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Comparative and Experimental Pathology

Comparative pathology is a subspecialty of pathology (the study of disease) that compares and contrasts the manifestations of disease across species, including both humans and animals (as models for human physiological processes and diseases).

Experimental pathology is a subspecialty of pathology that investigates mechanisms of disease by testing hypothesis through carefully designed experiments. Veterinary pathologists are well suited to such work since they already deal with numerous animal species by way of both training and subsequent on-the-job diagnostic experience.

Dr. Bolon’s practice of comparative and experimental pathology embraces a large constellation of basic biological questions.  His main areas of expertise in this arena include: 

Animal Models

Traditional animal models employ animals with a spontaneous disease or induced condition (by deliberate manipulation) to test a hypothesis regarding the cause or progression of a disease.  In terms of toxicologic pathology, the manipulation is administration of a toxic substance.

Dr. Bolon is most familiar with animal models of immune-mediated joint disease (which resemble rheumatoid arthritis in humans) and neurodegenerative diseases (similar to human conditions like Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, and others).  He also is well versed in alternative systems for evaluating neurotoxicity including cell and whole embryo culture, microphysiological systems (“nerve-on-a-chip”), and tissue slices.

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Genetically Engineered Models

In recent years, intentional modification of genes to disrupt their function has exploded as a way of examining their involvement in causing a disease. In terms of toxicologic pathology, common uses for genetically engineered animals (mainly mice and rats) are as models for:

  • evaluating the structure and function of cells, tissues, and organs in animals with novel genetic modifications (a process called phenotypic analysis or phenotyping),
  • testing whether or not new therapeutic products might be effective treatments for a disease (by using an animal with the same gene defect and similar signs of disease as those seen in the human condition), or
  • examining how human-origin biomolecules interact with human cells inside the body (which is done in specially modified animals that contain human genes or human cells).
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Mouse Developmental Pathology

Mice are acknowledged models for evaluating normal and abnormal developmental events. In terms of toxicology, rodents and rabbits are the traditional models to screen for malformations following chemical exposure when assessing the safety of new materials.

Dr. Bolon has published widely in this area, coauthoring many well-recognized papers, book chapters, and reference book (Pathology of the Developing Mouse: A Systematic Approach) on various aspects of the anatomy and toxicologic pathology of embryonic and infant mice as well as the mouse placenta.

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White Papers

Animal Models

Classic Experimental Systems
Experimental “best” practices

  • Scudamore CL, Soilleux EJ, Karp NA, Smith K, Poulsom R, Herrington CS, Day MJ, Brayton CF, Bolon B, Whitelaw B, White ES, Everitt JI, Arends MJ (2016). Recommendations for minimum information for publication of experimental pathology data: MINPEPA guidelines. J Pathol 238(2):359-367

Immune-Mediated Arthritis

  • Bolon B, Morony S, Cheng Y, Hu Y-L, Feige U (2004). Osteoclast numbers in Lewis rats with adjuvant-induced arthritis: Identification of preferred sites and parameters for rapid quantitative analysis. Vet Pathol 41(1): 30-36.
  • Stolina M, Bolon B, Dwyer D, Middleton S, Duryea D, Kostenuik PJ, Feige U, Zack DJ (2008). The evolving systemic and local biomarker milieu at different stages of disease progression in rat collagen-induced arthritis. Biomarkers 13(7): 692-712
  • Stolina M, Bolon B, Middleton S, Dwyer D, Brown H, Duryea D, Zhu L, Rohner A, Pretorius J, Kostenuik P, Feige U, Zack D (2009). The evolving systemic and local biomarker milieu at different stages of disease progression in rat adjuvant-induced arthritis. J Clin Immunol 29(2): 158-174
  • Bolon B, Stolina M, King C, Middleton S, Gasser J, Zack D, Feige U (2011). Rodent preclinical models for developing novel anti-arthritic molecules: comparative biology and preferred methods for evaluating efficacy. J Biomed Biotechnol doi:10.1155/2011/569068, 21 pp [invited review]
  • Bolon B (2012). Cellular and molecular mechanisms of autoimmune disease. Toxicol Pathol 40(2): 216-229 [invited review]
  • Caplazi P, Baca M, Barck K, Carano RAD, DeVoss J, Lee WP, Bolon B, Diehl L (2015). Mouse models of rheumatoid arthritis. Vet Pathol 52(5): 819-826

Miscellaneous Systems and Diseases

  • Bucci TJ, Bolon B, Warbritton, AR, Chen JJ, Heindel JJ (1997). Influence of sampling on the reproducibility of ovarian follicle counts in mouse toxicity studies. Repro Toxicol 11(5): 689-696
  • Aeffner F, Bolon B, Davis IC (2015). Mouse models of acute respiratory distress syndrome: Approaches, features, and measurements. Toxicol Pathol 43(8): 1074-1092 [invited review]

Novel Experimental Systems
Cell culture (mouse cerebrocortical cells)

  • Bolon B, Dorman DC, Bonnefoi MS, Randall H, Morgan KT (1993). Histopathologic approaches to chemical toxicity using primary cultures of dissociated neural cells grown in chamber slides. Toxicol Pathol 21(5): 465-479

    Microphysiological Systems

    • Sharma AD, McCoy L, Jacobs E, Willey H, Behn JQ, Nguyen H, Bolon B, Curley JL, Moore MJ (2019). Engineering a 3D functional human peripheral nerve in vitro using the Nerve-on-a-Chip platform. Sci Rep 9(1): 8921 (12 pp)

      Tissue Slices (brain)

      • Purcell R, Lynch G, Gall C, Johnson S, Sheng Z, Stephen MR, Cook J, Garman RH, Jortner B, Bolon B, Radin D, Lippa A (2018). Brain vacuolation resulting from administration of the type II ampakine CX717 is an artifact related to molecular structure and chemical reaction with tissue fixative agents. Toxicol Sci 162(2): 383-395

        Whole Embryo Culture (mouse)

        • Dorman DC, Bolon B, Struve MF, LaPerle KMD, Wong BA, Elswick B, Welsch F (1995). The role of formate in methanol-induced exencephaly in CD-1 mice. Teratology 52(1): 30-40

        Genetically Engineered Models

        Editorial Opinions

        • Bolon B, Brayton C, Cantor GH, Kusewitt DF, Loy JK, Sartin EA, Schoeb TR, Sellers RS, Schuh JCL, Ward JM (2008). Editorial: Best pathology practices in research using genetically engineered mice. Vet Pathol 45(6): 939-940

        Reviews

        • Bolon B (2004). Genetically engineered animals in drug discovery and development: A maturing resource for toxicologic research. Basic Clin Pharmacol Toxicol 95(4): 154-161
        • Bolon B (2007). Genetically engineered animals. In: Comprehensive Medicinal Chemistry, 2nd ed. (Taylor JB, Triggle DJ, series eds.), Vol. 3: Drug Discovery Technologies. (Kubinyi H, volume ed.). Elsevier, Oxford, pp. 151-170
        • Couto S, Bolon B, Cardiff RD (2012). Morphologic manifestations of gene-specific molecular alterations (“genetic addictions”) in mouse models of disease. Vet Pathol 49(1): 116-129 [invited review]
        • Bolon B, Couto S, Fiette L, La Perle K (2012). Internet and print resources to facilitate pathology analysis when phenotyping genetically engineered rodents. Vet Pathol 49(1): 224-235 [invited review].
        • Galbreath EJ, Pinkert CA, Bolon B, Morton D (2013). Genetically engineered animals in product discovery and development. In: Haschek and Rousseaux’s Handbook of Toxicologic Pathology, 3rd ed. (Haschek WM, Rousseaux CG, Wallig MA, Bolon B, Ochoa R, Mahler BW, eds.). Academic Press (Elsevier), San Diego, pp. 405–460

        Methods

          • Bolon B (2008). Whole mount enzyme histochemistry as a rapid screen at necropsy for expression of ß-galactosidase (LacZ)-bearing transgenes: Considerations for separating specific LacZ activity from non-specific (endogenous) galactosidase activity. Toxicol Pathol 36(2): 265-276

        Project Examples

        • Juan TS-C, Bolon B, Lindberg RA, Sun Y, Van G, Fletcher FA (2009). Mice over-expressing murine oncostatin M (OSM) exhibit changes in hematopoietic and other organs that are distinct from those of mice over-expressing human OSM or bovine OSM. Vet Pathol 46(1): 124-137
        • Berman-Booty LD, Thomas-Ahner JM, Bolon B, Oglesbee MJ, Clinton SK, Kulp SK, Chen C-S, La Perle KMD (2015). Extra-prostatic transgene-associated neoplastic lesions in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Toxicol Pathol 43(2): 186-197
        • Bolon B, Grisanti M, Villasenor K, Morony S, Feige U, Simonet WS (2015). Generalized degenerative joint disease in osteoprotegerin (Opg) null mutant mice. Vet Pathol 52(5): 873-882 [Featured article on cover]
        • Huey DD, Bolon B, La Perle KMD, Kannian P, Jacobson S, Ratner L, Green PL, Niewiesk S (2018). Role of wild-type and recombinant human T-cell leukemia viruses in lymphoproliferative disease in humanized NSG mice. Comp Med 68(1): 4-14

        Mouse Developmental Pathology

        • Bolon B, Welsch F, Morgan KT (1994). Methanol-induced neural tube defects in mice: Pathogenesis during neurulation. Teratology 49(6): 497-517
        • Bolon B (2014). Protocols for placental histology. In: The Guide to Investigations of Mouse Pregnancy (Croy A, Yamada AT, DeMayo FJ, Adamson SL, eds.). Academic Press (Elsevier), pp. 537–544.
        • Bolon B (2014). Pathology analysis of the placenta. In: Guide to Investigations of Mouse Pregnancy (Croy A, Yamada AT, DeMayo FJ, Adamson SL, eds.). Academic Press (Elsevier), pp. 175-188
        • Bolon B, Newbigging S, Boyd KL (2017). Pathology evaluation of developmental phenotypes in neonatal and juvenile mice. Curr Prot Mouse Biol 7(3): 191-219 [invited review].
        • Bolon B (2015). Pathology of the Developing Mouse: A Systematic Approach. CRC Press (Taylor and Francis), Boca Raton, FL, 430 pp