ABSTRACT
Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder characterized by synovitis that leads to cartilage and bone erosion by invading fibrovascular tissue. Mouse models of RA recapitulate many features of the human disease. Despite the availability of medicines that are highly effective in many patient populations, autoimmune diseases (including RA) remain an area of active biomedical research, and consequently mouse models of RA are still extensively used for mechanistic studies and validation of therapeutic targets. This review aims to integrate morphologic features with model biology and cover the key characteristics of the most commonly used induced and spontaneous mouse models of RA. Induced models emphasized in this review include collagen-induced arthritis and antibody-induced arthritis. Collagen-induced arthritis is an example of an active immunization strategy, whereas antibody- induced arthritis models, such as collagen antibody-induced arthritis and K/BxN antibody transfer arthritis, represent examples of passive immunization strategies. The coverage of spontaneous models in this review is focused on the TNFΔ (ARE) mouse, in which arthritis results from overexpression of TNF-α, a master proinflammatory cytokine that drives disease in many patients.
Subject(s)
Arthritis, Rheumatoid/veterinary , Disease Models, Animal , Animals , Arthritis/veterinary , Arthritis, Rheumatoid/etiology , Arthritis, Rheumatoid/pathology , Collagen/pharmacology , Inflammation/veterinary , MiceABSTRACT
Current treatments for acute myeloid leukemia (AML) are designed to target rapidly dividing blast populations with limited success in eradicating the functionally distinct leukemia stem cell (LSC) population, which is postulated to be responsible for disease resistance and relapse. We have previously reported high miR-126 expression levels to be associated with a LSC-gene expression profile. Therefore, we hypothesized that miR-126 contributes to 'stemness' and is a viable target for eliminating the LSC in AML. Here we first validate the clinical relevance of miR-126 expression in AML by showing that higher expression of this microRNA (miR) is associated with worse outcome in a large cohort of older (⩾60 years) cytogenetically normal AML patients treated with conventional chemotherapy. We then show that miR-126 overexpression characterizes AML LSC-enriched cell subpopulations and contributes to LSC long-term maintenance and self-renewal. Finally, we demonstrate the feasibility of therapeutic targeting of miR-126 in LSCs with novel targeting nanoparticles containing antagomiR-126 resulting in in vivo reduction of LSCs likely by depletion of the quiescent cell subpopulation. Our findings suggest that by targeting a single miR, that is, miR-126, it is possible to interfere with LSC activity, thereby opening potentially novel therapeutic approaches to treat AML patients.
Subject(s)
Leukemia, Myeloid, Acute/therapy , MicroRNAs/antagonists & inhibitors , Nanoparticles/administration & dosage , Neoplastic Stem Cells/physiology , Animals , DNA Methylation , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Leukocyte Common Antigens/antagonists & inhibitors , Mice , Mice, Inbred C57BL , MicroRNAs/physiology , Neoplastic Stem Cells/drug effectsABSTRACT
Bone structure is modulated by the interaction between receptor activator of nuclear factor-κB (RANK) and RANK ligand (RANKL). Osteoprotegerin (OPG), a decoy receptor for RANKL, modifies osteoclast-mediated bone resorption directly and spares articular cartilage indirectly in rodents with immune-mediated arthritis by preventing subchondral bone destruction. The OPG/RANKL balance also seems to be critical in maintaining joint integrity in osteoarthritis, a condition featuring articular bone and cartilage damage in the absence of profound inflammation. The current study explored the role of OPG in sparing articular cartilage by evaluating joint lesions in adult C57BL/6J mice lacking osteoprotegerin (Opg (-) (/-)). At 3, 5, 7, 9, and 12 months of age, both sexes of Opg (-) (/-) mice developed severe degenerative joint disease (DJD) characterized by progressive loss of cartilage matrix and eventually articular cartilage. Lesions developed earlier and more severely in Opg (-) (/-) mice relative to age-matched, wild-type (Opg (+) (/+)), or heterozygous (Opg (+) (/-)) littermates (P ≤ .05). The femorotibial joint was affected bilaterally at 3 months, while other key weight-bearing diarthrodial joints (eg, coxofemoral, scapulohumeral, humeroradioulnar) were affected later and unilaterally. Cortical bone in subchondral plates and long bone diaphyses of Opg (-) (/-) mice but not Opg (+/+) or Opg (+) (/-) animals was osteoporotic by 3 months of age (P ≤ .05); the extent of porosity was less than the degree of DJD. Closure of the physes in long bones (P ≤ .05) and cartilage retention in the femoral primary spongiosa (P ≤ .05) affected chiefly Opg (-) (/-) mice. These data suggest that OPG plays an essential direct role in maintaining cartilage integrity in the articular surfaces and physes.
Subject(s)
Joint Diseases/pathology , Osteoprotegerin/physiology , Animals , Bone and Bones/pathology , Joint Diseases/physiopathology , Joints/pathology , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
Veterinary pathologists working as toxicologic pathologists in academic settings fill many vital roles, such as diagnosticians, educators, and/or researchers. These individuals have spent years investigating pathology problems that mainly or exclusively focus on the reactions of cells, organs, or systems to toxic materials. Thus, academic toxicologic pathologists are uniquely suited both to help trainees understand toxicity as a cause of pathology responses and also to provide expert consultation on toxicologic pathology. Most toxicologic pathologists in academia are employed at colleges of medicine or veterinary medicine, even though specific toxicologic pathology faculty appointments are uncommon in Europe and North America. Academic toxicologic pathologists typically receive lower financial compensation than do toxicologic pathologists in industry, but academic positions generally provide alternative rewards, such as higher workplace autonomy and scheduling flexibility, professional enrichment through student interactions, and enhanced opportunities for collaborative research and advanced diagnostic investigations. Regular participation by academic toxicologic pathologists in professional training opportunities (eg, as pathology and toxicology instructors in medical and veterinary medical courses, graduate programs, and residencies) offers an important means of engendering interest and inspiring veterinarians to select toxicologic pathology and toxicology as their own areas of future expertise.
Subject(s)
Education, Veterinary , Pathology, Veterinary/education , Toxicology/education , Animals , Europe , Humans , North America , ResearchABSTRACT
T-cell acute lymphoblastic leukemia (T-ALL) is a neoplasia of thymocytes characterized by the rapid accumulation of the precursors of T lymphocytes. HMGA2 (high-mobility group AT-hook 2) gene expression is extremely low in normal adult tissues, but it is overexpressed in many tumors. To identify the biological function of HMGA2, we generated transgenic mice carrying the human HMGA2 gene under control of the VH promoter/Eµ enhancer. Approximately 90% of Eµ-HMGA2 transgenic mice became visibly sick between 4 and 8 months due to the onset and progression of a T-ALL-like disease. Characteristic features included severe alopecia (30% of mice); enlarged lymph nodes and spleen; and profound immunological abnormalities (altered cytokine levels, hypoimmunoglobulinemia) leading to reduced immune responsiveness. Immunophenotyping showed accumulation of CD5+CD4+, CD5+CD8+ or CD5+CD8+CD4+ T-cell populations in the spleens and bone marrow of sick animals. These findings show that HMGA2-driven leukemia in mice closely resembles spontaneous human T-ALL, indicating that HMGA2 transgenic mice should serve as an important model for investigating basic mechanisms and potential new therapies of relevance to human T-ALL.
Subject(s)
HMGA2 Protein/biosynthesis , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Animals , Cell Proliferation/physiology , Female , HMGA2 Protein/genetics , HMGA2 Protein/metabolism , Humans , Male , Mice , Mice, Transgenic , Phenotype , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathologyABSTRACT
Genetically engineered mice and rats are increasingly used as models for exploring disease progression and mechanisms. The full spectrum of anatomic, biochemical, and functional changes that develop in novel, genetically engineered mouse and rat lines must be cataloged before predictions regarding the significance of the mutation may be extrapolated to diseases in other vertebrate species, including humans. A growing list of reference materials, including books, journal articles, and websites, has been produced in the last 2 decades to assist researchers in phenotyping newly engineered rodent lines. This compilation provides an extensive register of materials related to the pathology component of rodent phenotypic analysis. In this article, the authors annotate the resources they use most often, to allow for quick determination of their relevance to research projects.
Subject(s)
Animals, Genetically Modified , Internet , Pathology , Phenotype , Publications , Rodentia/genetics , Animals , Female , Genetic Engineering , Genomics , Humans , Male , Mice , Mutation , Rats , Rodentia/classificationABSTRACT
Neoplasia in both animals and humans results in part from lasting activation of tumor-promoting genes ("oncogenes") or diminished function of genes responsible for preventing neoplastic induction ("tumor suppressor genes"). The concept of "genetic addiction" has emerged to indicate that neoplastic cells cannot maintain a malignant phenotype without sustained genotypic abnormalities related to aberrant activity of oncogene(s) and/or inactivity of tumor suppressor gene(s). Interestingly, some genetic abnormalities reliably produce distinct morphologic patterns that can be used as structural signatures indicating the presence of a specific molecular alteration. Examples of such consistent genetic/microanatomic pairings have been identified for mutated oncogenes, such as rising mucin-producing capacity with RAS overexpression, and mutated tumor suppressor genes-including PTEN eliciting cell hypertrophy, RB1 dictating neuroendocrine differentiation, and TRP53 encouraging sarcomatous transformation. Familiarity with the concept of genetic addiction, as well as the ability to recognize such regular genomic-phenotypic relationships, are of paramount importance for comparative pathologists who are engaged in phenotyping genetically engineered mice to help unravel genomic intricacies in both health and disease.
Subject(s)
Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/genetics , Genotype , Neoplasms/genetics , Phenotype , Animals , Disease Models, Animal , Genes, Tumor Suppressor , Genetic Engineering , Humans , Mice , Mice, Transgenic , Mutation , Neoplasms/pathology , OncogenesABSTRACT
The American College of Veterinary Pathologists commissioned a role delineation survey to define the specialized tasks, knowledge, and tools that define the current practice of veterinary clinical pathology and veterinary anatomic pathology. The survey also identified when competence was acquired for each task (i.e., before certification or after certification). The response rate by diplomates was high, with approximately 50% of practicing pathologists within each specialty responding to each survey. Using the survey results, all tasks for each specialty were classified as either appropriate or unsuitable for testing in the certifying examinations. The role delineation survey data will facilitate the creation of test plans that objectively define the content in each certifying examination, the evaluation and enhancement of training curricula, and the optimization of continuing education opportunities for practicing veterinary pathologists.
Subject(s)
Attitude of Health Personnel , Medicine , Pathology, Veterinary/education , Pathology, Veterinary/methods , Societies, Scientific , Specialization , Focus Groups , Pathology, Veterinary/standards , United StatesABSTRACT
Oncostatin M (OSM) and leukemia inhibitory factor (LIF) belong to the interleukin-6 family of cytokines. The authors' previous in vitro work demonstrated that in mouse cells mouse OSM (mOSM) signals through a heterodimeric receptor complex incorporating the mOSM-specific receptor mOSMRbeta while human OSM (hOSM) and bovine OSM (bOSM) use the mouse LIF receptor mLIFRbeta rather than mOSMRbeta. These in vitro data suggest that prior studies in mouse systems with hOSM or bOSM (the usual molecules used in early studies) reflect LIF rather than OSM biology. The current work assessed whether or not this divergence in actions among these three OSMs also occurs in vivo in mouse models. Adult female (C57BL/6J x DBA/2J) F(1) mice were engineered to stably overexpress mOSM, hOSM, or bOSM by retrovirus-mediated gene transfer (n = 10 or more per group). After 4 weeks, molecular and hematologic profiles and anatomic phenotypes in multiple organs were assessed by standard techniques. Animals overexpressing either hOSM or bOSM had an identical phenotype resembling that associated with LIF activation, including significant hematologic abnormalities (anemia, neutrophilia, lymphopenia, eosinopenia, and thrombocytosis); weight loss; profound enlargement (lymph node, spleen) and/or structural reorganization (lymph node, spleen, thymus) of lymphoid organs; and severe osteosclerosis. In contrast, mice overexpressing mOSM did not develop hematologic changes, weight loss, or osteosclerosis and exhibited more modest and anatomically distinct restructuring of lymphoid organs. These data indicate that activities imputed to OSM and the mOSMRbeta signaling pathway using in vitro and in vivo mouse experimental systems are unique to mOSM.
Subject(s)
Gene Expression , Oncostatin M Receptor beta Subunit/metabolism , Oncostatin M/metabolism , Phenotype , Receptors, OSM-LIF/metabolism , Signal Transduction/physiology , Animals , Blotting, Northern , Bone Marrow Transplantation , Cattle , Female , Genetic Vectors/genetics , Humans , Lymph Nodes/metabolism , Lymph Nodes/pathology , Mice , NIH 3T3 Cells , Oligonucleotides/genetics , Oncostatin M/genetics , Spleen/metabolism , Spleen/pathology , Thymus Gland/metabolism , Thymus Gland/pathologyABSTRACT
Mice with null mutations of ciliary neurotrophic factor (Cntf) receptor alpha (Cntf-Ralpha), or cytokine-like factor 1 (Clf), one component of Cntf-II (a heterodimeric Cntf-Ralpha ligand), die as neonates from motor neuron loss affecting the facial nucleus and ventral horn of the lumbar spinal cord. Exposure to cardiotrophin-like cytokine (Clc), the other putative Cntf-II element, supports motor neuron survival in vitro and in ovo. Confirmation that Clc ablation induces an equivalent phenotype to Clf deletion would support a role for Clc in the functional Cntf-II complex. In this study, Clc knockout mice had decreased facial motility, did not suckle, died within 24 hours, and had 32% and 29% fewer motor neurons in the facial nucleus and lumbar ventral horn, respectively; thus, Clc is essential for motor neuron survival during development. The concordance of the Clc knockout phenotype with those of mice lacking Cntf-Ralpha or Clf bolsters the hypothesis that Clc participates in Cntf-II.
Subject(s)
Cytokines/genetics , Cytokines/metabolism , Spinal Cord Diseases/genetics , Animals , Animals, Newborn , Mice , Mice, Knockout , Motor Neurons/pathology , Muscle, Skeletal/innervation , Spinal Cord/pathology , Spinal Cord Diseases/mortalityABSTRACT
Chronic exposure to low levels of fluorocarbon-based waste anaesthetic gas (WAG) has been linked to a multitude of human health problems. We have shown that isoflurane exhaust from passive gas-scavenging canisters is often quite high when using conventional rodent anaesthesia protocols and equipment. Another likely source of WAG build-up in rodent procedure rooms is leakage at the interface between the breathing circuit and the animal's face. We evaluated this possibility using three non-rebreathing circuits: traditional Bain, modified Bain, and Mapleson (type E). For the Mapleson E circuit, a conical rodent facemask was attached and used in one of two configurations: normal aperture, or aperture modified with a latex diaphragm (cut from an unpowdered surgical glove) to reduce the orifice diameter and tighten the seal. Adult female Sprague-Dawley rats were anaesthetized with isoflurane (5% for induction, 2% or 3.5% for maintenance) in oxygen (2 L/min for induction, 1 L/min for maintenance). Isoflurane leakage was assessed by real-time spectrophotometry. In 94% of the trials, three configurations - traditional Bain, modified Bain, and Mapleson E with unmodified mask - permitted isoflurane leakage approaching or exceeding 100 ppm at the face/port interface. In contrast, the Mapleson circuit with diaphragm-modified mask emitted significantly (PSubject(s)
Air Pollutants, Occupational/analysis
, Anesthesia, Inhalation/veterinary
, Anesthetics, Inhalation/analysis
, Isoflurane/analysis
, Occupational Exposure/adverse effects
, Anesthesia, Inhalation/adverse effects
, Animals
, Female
, Gas Scavengers/veterinary
, Humans
, Rats
, Rats, Sprague-Dawley
ABSTRACT
Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) synergistically induce and sustain arthritis. Two competing hypotheses of arthritis induction are 1) that TNF preferentially mediates inflammation, whereas IL-1 impels bone destruction, or 2) that either cytokine controls the entire process. In this study, these propositions were tested in two experiments by instilling IL-1beta or TNF-alpha into one knee of Lewis rats (n = 6/group) to incite arthritis, after which semiquantitative scores for inflammation, bone resorption, osteoclasts, and cartilage integrity were acquired. In the induction study, IL-1beta or TNF-alpha (3, 10, or 30 micro g) was given once to incite arthritis. After 2 days, IL-1beta induced significant, dose-dependent increases in inflammation (mild to marked), bone resorption (minimal to moderate), and osteoclasts (minimal to moderate). In contrast, TNF-alpha induced minimal to mild inflammation but had little impact on resorption or osteoclasts. Both IL-1 and TNF (>/=10 micro g) yielded mild cartilage degeneration. Most lesion scores in TNF-treated rats were significantly lower than those in animals given the same dose of IL-1beta. In the persistence study, rats were injected once with IL-1 or TNF (10 micro g) and maintained for 2, 3, or 7 days. IL-1beta significantly enhanced inflammation (all 3 days), bone resorption (days 2 and 3), osteoclasts (days 2 and 3), and cartilage matrix loss (days 2 and 3), whereas TNF-alpha augmented inflammation (days 2 and 3) and cartilage degeneration (day 2) but not bone resorption or osteoclasts. Thus, both IL-1beta and TNF-alpha can launch inflammation, but IL-1beta drives skeletal destruction.
Subject(s)
Arthritis, Experimental/pathology , Hindlimb/pathology , Interleukin-1/pharmacology , Joints/pathology , Tumor Necrosis Factor-alpha/pharmacology , Animals , Arthritis, Experimental/chemically induced , Bone Resorption/chemically induced , Cartilage/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Histological Techniques , Male , Osteoclasts/drug effects , Rats , Rats, Inbred LewABSTRACT
This study defined the best site for quantifying osteoclasts in male Lewis rats with mycobacteria-induced adjuvant arthritis. Hind paw sections of normal and arthritic rats (n = 6 per group) taken 7 days after disease onset were stained for osteoclasts using an anti-human cathepsin K primary antibody. Erosions and osteoclasts were assessed using semiquantitative scores (entire section) and quantitative measures (in calcaneus, navicular tarsal, and tibia). Bone area in arthritic rats was significantly reduced (P = 0.05) by 39-55%, with the greatest decrease in the tarsal. Osteoclasts in arthritic rats were significantly increased (P = 0.05) relative to normal in calcaneus (sevenfold), tarsal (194-fold), and tibia (threefold). The most useful quantitative indices were bone area and total osteoclasts, both defined as a percentage of total area measured. Semiquantitative scores for bone erosion and osteoclasts paralleled the quantitative indices. These data show that the navicular tarsal is the most sensitive site at which to assess arthritis in rats with this variant of adjuvant-induced arthritis.
Subject(s)
Arthritis, Experimental/pathology , Mycobacterium tuberculosis , Osteoclasts/pathology , Tuberculosis, Osteoarticular/pathology , Animals , Arthritis, Experimental/microbiology , Body Weights and Measures , Bone Resorption/veterinary , Cell Count , Histological Techniques , Male , Rats , Rats, Inbred Lew , Tarsus, Animal/pathology , Tuberculosis, Osteoarticular/microbiologyABSTRACT
Daily osteoprotegerin (OPG) injection for 7 or more days prevents bone loss for 3 weeks in rats with adjuvant-induced arthritis (AdA). The present experiments defined the duration of bone protection in AdA provided by a single OPG bolus. Male Lewis rats received OPG at the onset or peak of clinical disease, after which bone mineral density (BMD), erosions, and osteoclasts were evaluated. An OPG bolus (4 mg/kg subcutaneously) at onset eliminated osteoclasts, preserved BMD for 7 days, and prevented bone erosions for 4 days. In contrast, an OPG bolus (1, 3, 10, or 30 mg/kg intravenously) given at the peak of disease eradicated osteoclasts in a dose-dependent manner but had no impact on bone integrity due to extensive pre-existing bone loss. These data indicate that one OPG injection will inhibit joint erosions for several days, and confirm that bone-sparing therapy must be initiated early in disease to protect joint integrity.
Subject(s)
Arthritis, Experimental/drug therapy , Bone and Bones/drug effects , Glycoproteins/pharmacology , Glycoproteins/therapeutic use , Receptors, Cytoplasmic and Nuclear/therapeutic use , Animals , Apoptosis/physiology , Bone Density , Bone Resorption , Bone and Bones/pathology , Disease Models, Animal , Hindlimb/pathology , Joints/drug effects , Joints/pathology , Male , Osteoclasts/metabolism , Osteoprotegerin , Rats , Rats, Inbred Lew , Receptors, Tumor Necrosis Factor , Recombinant Fusion ProteinsABSTRACT
Initially identified in high-grade gliomas, mutations in the PTEN tumor-suppressor are also found in many sporadic cancers and a few related autosomal dominant hamartoma syndromes. PTEN is a 3'-specific phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) phosphatase and functions as a negative regulator of PI3K signaling. We generated a tissue-specific deletion of the mouse homolog Pten to address its role in brain function. Mice homozygous for this deletion (PtenloxP/loxP;Gfap-cre), developed seizures and ataxia by 9 wk and died by 29 wk. Histological analysis showed brain enlargement in PtenloxP/loxP;Gfap-cre mice as a consequence of primary granule-cell dysplasia in the cerebellum and dentate gyrus. Pten mutant cells showed a cell-autonomous increase in soma size and elevated phosphorylation of Akt. These data represent the first evidence for the role of Pten and Akt in cell size regulation in mammals and provide an animal model for a human phakomatosis condition, Lhermitte-Duclos disease (LDD).
Subject(s)
Ataxia/genetics , Brain/metabolism , Cerebellar Diseases/genetics , Gene Deletion , Genes, Tumor Suppressor , Phosphoric Monoester Hydrolases/genetics , Seizures/genetics , Tumor Suppressor Proteins/genetics , Animals , Base Sequence , Brain/pathology , Cell Death/genetics , Cell Division/genetics , DNA Primers , Immunohistochemistry , Mice , Mice, Mutant Strains , Neurons/pathology , PTEN PhosphohydrolaseABSTRACT
Osteoprotegerin (OPG) regulates bone resorption by inhibiting osteoclast formation, function, and survival. The current studies employed a mouse ovariectomy (OVX) model of estrogen deficiency to investigate gene therapy with OPG as a means of preventing osteoporosis. Young adult females injected with a recombinant adenoviral (Ad) vector carrying cDNA of either full-length OPG or a fusion protein combining the hOPG ligand-binding domain with the human immunoglobulin constant domain (Ad-hOPG-Fc) developed serum OPG concentrations exceeding the threshold needed for efficacy. However, elevated circulating OPG levels were sustained for up to 18 months only in mice given Ad-hOPG-Fc. Administration of Ad-hOPG-Fc titers between 10(7) and 10(9) pfu yielded dose-dependent increases in serum OPG. Mice subjected to OVX or sham surgery followed by immediate treatment with Ad-hOPG-Fc had significantly more bone volume with reduced osteoclast numbers in axial and appendicular bones after 4 weeks. In contrast, animals given OVX and either a control vector or vehicle had significantly less bone than did comparably treated sham-operated mice. This study demonstrates that a single adenoviral gene transfer can produce persistent high-level OPG expression and shows that gene therapy to provide sustained delivery of OPG may prove useful in treating osteoporosis.
Subject(s)
Adenoviridae/genetics , Glycoproteins/genetics , Osteoporosis/therapy , Receptors, Cytoplasmic and Nuclear/genetics , Animals , Biological Assay , Blotting, Southern , Blotting, Western , Bone Density/drug effects , Bone Resorption , DNA, Complementary/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , Female , Humans , Ligands , Mice , Mice, Inbred C57BL , Osteoprotegerin , Ovariectomy , Ovary/physiology , Pelvis/diagnostic imaging , Radiography , Receptors, Tumor Necrosis Factor , Recombinant Fusion Proteins/metabolism , Time FactorsSubject(s)
Alzheimer Disease/enzymology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases/deficiency , Amyloid Precursor Protein Secretases , Amyloid beta-Protein Precursor/metabolism , Animals , Aspartic Acid Endopeptidases/genetics , Central Nervous System/enzymology , Endopeptidases , Mice , Mice, Knockout/genetics , Mice, Knockout/metabolism , Peripheral Nervous System/enzymology , Phenotype , Plaque, Amyloid/enzymologyABSTRACT
The chloracetanilide herbicide alachlor (2-chloro-2',6-diethyl-N-(methoxymethyl)-acetanilide) induces nasal neoplasms in rats following chronic dietary exposure. The present study sought to identify the cellular origin and mechanisms of tumor induction and progression. Male Long-Evans rats were fed alachlor (0 or 126 mg/kg/day) beginning at 6 weeks of age. Following 1 month of alachlor ingestion, neither histological abnormalities nor enhanced cell division (assessed by BrdU incorporation) occurred in any region of the nasal cavity. Six months of alachlor exposure resulted in proliferation of basal and nonbasal cells in the olfactory mucosa while inducing nasal masses in 7 of 15 animals. Tumors ranged from dysplastic plaques to polypoid adenomas and originated in the olfactory regions of the nasal cavity. Neoplasms were associated with regions of respiratory metaplasia and were often covered with a low cuboidal, poorly ciliated epithelium. Tumor cells did not express characteristics of the olfactory mucosa, including olfactory marker protein (OMP, for neurons) and NMa (antibody recognizing cytochrome P450 [CYP] 2A3, found in Bowman's glands). Sites of plaque and tumor development coincided with regions of NMa immunoreactivity. These data suggest that local metabolism is important in alachlor-induced olfactory tumors and support the concept that metaplastic respiratory epithelial cells give rise to the observed neoplasms.