinogenesis modifiers effects with weak or controversial modifiers.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

A new medium-term rat colorectal bioassay applying neoplastic lesions as end points for detection of carcinogenesis modifiers effects with weak or controversial modifiers.

Toxicol Pathol. 2008;36(3):459-64

Authors: Cho YM, Imai T, Ota Y, Hasumura M, Takami S, Hirose M, Nishikawa A

We have established a two-stage, medium-term rat colorectal carcinogenesis model featuring induction of neoplastic lesions within ten weeks. In the present study, we examined the ability of this model to detect weak modifiers. F344 male rats were given three subcutaneous (sc) injections of 1,2-dimethyl-hydrazine (DMH, 40 mg/kg b.w.) in one week followed by drinking water containing 1% dextran sodium sulfate (DSS) for a second week. One week after this regimen, basal diet alone, or diets containing 10% perilla oil, 10% corn oil, 10% dextrin, or 0.1% indole-3-carbinol (I3C) were supplied. The perilla oil and corn oil groups did not show significant differences in the numbers of aberrant crypt foci (ACF) and incidences or multiplicity of proliferative lesions as compared to the controls at either time point. In the dextrin group, the total number of ACF at week ten was significantly increased. With I3C, the total number of ACF and incidence and multiplicities of adenocarcinomas at week ten and the incidence of invasive tumors at week twenty were significantly increased. These data essentially correspond with earlier reported results, except in the vegetable oil cases. Thus, the system is suitable for detection of colorectal carcinogenesis modifiers with advantages over previous models using ACF alone as end points.

PMID: 18349425 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Isoproterenol-induced cardiotoxicity in sprague-dawley rats: correlation of reversible and irreversible myocardial injury with release of cardiac troponin t and roles of inos in myocardial injury.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Isoproterenol-induced cardiotoxicity in sprague-dawley rats: correlation of reversible and irreversible myocardial injury with release of cardiac troponin T and roles of iNOS in myocardial injury.

Toxicol Pathol. 2008;36(2):277-8

Authors: Zhang J, Knapton A, Lipshultz SE, Weaver JL, Herman EH

The present study was undertaken to characterize myocardial lesions in the rat induced by low doses of isoproterenol (Iso) and to correlate lesion severity with release of cardiac troponin T (cTnT) and changes in myocyte iNOS expression. Two types of cardiac injury patterns were observed. A Type I response, noted 3 or 6 hours postdosing with 8, 16, 32, or 64 mug/kg Iso, included potential reversible myocardial alterations associated with slight increases in serum cTnT (< 0.3 ng/mL) and a slight reduction in myocyte cTnT immunoreactivity. The second type of response noted 3, 6, 12, 24 or 48 hours postdosing with 125, 250, or 500 mug/kg Iso consisted of irreversible myocyte alterations, together with significant increases in serum cTnT (3-14 ng/mL) and a marked reduction of cTnT immunoreactivity. By 48 hours the hearts of rats dosed with 125-500 mug/kg Iso had developed interstitial fibrosis, and serum cTnT had declined to near control levels (0.06-0.18 ng/mL). Increases in iNOS immunoreactivity correlated with the lesion severity. These findings suggest that low doses of Iso exert complex effects on the myocardium and that the generation of NO through increased expression of iNOS could be an important factor in the pathogenesis of myocyte injury.

PMID: 18349426 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Chronic microcystin exposure induces hepatocyte proliferation with increased expression of mitotic and cyclin-associated genes in p53-deficient mice.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Chronic microcystin exposure induces hepatocyte proliferation with increased expression of mitotic and cyclin-associated genes in P53-deficient mice.

Toxicol Pathol. 2008;36(2):190-203

Authors: Clark SP, Ryan TP, Searfoss GH, Davis MA, Hooser SB

Homozygous p53 deficient knockout mice were used to assess the role of p53 in tumor promotion by the protein phosphatase inhibitor and hepatic tumor promoter microcystin-LR (MCLR). More than 50% of human cancers bear mutations in the p53 gene, and in particular, p53 tumor suppressor gene mutations have been shown to play a major role in hepatocarcinogenesis. Trp53 homozygous (inactivated p53) and age-matched wild-type control mice were assigned to vehicle or MCLR-treated groups. MCLR or saline was administered daily for up to 28 days. RNA from the 28-day study was hybridized onto Mouse Genome GeneChip arrays. Selected RNA from 28 days and earlier time points was also processed for quantitative polymerase chain reaction (PCR). Livers from the 28-day, Trp53-deficient, MCLR group displayed greater hyperplastic and dysplastic changes morphologically and increases in Ki-67 and phosphohistone H3 (mitotic marker) immunoreactivity. Gene-expression analysis revealed significant increases in expression of cell-cycle regulation and cellular proliferation genes in the MCLR-treated, p53-deficient mutant mice compared to controls. These data suggest that regulation of the cell cycle by p53 is important in preventing the proliferative response associated with chronic, sublethal microcystin exposure, and therefore, conclude that p53 plays an important role in MCLR-induced tumor promotion.

PMID: 18349427 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults.

Toxicol Pathol. 2008;36(2):289-310

Authors: Calderón-Garcidueñas L, Solt AC, Henríquez-Roldán C, Torres-Jardón R, Nuse B, Herritt L, Villarreal-Calderón R, Osnaya N, Stone I, García R, Brooks DM, González-Maciel A, Reynoso-Robles R, Delgado-Chávez R, Reed W

Air pollution is a serious environmental problem. We investigated whether residency in cities with high air pollution is associated with neuroinflammation/neurodegeneration in healthy children and young adults who died suddenly. We measured mRNA cyclooxygenase-2, interleukin-1beta, and CD14 in target brain regions from low (n = 12) or highly exposed residents (n = 35) aged 25.1 +/- 1.5 years. Upregulation of cyclooxygenase-2, interleukin-1beta, and CD14 in olfactory bulb, frontal cortex, substantia nigrae and vagus nerves; disruption of the blood-brain barrier; endothelial activation, oxidative stress, and inflammatory cell trafficking were seen in highly exposed subjects. Amyloid beta42 (Abeta42) immunoreactivity was observed in 58.8% of apolipoprotein E (APOE) 3/3 < 25 y, and 100% of the APOE 4 subjects, whereas alpha-synuclein was seen in 23.5% of < 25 y subjects. Particulate material (PM) was seen in olfactory bulb neurons, and PM < 100 nm were observed in intraluminal erythrocytes from lung, frontal, and trigeminal ganglia capillaries. Exposure to air pollution causes neuroinflammation, an altered brain innate immune response, and accumulation of Abeta42 and alpha-synuclein starting in childhood. Exposure to air pollution should be considered a risk factor for Alzheimer's and Parkinson's diseases, and carriers of the APOE 4 allele could have a higher risk of developing Alzheimer's disease if they reside in a polluted environment.

PMID: 18349428 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Toxicity, dna binding, and cell proliferation in male f344 rats following short-term gavage exposures to trans-2-hexenal.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Toxicity, DNA binding, and cell proliferation in male F344 rats following short-term gavage exposures to trans-2-hexenal.

Toxicol Pathol. 2008;36(2):232-46

Authors: Stout MD, Bodes E, Schoonhoven R, Upton PB, Travlos GS, Swenberg JA

Hexenal is a genotoxic compound to which humans are exposed daily through the consumption of foods and beverages. The present studies were conducted to examine the relationships between the dose-responses of trans-2-hexenal-induced toxicity, DNA adduct formation, and cell proliferation. Male F344 rats were exposed by gavage to single doses of up to 500 mg/kg and killed 1, 2, or 4 days after dosing or were exposed to repeat doses of up to 100 mg/kg once daily for 5 days or 5 days per week for 4 weeks and killed 1 day after the end of the dosing period. Histologically, the primary observations were necroulcerative lesions, inflammation, and hyperplasia in the forestomach and inflammation in the glandular stomach. Hexenal-derived DNA adduct formation and cell proliferation were induced in the forestomach at doses of hexenal that also induced gastric toxicity; DNA adducts were not observed in the glandular stomach. These findings suggest that the toxicity of hexenal was limited to the site of contact (stomach) and that the observed DNA adduct formation and cell proliferation occurred in the setting of severe tissue damage.

PMID: 18362197 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

MedWorm Sponsored Message: Read news and analysis about clinical lab software and the clinical lab industry at the most widely read lab blog - Lab Soft News.

Fibro-osseous (fol) and degenerative joint lesions in female outbred nih black swiss mice.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Fibro-osseous (FOL) and degenerative joint lesions in female outbred NIH Black Swiss mice.

Toxicol Pathol. 2008;36(2):362-5

Authors: Wancket LM, Devor-Henneman D, Ward JM

A review of spontaneous bone and joint lesions in female aging NIH Black Swiss mice (Cr:NIH BL[S]) revealed a high incidence of fibro-osseous lesions (FOL; 89%) and degenerative joint lesions (90%). FOL was characterized by the replacement of bone marrow by fibrovascular tissue and was first seen at 59 weeks of age, most commonly in the nasal bone, femur, and tibia. FOL in female Black Swiss was often accompanied by reproductive-tract lesions, including ovarian atrophy and uterine cervical dysplasia with hydrometra. Mild degenerative femorotibial joint lesions developed by 59 weeks and progressed to full-thickness articular cartilage ulceration and osteophyte development by 75 weeks; joint inflammation was minimal. Although the underlying etiology of FOL remains unknown, an accurate assessment of FOL and degenerative joint disease as background lesions in this stock is necessary to interpret lesions in genetically engineered mice produced from this outbred line.

PMID: 18362198 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Rosuvastatin: characterization of induced myopathy in the rat.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Rosuvastatin: characterization of induced myopathy in the rat.

Toxicol Pathol. 2008;36(2):345-52

Authors: Westwood FR, Scott RC, Marsden AM, Bigley A, Randall K

Rosuvastatin is a relatively new member of the statin family (HMG-CoA reductase inhibitors), with superior lipid-lowering effects and a pattern of clinical side effects, including a low incidence of myopathy, similar to other widely prescribed statins. This article describes investigations of myopathy in the rat following administration of very high doses of rosuvastatin. The nature of the changes were found to be entirely consistent with those seen with other statins, including a differential sensitivity of muscle fibers (with glycolytic fibers [type IIB] the most sensitive and oxidative fibers [type I] the least), a delay of approximately 10 days after the start of oral dosing before necrosis was apparent, and ultrastructural alterations appearing first in mitochondria. In addition, the development of myopathy was prevented by coadministration of mevalonate, the product of HMG-CoA reductase. The findings illustrate a pattern of induced myopathy in the rat directly attributable to inhibition of HMG-CoA reductase that is entirely consistent between the various statins, with the oral dose required to produce the changes being a differentiating feature (based on these new data and a previously reported study from the same laboratory): cerivastatin dose less than simvastatin, and simvastatin dose less than rosuvastatin.

PMID: 18362199 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

A possible role of nrf2 in prevention of renal oxidative damage by ferric nitrilotriacetate.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

A possible role of nrf2 in prevention of renal oxidative damage by ferric nitrilotriacetate.

Toxicol Pathol. 2008;36(2):353-61

Authors: Kanki K, Umemura T, Kitamura Y, Ishii Y, Kuroiwa Y, Kodama Y, Itoh K, Yamamoto M, Nishikawa A, Hirose M

To ascertain the possible roles of nuclear erythroid 2 p45-related factor 2 (Nrf2), a key transcription factor of phase 2 drug-metabolizing enzymes, in renal cellular defense against oxidative stress, wild-type and Nrf2-knockout -/- mice were treated with ferric nitrilotriacetate (Fe-NTA) at doses of 3 or 6 mg iron/kg body weight. After Fe-NTA treatment, Nrf2 -/- mice consistently showed lower levels of glutathione (GSH) in the kidney at the low dose and the liver at the high dose than the wild-type mice. Gamma-glutamylcysteine ligase (GCL) activity in the kidney and liver of Nrf2-/- mice was also consistently lower than in wild-type mice after the Fe-NTA treatment. Histopathological examination revealed that nephrotoxicity of Fe-NTA, reflected in necrosis of renal tubule epithelial cells following nuclear damage, was more severe in the Nrf2-/- mice than in their wild-type counterparts. Overall, the data suggest that Nrf2 -/- mice are unable to compensate for depletion of renal GSH because of oxidative stress, being more susceptible to Fe-NTA-induced nephrotoxicity. In conclusion, the present study showed that Nrf2 might play an important role in protecting cells from oxidative stress in the kidney through its regulation of antioxidant enzymes.

PMID: 18364461 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Evaluation of the cynomolgus monkey stomach: recommendations for standard sampling procedures in nonclinical safety studies.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Evaluation of the cynomolgus monkey stomach: recommendations for standard sampling procedures in nonclinical safety studies.

Toxicol Pathol. 2008;36(2):250-5

Authors: Vidal JD, Mirabile RC, Thomas HC

The cynomolgus macaque is the most commonly used nonhuman primate in nonclinical toxicity testing, but the macroscopic and microscopic anatomy of the stomach in the cynomolgus macaque is poorly described. To develop a reliable sampling method for histologic evaluation of the cynomolgus macaque stomach in regulatory toxicity studies, the stomachs of control animals were prospectively evaluated using an extensive sectioning pattern. The stomach of the cynomolgus macaque differs from that described for the human stomach and has a prominent fundus that lacks parietal cells. A description of the macroscopic and microscopic anatomy is presented along with a recommended sectioning pattern for nonclinical toxicity studies and discussion of species differences. A thorough understanding of normal anatomy and species comparisons are critical to interpretation of potential toxicity findings and assessment of risk in humans.

PMID: 18364462 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Smad signaling in the rat model of monocrotaline pulmonary hypertension.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Smad signaling in the rat model of monocrotaline pulmonary hypertension.

Toxicol Pathol. 2008;36(2):311-20

Authors: Ramos MF, Lamé MW, Segall HJ, Wilson DW

Mutations in the bone morphogenetic protein receptor type II (BMPrII) gene have been implicated in the development of familial pulmonary artery hypertension (PAH). The function of BMP signal transduction within the pulmonary vasculature and the role BMPrII mutations have in the development of PAH are incompletely understood. We used the monocrotaline (MCT) model of PAH to examine alterations in Smad signal transduction pathways in vivo. Lungs harvested from Sprague-Dawley rats treated with a single 60-mg/kg intraperitoneal (IP) injection of MCT were compared to saline-treated controls 2 weeks following treatment. Smad 4 was localized by immunohistochemistry to endothelial nuclei of the intra-acinar vessels undergoing remodeling. Smad 4, common to both BMP and transforming growth factor beta (TGFbeta) signaling, and BMP-specific Smad 1 were significantly decreased in western blot from whole lungs of treated animals, while no change was found for TGFbeta-specific Smad 2. MCT-treated rats also had increased expression of phosphorylated Smad 1 (P-Smad 1) but not phosphorylated Smad 2 (P-Smad 2). There was a decrease in the expression of the full BMPrII protein but not its short form variant in MCT-treated rat lungs. The type I receptor Alk1 had increased expression. Collectively, our data indicate that vascular remodeling in the MCT model is associated with alterations in BMP receptors and persistent endothelial Smad 1 signaling.

PMID: 18367643 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

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Hemorrhagic cardiomyopathy in male mice treated with an nnrti: the role of vitamin k.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Hemorrhagic cardiomyopathy in male mice treated with an NNRTI: the role of vitamin K.

Toxicol Pathol. 2008;36(2):321-9

Authors: De Jonghe S, Verbeeck J, Vinken P, Lammens L, Starckx S, Lachau-Durand S, Bouche MP, Willems B, Coussement W

Dietary dosing of the non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125, under development for treatment of HIV-1, resulted in a syndrome in male mice in a previous experiment that was termed hemorrhagic cardiomyopathy. In literature, this syndrome, which was described in rodent species only, was linked to vitamin K deficiency. Two mechanistic studies were conducted, one with dietary administration and a second with gavage. The syndrome was reproduced in only 1 male mouse after continuous dietary dosing, and TMC125 was demonstrated to affect coagulation parameters (prothrombin time [PT], activated partial thromboplastin time [APTT], clotting factors II, VII and XI), particularly in males. This was counteracted by vitamin K supplementation, supporting the hypothesis that the effects were mediated via a vitamin K deficiency. It is therefore concluded that the observed cardiac changes were not caused by a direct cardiotoxic effect but occurred after a state of disabled clotting ability with subsequent effects on mouse cardiac muscle. Therefore, clotting times can be used as adequate safety biomarkers in clinical trials. To date, no changes have been observed at therapeutic doses of TMC125, following human monitoring of PT and APTT. One other NNRTI, Efavirenz (Sustiva), has been reported to cause prolongation of coagulation times in rats and monkeys.

PMID: 18367644 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Whole mount enzyme histochemistry as a rapid screen at necropsy for expression of beta-galactosidase (lacz)-bearing transgenes: considerations for separating specific lacz activity from nonspecific (endogenous) galactosidase activity.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Whole mount enzyme histochemistry as a rapid screen at necropsy for expression of beta-galactosidase (LacZ)-bearing transgenes: considerations for separating specific LacZ activity from nonspecific (endogenous) galactosidase activity.

Toxicol Pathol. 2008;36(2):265-76

Authors: Bolon B

Whole mount enzyme histochemistry to localize lacZ-bearing transgenes (lacZ-WMH) also detects endogenous beta-galactosidases. The experiments reported here evaluated lacZ-WMH as a potential tool for transgene expression analysis during high-throughput rodent necropsies. A lacZ-WMH survey of organs from adult, wild-type, male and female mice (C57BL/6, FVB/N) and female rats (Sprague-Dawley) performed at the optimal pH (> or = 7.0) for bacterial lacZ yielded intense endogenous staining in the gonads, kidney, male accessory sex organs, salivary glands, submucosal glands in the duodenum, and thyroid. Substantial staining occurred in the adrenal cortex, lymph nodes, and linings of the gastrointestinal tract, the urinary bladder and uterus, and (for rat only) in the adenohypophysis, bone marrow, thymus, and trigeminal ganglia. Endogenous galactosidases were distributed similarly in sections of flash-frozen organs used for slide-based lacZ histochemistry (lacZ-SBH) at pH < or = 5.0 (optimal for eukaryotic enzymes). Cerebral neurons were labeled only by lacZ-SBH. At pH 7.4, endogenous but not specific lacZ activity was abolished for lacZ-SBH, while endogenous activity was not halted without reducing specific activity for lacZ-WMH. These data demonstrate that lacZ-WMH is feasible during rodent necropsies for many but not all organs if species-, strain-, and sex-specific divergence in endogenous galactosidase activity is considered and special fixation (3% paraformaldehyde for 3 hours at 4 degrees C) is used.

PMID: 18369090 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Response to letter of vahle et al.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Response to letter of Vahle et al.

Toxicol Pathol. 2008;36(3):520-1

Authors: Jolette J, Wilker CE, Fox J

PMID: 18413785 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Temporal gene expression profiling indicates early up-regulation of interleukin-6 in isoproterenol-induced myocardial necrosis in rat.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Temporal gene expression profiling indicates early up-regulation of interleukin-6 in isoproterenol-induced myocardial necrosis in rat.

Toxicol Pathol. 2008;36(2):256-64

Authors: Mikaelian I, Coluccio D, Morgan KT, Johnson T, Ryan AL, Rasmussen E, Nicklaus R, Kanwal C, Hilton H, Frank K, Fritzky L, Wheeldon EB

Gene expression was evaluated in the myocardium of male Wistar rats after a single subcutaneous administration of 0.5 mg of isoproterenol, a beta-adrenergic agonist that causes acute tachycardia with subsequent myocardial necrosis. Histology of the heart, clinical chemistry, and hematology were evaluated at 9 time points (0.5 hours to 14 days postinjection). Myocardial gene expression was evaluated at 4 time points (1 hour to 3 days). Contraction bands and loss of cross-striation were identified on phosphotungstic acid-hematoxylin-stained sections 0.5 hours postdosing. Plasma troponin I elevation was detected at 0.5 hours, peaked at 3 hours, and returned to baseline values at 3 days postdosing. Interleukin 6 (Il6) expression spiked at 1 to 3 hours and was followed by a short-lived, time-dependent dysregulation of its downstream targets. Concurrently and consistent with the kinetics of the histologic findings, many pathways indicative of necrosis/apoptosis (p38 mitogen-activated protein kinase [MAPK] signaling, NF-kappaB signaling) and adaptation to hypertension (PPAR signaling) were overrepresented at 3 hours. The 1-day and 3-day time points indicated an adaptive response, with down-regulation of the fatty acid metabolism pathway, up-regulation of the fetal gene program, and superimposed inflammation and repair at 3 days. These results suggest early involvement of Il6 in isoproterenol-induced myocardial necrosis and emphasize the value of early time points in transcriptomic studies.

PMID: 18413786 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Neuroexcitatory targets in the female reproductive system of the nonhuman primate (macaca fascicularis).

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Neuroexcitatory targets in the female reproductive system of the nonhuman primate (Macaca fascicularis).

Toxicol Pathol. 2008;36(3):478-84

Authors: Gill S, Barker M, Pulido O

Glutamate receptors (GluRs) have been implicated in brain function and pathology. Their presence in peripheral tissues suggests a vital role in the pathophysiology of various organ systems. In earlier studies, the authors reported the differential distribution of ionotropic and metabotropic GluRs in neural and nonneural peripheral tissues of the rat. In this study, they investigated the presence and the localization of the GluRs in the reproductive organs of Macaca fascicularis. The data illustrate the presence of the GluR 2/3, metabotropic glutamate receptor 2/3, kainate 2, and N-methyl-D-aspartate receptor 1 (NMDAR 1). These are localized in the different structures of the ovaries, uterine cervix, myometrium, endometrium, and inflammatory cells. Smooth muscle of the myometrium and arterioles showed strong immunolabeling with anti-GluR 2/3 and, to a lesser intensity, with the other ionotropic glutamate receptor antibodies. NMDAR 1 showed the most widespread staining in all the structures. Mast cells showed strong immunolabeling with the anti-NMDA antibody. The demonstration and the differential expression of GluRs in the female reproductive system of nonhuman primate experimental models provide first evidence suggesting excitatory signaling in these tissues.

PMID: 18413787 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

MedWorm Sponsored Message: Read news and analysis about clinical lab software and the clinical lab industry at the most widely read lab blog - Lab Soft News.

Evidence of a threshold-effect for 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline liver carcinogenicity in f344/ducrj rats.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Evidence of a threshold-effect for 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline liver carcinogenicity in F344/DuCrj rats.

Toxicol Pathol. 2008;36(3):472-7

Authors: Murai T, Mori S, Kang JS, Morimura K, Wanibuchi H, Totsuka Y, Fukushima S

To estimate potential human risk of exposure to a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a 2-year carcinogenicity test was conducted using male F344 rats administered MeIQx-containing diet at doses of 0 (control), 0.001, 1, and 100 ppm. The lowest dose 0.001 ppm was established as equivalent to the daily intake of this carcinogen in humans (0.2 to 2.6 microg/man/day). Significant decreases of survival rate and body weight gain were observed in rats treated with 100 ppm MeIQx. Histopathological examination revealed significant induction of hepatocellular carcinomas, adenomas, and development of glutathione S-transferase placental form-positive foci with MeIQx at 100 ppm. Moreover, the incidences of Zymbal's glands carcinoma, mammary fibroadenoma, and subcutaneous fibroma were found significantly increased in a 100 ppm MeIQx group. However, no significant induction of altered preneoplastic hepatocellular foci was observed in 0.001 and 1 ppm groups as compared to the controls. 8-Hydroxy-2'-deoxyguanosine levels in the rat liver DNA of the 100 ppm-treated group were not elevated, but MeIQx-DNA adduct formation increased as compared with the 1 ppm case, albeit without significance. No significant induction of any other neoplastic lesions related to the carcinogen administration was found in MeIQx-administered groups except for 100 ppm. These results imply that 1 ppm may be a no-effect level for MeIQx carcinogenesis.

PMID: 18413788 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Changes in clara cell 10 kda protein (cc10)-positive cell distribution in acute lung injury following repeated lipopolysaccharide challenge in the rat.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Changes in Clara cell 10 kDa protein (CC10)-positive cell distribution in acute lung injury following repeated lipopolysaccharide challenge in the rat.

Toxicol Pathol. 2008;36(3):440-8

Authors: Bolton SJ, Pinnion K, Marshall CV, Wilson E, Barker JE, Oreffo V, Foster ML

Clara cell 10 kDa protein (CC10) is the major secretory protein of Clara cells and is thought to play a protective role in the lung owing to its anti-inflammatory properties. There is little information on the anatomical distribution of CC10-positive cells in rat lung following lipopolysaccharide (LPS) challenge. We have determined the expression of CC10 along the tracheobronchial tree in saline-treated and LPS-treated rats. Saline-treated rats showed sporadic CC10 staining in central airways and abundant staining in bronchioles. In transitional airways, most cells were positive except for squamous cells. Following LPS challenge, there was a reduction in staining in the upper airways but little change within bronchioles. Squamous epithelia within the transitional airways now showed positive staining. These cells also co-stained for pancytokeratin and appeared to co-localize with surfactant D- and Ki67-positive cells, indicating the presence of a dedifferentiated cell type with both epithelial and pneumocyte phenotypes. These data show that diffuse inflammatory injury results in generalized loss of CC10 in central airways. Conversely, the transitional airways showed evidence of a dedifferentiated population of squamous cells that now stained for CC10. We hypothesize that this is an attempt by peripheral lung to maintain alveolar sac integrity during an inflammatory episode.

PMID: 18420837 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Trans-species comparison of ppar and rxr expression by rat and human urothelial tissues.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Trans-species comparison of PPAR and RXR expression by rat and human urothelial tissues.

Toxicol Pathol. 2008;36(3):485-95

Authors: Chopra B, Hinley J, Oleksiewicz MB, Southgate J

Because some investigational peroxisome proliferator-activated receptors (PPAR) agonists cause tumors in the lower urinary tract of rats, we compared normal human and rat urothelium in terms of PPAR and retinoid X receptor (RXR) expression and proliferation-associated phenotypes. In situ, few human but most rat urothelial cells were Ki67 positive, indicating fundamental differences in cell cycle control. Rat and human urothelia expressed all 3 PPAR and the RXRalpha and RXRbeta isoforms in a predominantly nuclear localization, indicating that they may be biologically active. However, immunolocalization differences were observed between species. First, whereas PPARalpha and PPARbeta/delta were expressed throughout the human bladder or ureteric urothelium, in the rat urothelium PPARalpha was primarily, and PPARbeta/delta exclusively, restricted to superficial cells. Second, RXRbeta was restricted to intermediate and superficial layers of the human urothelium but tended to be absent from the rat superficial cells. Third, PPARgamma expression was present throughout the urothelia of both species but was most intense in the superficial human urothelium. Species differences were also observed in the expression of PPAR and RXR isoforms between cultured rat and human urothelial cells and in the smooth muscle. Our findings highlight the unique coexpression of multiple PPAR and RXR isoforms by urothelium and suggest that species differences in PPAR function between rat and human urothelia may be explored in an in vitro setting.

PMID: 18441255 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Relationship between gst yp induction and hepatocyte proliferation in rats treated with phase ii drug metabolizing enzyme inducers.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Relationship between GST Yp induction and hepatocyte proliferation in rats treated with phase II drug metabolizing enzyme inducers.

Toxicol Pathol. 2008;36(3):420-7

Authors: Makino T, Ishikawa K, Igarashi I, Yamoto T, Manabe S, Nakayama H

Butylated hydroxyanisole (BHA) and 1,2-bis(2-pyridyl)ethylene (2PY-e) are phase II drug metabolizing enzyme inducers which cause hepatomegaly without hepatocyte hypertrophy and induce glutathione S-transferase Yp (GST Yp, pi-class GST), which is known as a tumor marker. To evaluate the relationship between GST Yp induction and hepatocyte proliferation, male F344/DuCrj rats were treated with BHA, 2PY-e, or phenobarbital (PB) for three or seven days. All three chemicals caused increases in liver weight after three and seven days. Immunohistochemical examinations revealed that BHA and 2PY-e induced GST Yp in the hepatocytes of the periportal and centrilobular areas at three and seven days, respectively, whereas PB did not. Significant increases in the BrdU labeling indices were found in the livers of rats in each of the three-day treatment groups, but the labeling index of rat livers treated with BHA was decreased to the control level at seven days, although the high labeling indices of 2PY-e and PB persisted at seven days. Double immunostaining confirmed that BrdU-positive nuclei corresponded to GST Yp-positive hepatocytes in both BHA and 2PY-e treated rats. These results suggest that the GST Yp induction caused by BHA or 2PY-e has some kind of relationship with hepatocyte proliferation.

PMID: 18441256 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Acute effects of microcystins mc-lr and mc-rr on acid and alkaline phosphatase activities and pathological changes in intraperitoneally exposed tilapia fish (oreochromis sp.).

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Acute effects of microcystins MC-LR and MC-RR on acid and alkaline phosphatase activities and pathological changes in intraperitoneally exposed tilapia fish (Oreochromis sp.).

Toxicol Pathol. 2008;36(3):449-58

Authors: Atencio L, Moreno I, Prieto AI, Moyano R, Molina AM, Cameán AM

Microcystins (MC) are frequently present in cyanobacterial blooms in rivers and lakes, increasing the risk of toxicity to both animals and humans. There more than eighty reported microcystins, and the present study was undertaken to determine whether MC-LR and MC-RR can induce different enzyme alterations and histopathological changes in tilapia fish (Oreochromis sp.) exposed to a single intraperitoneal (i.p.) injection of the pure standards (MC-LR and MC-RR) at a dose of 500 mug/kg; the tilapia fish were then observed for seven days. The two MC variants caused significant changes in the activities of acid and alkaline phosphatases (ACP and ALP) in vital organs, showing a different response pattern. The livers and kidneys of fish injected with MC-LR were particularly affected. MC-RR induced a very pronounced increase of ACP in the kidney and a significant increase of ALP in the liver. Both MC variants caused pathological lesions in hepatic tissues, such as megalocytosis, necrotic process, and microvesicular steatosis, particularly in fish treated with MC-LR, and degenerative renal changes, glomerulopathy, were more severe in tilapias exposed to MC-RR. In addition, both microcystins also caused significant myopathy in the heart. In contrast, the gills did not show any change in enzyme activity or histopathological injury.

PMID: 18441257 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

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Immunolocalization of kim-1, rpa-1, and rpa-2 in kidney of gentamicin-, mercury-, or chromium-treated rats: relationship to renal distributions of inos and nitrotyrosine.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Immunolocalization of Kim-1, RPA-1, and RPA-2 in kidney of gentamicin-, mercury-, or chromium-treated rats: relationship to renal distributions of iNOS and nitrotyrosine.

Toxicol Pathol. 2008;36(3):397-409

Authors: Zhang J, Brown RP, Shaw M, Vaidya VS, Zhou Y, Espandiari P, Sadrieh N, Stratmeyer M, Keenan J, Kilty CG, Bonventre JV, Goering PL

Immunohistochemical studies for kidney injury molecule-1 (Kim-1), renal papillary antigen-1 (RPA-1), and renal papillary antigen-2 (RPA-2) were conducted to explore their relationship to inducible nitric oxide synthase (iNOS) and nitrotyrosine expression. Male Sprague-Dawley rats were exposed to gentamicin (100 mg/kg/day Gen, sc, for 3 days), mercury (0.25 mg Hg/kg, iv, single dose), or chromium (5 mg Cr/kg, sc, single dose) and kidney tissue was examined 24 hours or 72 hours after the last dose of the nephrotoxicant. Another group of kidneys was evaluated 24 hours after rats were administered 3 daily doses (50, 100, 150, 200, or 300 mg/kg/day) of Gen. Gen- and Cr-treated rats exhibited increased immunoreactivity of Kim-1, RPA-1, and RPA-2 largely in the S1/S2 segments and to a lesser extent in the S3 segments of the proximal tubule of the kidney, whereas Hg-treated rats showed increased immunoreactivity of Kim-1, RPA-1, and RPA-2 in the S3 segments. Up-regulation of Kim-1, RPA-1, and RPA-2 expression correlated with injured tubular epithelial cells and also correlated with immunoreactivity of iNOS and nitrotyrosine. It is possible that iNOS activation with nitrotyrosine production in injured nephron segments may be involved in the induction of Kim-1, RPA-1, and RPA-2 following exposure to nephrotoxicants.

PMID: 18441258 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Summary of chemically induced pulmonary lesions in the national toxicology program (ntp) toxicology and carcinogenesis studies.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Summary of chemically induced pulmonary lesions in the National Toxicology Program (NTP) toxicology and carcinogenesis studies.

Toxicol Pathol. 2008;36(3):428-39

Authors: Dixon D, Herbert RA, Kissling GE, Brix AE, Miller RA, Maronpot RR

The lung is the second most common target site of neoplasia of chemicals tested by the National Toxicology Program (NTP). Of all peer-reviewed NTP studies to date (N = 545), a total of sixty-four chemicals in sixty-six reports produced significant site-specific neoplasia in the lungs of rats and/or mice. Of the studies associated with lung tumor induction, approximately 35% were inhalation and 35% were gavage studies, with dosed-feed, dosed-water, topical, intraperitoneal, or in utero routes of chemical administration accounting for 18%, 6%, 3%, 1%, and 1% of the studies, respectively. The most commonly induced lung tumors were alveolar/bronchiolar (A/B) adenoma and/or carcinoma for both species. The most frequently observed nonneoplastic lesions included hyperplasia and inflammation in both species. The liver was the most common primary site of origin of metastatic lesions to the lungs of mice; however, skin was most often the primary site of origin of metastatic lesions to the lungs of rats. In summary, A/B adenoma and carcinoma were the most frequently diagnosed chemically induced tumors in the lungs of both rats and mice in the NTP toxicology and carcinogenesis bioassays, and hyperplasia and inflammation were the most common nonneoplastic changes observed.

PMID: 18441259 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

The female rat reproductive cycle: a practical histological guide to staging.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

The female rat reproductive cycle: a practical histological guide to staging.

Toxicol Pathol. 2008;36(3):375-84

Authors: Westwood FR

During preclinical investigations into the safety of drugs and chemicals, many are found to interfere with reproductive function in the female rat. This interference is commonly expressed as a change in normal morphology of the reproductive tract or a disturbance in the duration of particular phases of the estrous cycle. Such alterations can be recognized only if the pathologist has knowledge of the continuously changing histological appearance of the various components of the reproductive tract during the cycle and can accurately and consistently ascribe an individual tract to a particular phase of the cycle. Unfortunately, although comprehensive reports illustrating the normal appearance of the tract during the rat estrous cycle have been available over many years, they are generally somewhat ambiguous about distinct criteria for defining the end of one stage and the beginning of another. This detail is absolutely essential to achieve a consistent approach to staging the cycle. For the toxicologic pathologist, this report illustrates a pragmatic and practical approach to staging the estrous cycle in the rat based on personal experience and a review of the literature from the last century.

PMID: 18441260 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Spontaneous occurrence of a distinctive renal tubule tumor phenotype in rat carcinogenicity studies conducted by the national toxicology program.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Spontaneous occurrence of a distinctive renal tubule tumor phenotype in rat carcinogenicity studies conducted by the national toxicology program.

Toxicol Pathol. 2008;36(3):388-96

Authors: Hard GC, Seely JC, Kissling GE, Betz LJ

The Toxicology Data Management System (TDMS) of the National Toxicology Program, National Institutes of Environmental Health Sciences, National Institutes of Health, was surveyed for occurrence and distribution of a distinctive renal tubule tumor type in rats. The hallmark features of this tumor included eosinophilic/amphophilic staining, large finely granular cells, and numerous vacuoles and/or minilumens. It is referred to here as the amphophilic-vacuolar (AV) variant of renal tubule tumor. Of 154 studies in which renal tubule tumors had been recorded in the standard single sections of kidney in the TDMS, there were collectively 1012 rats with renal adenomas, carcinomas, or adenocarcinomas, and of these, 100 displayed the distinctive AV morphology, representing 74 studies involving mostly the F344 rat, but also the Sprague-Dawley and Wistar strains. The AV tumors (mainly adenomas but also some carcinomas) occurred usually as solitary lesions in the affected animals. However, they were multiple and bilateral in a few cases. They were equally distributed between the sexes, did not metastasize (at least to the lung), and were not associated with chronic progressive nephropathy. The distribution of this renal tumor type was random across studies and dose groups, underscoring the likelihood that it was of spontaneous origin and not chemically induced. Accordingly, it is suggested that this distinctive renal tumor phenotype be recorded as a separate category from conventional RTT when assessing the carcinogenic potential of a test compound.

PMID: 18441261 [PubMed - indexed for MEDLINE]

(Source: Toxicologic Pathology)

Ovarian follicle counts using proliferating cell nuclear antigen (pcna) and semi-automated image analysis in rats.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Ovarian follicle counts using proliferating cell nuclear antigen (PCNA) and semi-automated image analysis in rats.

Toxicol Pathol. 2008;36(5):674-9

Authors: Picut CA, Swanson CL, Scully KL, Roseman VC, Parker RF, Remick AK

Ovarian follicle counting is a method to assess ovarian toxicity in reproductive toxicity studies in rats. Although ovarian follicle counting has been traditionally performed manually on hematoxylin and eosin (H&E)-stained sections, the use of immunohistochemical methods, including human cytochrome P450 1B1 (CYP1B1) and proliferating cell nuclear antigen (PCNA), have been used to enhance the visibility of the primordial and primary follicles to facilitate manual counting. In this study, serial sections from both ovaries from ten 3-month-old female Sprague Dawley rats were stained using routine H&E and immunohistochemistry for PCNA. Counting of primordial and primary follicles was performed manually using these two stains and by semi-automated image analysis of PCNA-stained slides. Although manual counting of PCNA-stained slides is preferable to manual counting of H&E-stained slides, manual counting involves variability between individual counters. Semi-automated image analysis of PCNA-stained slides yields an accurate and consistent count of these primordial/primary follicles and eliminates variability between individual counters.

PMID: 18467674 [PubMed - in process]

(Source: Toxicologic Pathology)

MedWorm Sponsored Message: Read news and analysis about clinical lab software and the clinical lab industry at the most widely read lab blog - Lab Soft News.

Lung toxicity of 16 fine particles on intratracheal instillation in a bioassay model using f344 male rats.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Lung toxicity of 16 fine particles on intratracheal instillation in a bioassay model using f344 male rats.

Toxicol Pathol. 2008;36(4):620-31

Authors: Yokohira M, Kuno T, Yamakawa K, Hosokawa K, Matsuda Y, Hashimoto N, Suzuki S, Saoo K, Imaida K

We have developed a bioassay model to estimate toxicity of fine particles in the lungs at an early stage after intratracheal instillation (Yokohira et al. 2005; Yokohira et al. 2007). The present experiment was conducted to improve the model by estimating appropriate doses based on dose-dependent toxicity of instilled quartz (4 mg to 0 mg) as a positive control and assessing the impact of powdered particles without suspension (Experiment 1). In addition, examination of the toxicity of a series of particles was performed with the developed bioassay (Experiments 2A, 2B, and 2C). The materials chosen were sixteen particles, including nanoparticles and diesel powder. Histopathological and immunohistochemical analysis of bromodeoxyuridine (BrdU) incorporation and inducible nitric oxide synthase (iNOS) were performed after exposure of the lungs. A dose of 2 mg quartz suspended in 0.2 mL saline was suggested to be most appropriate for sensitive detection of acute and subchronic inflammatory changes. Although some materials, including nanoparticles, demonstrated toxicity that was too strong for sensitive assessment, the ranking order could be given as follows: CuO > quartz > neutralized Na2PdCl4 > NiO > hydrotalcite > MnO2 > diesel > titanium dioxide (in Experiment 2B) > beta-cyclodextrin > diesel standard > titanium dioxide (in Experiment 2A) > CaCO3.

PMID: 18467675 [PubMed - in process]

(Source: Toxicologic Pathology)

Pharmacological effects of nicotine on norepinephrine metabolism in rat brown adipose tissue: relevance to nicotinic therapies for smoking cessation.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Pharmacological effects of nicotine on norepinephrine metabolism in rat brown adipose tissue: relevance to nicotinic therapies for smoking cessation.

Toxicol Pathol. 2008;36(4):568-75

Authors: Brees DJ, Elwell MR, Tingley FD, Sands SB, Jakowski AB, Shen AC, Cai JH, Finkelstein MB

In a two-year carcinogenicity study with administration of high doses of the partial nicotinic agonist varenicline (recently approved for smoking cessation), mediastinal hibernomas occurred in three male rats. To investigate potential mechanisms for partial and full nicotinic agonists to contribute to development of hibernomas, the effects of nicotine on rat brown adipose tissue (BAT) were studied. Male and female rats were administered nicotine at doses of 0, 0.3, and 1 mg/kg subcutaneously for fourteen days. Intrathoracic (mediastinal periaortic and mediastinal perithymic) BAT and interscapular BAT were examined microscopically, and determinations of uncoupling protein-1 (UCP-1) expression and norepinephrine (NE) content were made. Additionally, NE turnover was measured in mediastinal periaortic and perithymic BAT. Nicotine (1 mg/kg) administration resulted in decreased vacuolation only in mediastinal periaortic and mediastinal perithymic BAT of males and elevated UCP-1 in mediastinal periaortic BAT of males and females. Increased NE content occurred only in mediastinal periaortic BAT of males given 0.3 and 1 mg/kg doses, whereas NE turnover was decreased in both males and females given 1 mg/kg. Together, these data demonstrate that nicotine primarily affects mediastinal BAT in male rats, consistent with the gender and location of the hibernomas observed in the two-year carcinogenicity study.

PMID: 18467676 [PubMed - in process]

(Source: Toxicologic Pathology)

Gene profiling in the livers of wild-type and pparalpha-null mice exposed to perfluorooctanoic acid.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Gene profiling in the livers of wild-type and PPARalpha-null mice exposed to perfluorooctanoic acid.

Toxicol Pathol. 2008;36(4):592-607

Authors: Rosen MB, Abbott BD, Wolf DC, Corton JC, Wood CR, Schmid JE, Das KP, Zehr RD, Blair ET, Lau C

Health concerns have been raised because perfluorooctanoic acid (PFOA) is commonly found in the environment and can be detected in humans. In rodents, PFOA is a carcinogen and a developmental toxicant. PFOA is a peroxisome proliferator-activated receptor alpha (PPARalpha) activator; however, PFOA is capable of inducing heptomegaly in the PPARalpha-null mouse. To study the mechanism associated with PFOA toxicity, wild-type and PPARalpha-null mice were orally dosed for 7 days with PFOA (1 or 3 mg/kg) or the PPARalpha agonist Wy14,643 (50 mg/kg). Gene expression was evaluated using commercial microarrays. In wild-type mice, PFOA and Wy14,643 induced changes consistent with activation of PPARalpha. PFOA-treated wild-type mice deviated from Wy14,643-exposed mice with respect to genes involved in xenobiotic metabolism. In PFOA-treated null mice, changes were observed in transcripts related to fatty acid metabolism, inflammation, xenobiotic metabolism, and cell cycle regulation. Hence, a component of the PFOA response was found to be independent of PPARalpha. Although the signaling pathways responsible for these effects are not readily apparent, overlapping gene regulation by additional PPAR isoforms could account for changes related to fatty acid metabolism and inflammation, whereas regulation of xenobiotic metabolizing genes is suggestive of constitutive androstane receptor activation.

PMID: 18467677 [PubMed - in process]

(Source: Toxicologic Pathology)

Gene expression changes following acute hydrogen sulfide (h2s)-induced nasal respiratory epithelial injury.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Gene expression changes following acute hydrogen sulfide (H2S)-induced nasal respiratory epithelial injury.

Toxicol Pathol. 2008;36(4):560-7

Authors: Roberts ES, Thomas RS, Dorman DC

Hydrogen sulfide (H2S) is a naturally occurring gas that is also associated with several industries. The potential for widespread human inhalation exposure to this toxic gas is a public health concern. The nasal epithelium is especially susceptible to H2S-induced pathology. Injury to and regeneration of the nasal respiratory mucosa occurred in animals with ongoing H2S exposure, suggesting that the regenerated respiratory epithelium under-goes an adaptive response and becomes resistant to further injury. To better understand this response, ten-week-old male Sprague-Dawley rats were exposed nose-only to either air or 200 ppm H2S for three hours per day for one day or five consecutive days. Nasal respiratory epithelial cells at the site of injury and regeneration were laser capture microdissected, and gene expression profiles were generated at three, six, and twenty-four hours after the initial three-hour exposure and at twenty-four hours after the fifth exposure using the Affymetrix Rat Genome 230 2.0 microarray. Gene ontology enrichment analysis showed that H2S exposure altered gene expression associated with a variety of biological processes, including cell cycle regulation, protein kinase regulation, and cytoskeletal organization and biogenesis. Surprisingly, our results did not show a significant change in cytochrome oxidase gene expression or bioenergetics.

PMID: 18467678 [PubMed - in process]

(Source: Toxicologic Pathology)

Human hepatocytes can repopulate mouse liver: histopathology of the liver in human hepatocyte-transplanted chimeric mice and toxicologic responses to acetaminophen.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Human hepatocytes can repopulate mouse liver: histopathology of the liver in human hepatocyte-transplanted chimeric mice and toxicologic responses to acetaminophen.

Toxicol Pathol. 2008;36(4):581-91

Authors: Sato Y, Yamada H, Iwasaki K, Tateno C, Yokoi T, Yoshizato K, Horii I

A human hepatocyte-transplanted chimeric mouse has been established by transplantation of human hepatocytes to urokinase-type plasminogen activator transgenic/severe combined immunodeficiency (uPA(+/+)/SCID) mice. These chimeric mice have various amounts of human hepatocytes that proliferate extensively and progressively replace mouse hepatocytes. In the chimeric liver, hepatic cords and sinusoid-like structures were observed. The human hepatocytes expressed human albumin, human cytochrome P450 enzymes, and human transporter proteins. Furthermore, electron microscopic analysis demonstrated bile canaliculi associated with human hepatocytes in the chimeric mouse livers. These results indicate that the chimeric mouse livers contain functionally intact and differentiated human hepatocytes. Additionally, the toxicologic response of hepatocytes to acetaminophen (APAP) administration was compared in normal and chimeric mouse livers. Following 1,400 mg/kg APAP, mild hepatocellular degeneration was observed in the human hepatocyte areas in the chimeric mice, compared with severe centrilobular hepatocellular necrosis in the ICR mouse livers. In conclusion, these chimeric livers contain functionally differentiated human hepatocytes, and are less susceptible to APAP toxicity, compared to ICR mice.

PMID: 18467679 [PubMed - in process]

(Source: Toxicologic Pathology)

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Comparative hepatic effects of perfluorooctanoic acid and wy 14,643 in ppar-alpha knockout and wild-type mice.

Toxicologic Pathology — Fri, 05 Sep 2008 07:49:55 +0100

Comparative hepatic effects of perfluorooctanoic acid and WY 14,643 in PPAR-alpha knockout and wild-type mice.

Toxicol Pathol. 2008;36(4):632-9

Authors: Wolf DC, Moore T, Abbott BD, Rosen MB, Das KP, Zehr RD, Lindstrom AB, Strynar MJ, Lau C

Perfluorooctanoic acid (PFOA) is a chemical used in the production of fluoropolymers. Its persistence in the environment and presence in humans and wildlife has raised health concerns. Liver tumor induction by PFOA is thought to be mediated in rodents by PPAR-alpha. A recent US EPA scientific advisory board questioned the contribution of PPAR-alpha in PFOA-induced liver tumors. Liver response in CD-1, SV/129 wild-type (WT), and PPAR-alpha knockout (KO) SV/129 mice was evaluated after seven daily treatments of PFOA-NH4(+) (1, 3, or 10 mg/kg, p.o.) or the prototype PPARalpha-agonist Wyeth 14,643 (WY, 50 mg/kg). Livers were examined by light and electron microscopy. Proliferation was quantified after PCNA immunostaining. PFOA treatment induced a dose-dependent increase in hepatocyte hypertrophy and labeling index (LI) similar to WY in WT mice. Ultrastructural alterations of peroxisome proliferation were similar between WY-treated and 10 mg/kg PFOA-treated WT mice. KO mice had a dose-dependent increase in hepatocyte vacuolation but increased LI only at 10 mg PFOA/kg. WY-treated KO mice were not different from KO control. These data suggest that PPAR-alpha is required for WY- and PFOA-induced cellular alterations in WT mouse liver. Hepatic enlargement observed in KO mice may be due to an accumulation of cytoplasmic vacuoles that contain PFOA.

PMID: 18467680 [PubMed - in process]

(Source: Toxicologic Pathology)