Skip to main content
SpringerLink
Log in
Book cover

Toxicologic Pathology for Non-Pathologists pp 137–199Cite as

Pathology of the Gastrointestinal Tract and Exocrine Pancreas

  • Chapter
  • First Online:

  • 921 Accesses

Abstract

Xenobiotic-induced adverse effects in the alimentary system can result in a significant liability in drug development as well as after environmental exposures. Many of these adverse effects are manifested as functional disturbances such as nausea and diarrhea, but with increased exposures (dose or time), there can be morphological changes resulting in various nonneoplastic and neoplastic conditions. As the first site of exposure to ingested substances, the alimentary system serves as the first line of defense against xenobiotic exposure, and the target organs of injury or carcinogenesis depend not only on the xenobiotic but also on the animal model being used. Significant species differences in anatomy and physiology require an understanding of how these differences relate to human health risk, as well as to appropriate model selection for preclinical or hazard identification studies. This chapter will focus on the functional anatomy and physiology, background, and species-specific pathology of various species used in preclinical studies. In addition, various background and test article-related lesions in various organs in the alimentary system such as the oral cavity, salivary glands, esophagus, stomach, small and large intestine, and exocrine pancreas will be discussed. Additionally, discussion of various animal models used to study test article-related effects and recapitulate gastrointestinal disease in humans will be reviewed.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   279.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Afonso-Pereira F, Dou L, Trenfield SJ, Madla CM, Murdan S, Sousa J, Veiga F, Basit AW (2018) Sex differences in the gastrointestinal tract of rats and the implications for oral drug delivery. Eur J Pharm Sci 115:339–344

    Article  CAS  PubMed  Google Scholar 

  • Al-Saffar A, Nogueira da Costa A, Delaunois A, Leishman DJ, Marks L, Rosseels ML, Valentin JP (2015) Gastrointestinal safety pharmacology in drug discovery and development. Handb Exp Pharmacol 229:291–321

    Article  PubMed  Google Scholar 

  • Anonymous (2012) ICH harmonized tripartite guideline: safety pharmacology studies for human pharmaceuticals S7A. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7A/Step4/S7A_Guideline.pdf

  • Aps JK, Martens LC (2005) Review: the physiology of saliva and transfer of drugs into saliva. Forensic Sci Int 150:119–131

    Article  CAS  PubMed  Google Scholar 

  • Arany S, Benoit DS, Dewhurst S, Ovitt CE (2013) Nanoparticle-mediated gene silencing confers radioprotection to salivary glands in vivo. Mol Ther 21:1182–1194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bertaccini G, Coruzzi G, Poli E (1991) Review article: the histamine H3-receptor: a novel prejunctional receptor regulating gastrointestinal function. Aliment Pharmacol Ther 5:585–591

    Article  CAS  PubMed  Google Scholar 

  • Bertram TA, Ludlow JW, Basu J, Muthupalani S (2013) Digestive tract. In: Haschek WM, Rousseaux CG, Wallig MA (eds) Haschek and Rousseaux’s handbook of toxicologic pathology, vol 3. Academic Press, New York, pp 2277–2359

    Chapter  Google Scholar 

  • Betton GR, Dormer CS, Wells T, Pert P, Price CA, Buckley P (1988) Gastric ECL-cell hyperplasia and carcinoids in rodents following chronic administration of H2-antagonists SK&F 93479 and oxmetidine and omeprazole. Toxicol Pathol 16:288–298

    Article  CAS  PubMed  Google Scholar 

  • Bhaskaran M, Cornwell PD, Sorden SD, Elwell MR, Russell NR, Pritt ML, Vahle JL (2018) Pancreatic effects of a Bruton’s tyrosine kinase small-molecule inhibitor in rats are strain-dependent. Toxicol Pathol 46:460–472

    Article  CAS  PubMed  Google Scholar 

  • Blom H (1986) Alterations in gastric mucosal morphology induced by long-term treatment with omeprazole in rats. Digestion 35 Suppl 1:98–105

    Article  CAS  PubMed  Google Scholar 

  • Bockman DE, Guo J, Buchler P, Muller MW, Bergmann F, Friess H (2003) Origin and development of the precursor lesions in experimental pancreatic cancer in rats. Lab Investig 83:853–859

    Article  PubMed  Google Scholar 

  • Bode G, Clausing P, Gervais F, Loegsted J, Luft J, Nogues V, Sims J, Steering Group of the RETHINK Project (2010) The utility of the minipig as an animal model in regulatory toxicology. J Pharmacol Toxicol Methods 62:196–220

    Article  CAS  PubMed  Google Scholar 

  • Boorman GA, Banas DA, Eustis SL, Haseman JK (1987) Proliferative exocrine pancreatic lesions in rats. The effect of sample size on the incidence of lesions. Toxicol Pathol 15:451–456

    Article  CAS  PubMed  Google Scholar 

  • Booth WD, Hay MF, Dott HM (1973) Sexual dimorphism in the submaxillary gland of the pig. J Reprod Fertil 33:163–166

    Article  CAS  PubMed  Google Scholar 

  • Botts S, Leininger JR (2018) Salivary glands. In: Boorman GA (ed) Boorman’s pathology of the rat. Academic Press, London/San Diego, pp 23–34

    Chapter  Google Scholar 

  • Botts S, Jokinen M, Gaillard ET, Elwell MR, Mann PC (1999) Salivary, Harderian, and lacrimal glands. In: Maronpot RR (ed) Pathology of the mouse. Cache Valley Press, St. Louis, pp 49–79

    Google Scholar 

  • Breider MA, Bleavins MR, Reindel JF, Gough AW, de la Iglesia FA (1996) Cellular hyperplasia in rats following continuous intravenous infusion of recombinant human epidermal growth factor. Vet Pathol 33:184–194

    Article  CAS  PubMed  Google Scholar 

  • Brenneman KA, Ramaiah SK, Rohde CM, Messing DM, O’Neil SP, Gauthier LM, Stewart ZS, Mantena SR, Shevlin KM, Leonard CG, Sokolowski SA, Lin H, Carraher DC, Jesson MI, Tomlinson L, Zhan Y, Bobrowski WF, Bailey SA, Vogel WM, Morris DL, Whiteley LO, Davis JW 2nd. (2014) Mechanistic investigations of test article-induced pancreatic toxicity at the endocrine-exocrine interface in the rat. Toxicol Pathol 42:229–242

    Article  CAS  PubMed  Google Scholar 

  • Brenner GM, Stanton HC (1970) Adrenergic mechanism responsible for submandibular salivary glandular hypertrophy in the rat. J Pharmacol Exp Ther 173:166–175

    CAS  PubMed  Google Scholar 

  • Britton RA, Young VB (2014) Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology 146:1547–1553

    Article  CAS  PubMed  Google Scholar 

  • Burger GT, Frith CH, Townsend JW (1985) Myoepithelioma, salivary glands, mouse. In: Jones TC, Mohr U, Hunt RD (eds) Digestive system. Monographs on pathology of laboratory animals. Springer-Verlag, Berlin, pp 185–189

    Google Scholar 

  • Cattley RC, Popp JA, Vonderfecht SL (2019) Liver, gall bladder, and exocrine pancreas. In: Sahota PS et al (eds) Toxicologic pathology nonclinical safety assessment. CRC Press, Boca Raton, pp 451–484

    Google Scholar 

  • Caverly Rae JM, Frame SR, Kennedy GL, Butenhoff JL, Chang SC (2014) Pathology review of proliferative lesions of the exocrine pancreas in two chronic feeding studies in rats with ammonium perfluorooctanoate. Toxicol Rep 1:85–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chadwick KD, Fletcher AM, Parrula MC, Bonner-Weir S, Mangipudy RS, Janovitz E, Graziano MJ, Roy D, Reilly TP (2014) Occurrence of spontaneous pancreatic lesions in normal and diabetic rats: a potential confounding factor in the nonclinical assessment of GLP-1-based therapies. Diabetes 63:1303–1314

    Article  CAS  PubMed  Google Scholar 

  • Chamanza R, Marxfeld HA, Blanco AI, Naylor SW, Bradley AE (2010) Incidences and range of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) used in toxicity studies. Toxicol Pathol 38:642–657

    Article  PubMed  Google Scholar 

  • Chandra SA, Nolan MW, Malarkey DE (2010) Chemical carcinogenesis of the gastrointestinal tract in rodents: an overview with emphasis on NTP carcinogenesis bioassays. Toxicol Pathol 38:188–197

    Article  CAS  PubMed  Google Scholar 

  • Cheville NF (1979) Uremic gastropathy in the dog. Vet Pathol 16:292–309

    Article  CAS  PubMed  Google Scholar 

  • Chiu T, Chen HC (1986) Spontaneous basophilic hypertrophic foci of the parotid glands in rats and mice. Vet Pathol 23:606–609

    Article  CAS  PubMed  Google Scholar 

  • Creutzfeldt W, Stockmann F, Conlon JM, Folsch UR, Bonatz G, Wulfrath M (1986) Effect of short- and long-term feeding of omeprazole on rat gastric endocrine cells. Digestion 35 Suppl 1:84–97

    Article  CAS  PubMed  Google Scholar 

  • Dalziel JE, Young W, Bercik P, Spencer NJ, Ryan LJ, Dunstan KE, Lloyd-West CM, Gopal PK, Haggarty NW, Roy NC (2016) Tracking gastrointestinal transit of solids in aged rats as pharmacological models of chronic dysmotility. Neurogastroenterol Motil 28:1241–1251

    Article  CAS  PubMed  Google Scholar 

  • Dardick I, Jeans MT, Sinnott NM, Wittkuhn JF, Kahn HJ, Baumal R (1985) Salivary gland components involved in the formation of squamous metaplasia. Am J Pathol 119:33–43

    CAS  PubMed  PubMed Central  Google Scholar 

  • de Rijk EP, Ravesloot WT, Hafmans TG, van Esch E (2003) Multifocal ductal cell hyperplasia in the submandibular salivary glands of Wistar rats chronically treated with a novel steroidal compound. Toxicol Pathol 31:1–9

    Article  PubMed  CAS  Google Scholar 

  • Denny PC, Ball WD, Redman RS (1997) Salivary glands: a paradigm for diversity of gland development. Crit Rev Oral Biol Med 8:51–75

    Article  CAS  PubMed  Google Scholar 

  • Dethloff LA, Robertson DG, Tierney BM, Breider MA, Bestervelt LL (1997) Gastric gland degeneration induced in monkeys by the CCK-B/gastrin receptor antagonist CI-988. Toxicol Pathol 25:441–448

    Article  CAS  PubMed  Google Scholar 

  • Dincer Z, Jones S, Haworth R (2006) Preclinical safety assessment of a DNA vaccine using particle-mediated epidermal delivery in domestic pig, minipig and mouse. Exp Toxicol Pathol 57:351–357

    Article  CAS  PubMed  Google Scholar 

  • do Nascimento A, Barreto Rde C, Bozzo L, de Almeida OP (1985) Interaction of phenytoin and inflammation induces gingival overgrowth in rats. J Periodontal Res 20:386–391

    Article  PubMed  Google Scholar 

  • Dominick MA, Bobrowski WF, Metz AL (1990) Proliferative exocrine pancreatic lesions in aged Wistar rats. Toxicol Pathol 18:423–426

    Article  CAS  PubMed  Google Scholar 

  • Dressman JB (1986) Comparison of canine and human gastrointestinal physiology. Pharm Res 3:123–131

    Article  CAS  PubMed  Google Scholar 

  • Duarte-Vogel SM, Lawson GW (2011) Association between hair-induced oronasal inflammation and ulcerative dermatitis in C57BL/6 mice. Comp Med 61:13–19

    CAS  PubMed  PubMed Central  Google Scholar 

  • Elmore SA (2006) Enhanced histopathology of mucosa-associated lymphoid tissue. Toxicol Pathol 34:687–696

    Article  PubMed  PubMed Central  Google Scholar 

  • EPA (2005) Guidelines for carcinogen risk assessment, 40CFR part 261. US Government Printing Office, Washington, DC

    Google Scholar 

  • Esposito I, Konukiewitz B, Schlitter AM, Kloppel G (2014) Pathology of pancreatic ductal adenocarcinoma: facts, challenges and future developments. World J Gastroenterol 20:13833–13841

    Article  PubMed  PubMed Central  Google Scholar 

  • Frith CH, Heath JE (1994) Tumours of the salivary gland. In: Turusov VS, Mohr U (eds) Pathology of tumours in laboratory animals, vol 2. IARC Scientific Publications, Lyon, pp 115–139

    Google Scholar 

  • Frith CH, Townsend JW (1985) Histology and ultrastructure, salivary gland, mouse. In: Jones TC, Mohr U, Hunt RD (eds) Digestive system. Monographs on pathology of laboratory animals. Springer-Verlag, Berlin, pp 177–184

    Google Scholar 

  • Fujimiya M, Ataka K, Asakawa A, Chen CY, Kato I, Inui A (2012) Regulation of gastroduodenal motility: acyl ghrelin, des-acyl ghrelin and obestatin and hypothalamic peptides. Digestion 85:90–94

    Article  CAS  PubMed  Google Scholar 

  • Furness JB, Poole DP (2012) Nonruminant nutrition symposium: involvement of gut neural and endocrine systems in pathological disorders of the digestive tract. J Anim Sci 90:1203–1212

    Article  CAS  PubMed  Google Scholar 

  • Gelberg HB (2014) Comparative anatomy, physiology, and mechanisms of disease production of the esophagus, stomach, and small intestine. Toxicol Pathol 42:54–66

    Article  CAS  PubMed  Google Scholar 

  • Gold LS, Slone TH, Stern BR, Bernstein L (1993) Comparison of target organs of carcinogenicity for mutagenic and non-mutagenic chemicals. Mutat Res 286:75–100

    Article  CAS  PubMed  Google Scholar 

  • Gold LS, Manley NB, Slone TH, Ward JM (2001) Compendium of chemical carcinogens by target organ: results of chronic bioassays in rats, mice, hamsters, dogs, and monkeys. Toxicol Pathol 29:639–652

    Article  CAS  PubMed  Google Scholar 

  • Gopinath C, Prentise EE, Lewis DJ (1987) Atlas of experimental toxicologic pathology. In: Gresham GA (ed) Current histopathology. MPT Press, Lancaster, p 64

    Google Scholar 

  • Greaves P (2012) Histopathology of preclinical studies. Interpretation and relevance in drug safety evaluation. Elsevier, Amsterdam

    Google Scholar 

  • Hai B, Yang Z, Shangguan L, Zhao Y, Boyer A, Liu F (2012) Concurrent transient activation of Wnt/beta-catenin pathway prevents radiation damage to salivary glands. Int J Radiat Oncol Biol Phys 83:e109–e116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Havu N (1986) Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. Digestion 35 Suppl 1:42–55

    Article  CAS  PubMed  Google Scholar 

  • Hayakawa Y, Fox JG, Gonda T, Worthley DL, Muthupalani S, Wang TC (2013) Mouse models of gastric cancer. Cancers (Basel) 5:92–130

    Article  PubMed Central  Google Scholar 

  • Hirth RS, Evans LD, Buroker RA, Oleson FB (1988) Gastric enterochromaffin-like cell hyperplasia and neoplasia in the rat: an indirect effect of the histamine H2-receptor antagonist, BL-6341. Toxicol Pathol 16:273–287

    Article  CAS  PubMed  Google Scholar 

  • Horn CC, Kimball BA, Wang H, Kaus J, Dienel S, Nagy A, Gathright GR, Yates BJ, Andrews PL (2013) Why can’t rodents vomit? A comparative behavioral, anatomical, and physiological study. PLoS One 8:e60537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Igarashi T, Nakane S, Kitagawa T (1995) Predictability of clinical adverse reactions of drugs by general pharmacology studies. J Toxicol Sci 20:77–92

    Article  CAS  PubMed  Google Scholar 

  • Kanda N, Seno H, Kawada M, Sawabu T, Uenoyoma Y, Nakajima T, Konda Y, Fukui H, Takeuchi T, Chiba T (2006) Involvement of cyclooxygenase-2 in gastric mucosal hypertrophy in gastrin transgenic mice. Am J Physiol Gastrointest Liver Physiol 290:G519–G527

    Article  CAS  PubMed  Google Scholar 

  • Kararli TT (1995) Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm Drug Dispos 16:351–380

    Article  CAS  PubMed  Google Scholar 

  • Kinoshita H, Abe J, Akadegawa K, Yurino H, Uchida T, Ikeda S, Matsushima K, Ishikawa S (2006) Breakdown of mucosal immunity in gut by 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD). Environ Health Prev Med 11:256–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klein-Szanto AJ, Martin D, Sega M (1982) Hyperkeratinization and hyperplasia of the forestomach epithelium in vitamin A deficient rats. Virchows Arch B Cell Pathol Incl Mol Pathol 40:387–394

    Article  CAS  PubMed  Google Scholar 

  • Kostic AD, Xavier RJ, Gevers D (2014) The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146:1489–1499

    Article  CAS  PubMed  Google Scholar 

  • Kramer AW Jr, Dougherty WJ, Belson AR, Iatropoulos MJ (1985) Morphologic changes in the gastric mucosa of rats and dogs treated with an analog of prostaglandin E1. Toxicol Pathol 13:26–35

    Article  PubMed  Google Scholar 

  • Latimer KS, Rakich PM, Purswell BJ, Kircher IM (1986) Effects of cyclosporin A administration in cats. Vet Immunol Immunopathol 11:161–173

    Article  CAS  PubMed  Google Scholar 

  • Leininger JR, Schutten M (2018) Oral cavity, teeth, and gingiva. In: Boorman GA (ed) Boorman’s pathology of the rat. Academic Press, London/San Diego, pp 15–21

    Chapter  Google Scholar 

  • Leininger JR, McDonald MM, Abbott DP (1990) Hepatocytes in the mouse stomach. Toxicol Pathol 18:678–686

    Article  CAS  PubMed  Google Scholar 

  • Leininger JR, Jokinen MP, Dangler CA, Whiteley LO (1999) Oral cavity, esophagus and stomach. In: Maronpot RR (ed) Pathology of the mouse. Cache River Press, St. Louis, pp 29–48

    Google Scholar 

  • Logsdon CD, Lu W (2016) The significance of Ras activity in pancreatic cancer initiation. Int J Biol Sci 12:338–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lowenstine LJ (2003) A primer of primate pathology: lesions and nonlesions. Toxicol Pathol 31 Suppl:92–102

    PubMed  Google Scholar 

  • MacDonald JS, Scribner HE (1999) The maximum tolerated dose and secondary mechanisms of carcinogenesis. In: Kitchin K (ed) Carcinogenicity: testing, predicting, and interpreting chemical effects. Marcel Dekker, New York, pp 125–144

    Google Scholar 

  • Maekawa A, Enomoto M, Hirouchi Y, Yamakawa S (1996) Changes in the upper digestive tract and stomach. In: Mohr U, Dungworth DL, Capen CC, Carlton WW, Sundberg JP, Ward JM (eds) Pathobiology of the aging mouse, vol 2. ILSI Press, Washington, DC, pp 267–286

    Google Scholar 

  • Marks L, Beard E, Cobey D, Moore N, Motyer V, Valentin JP, Ewart L (2013) An evaluation of the non-invasive faecal pellet assessment method as an early drug discovery screen for gastrointestinal liability. J Pharmacol Toxicol Methods 68:123–136

    Article  CAS  PubMed  Google Scholar 

  • Matsuzaki J, Suzuki H, Minegishi Y, Sugai E, Tsugawa H, Yasui M, Hibi T (2010) Acid suppression by proton pump inhibitors enhances aquaporin-4 and KCNQ1 expression in gastric fundic parietal cells in mouse. Dig Dis Sci 55:3339–3348

    Article  CAS  PubMed  Google Scholar 

  • Mazzacca G, Cascione F, Budillon G, D’Agostino L, Cimino L, Femiano C (1978) Parietal cell hyperplasia induced by long-term administration of antacids to rats. Gut 19:798–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McInnes EF (2012) Background lesions in laboratory animals: a color atlas. Elsevier, Edinburgh

    Google Scholar 

  • McQuade RM, Stojanovska V, Donald E, Abalo R, Bornstein JC, Nurgali K (2016) Gastrointestinal dysfunction and enteric neurotoxicity following treatment with anticancer chemotherapeutic agent 5-fluorouracil. Neurogastroenterol Motil 28:1861–1875

    Article  CAS  PubMed  Google Scholar 

  • Merchant HA, McConnell EL, Liu F, Ramaswamy C, Kulkarni RP, Basit AW, Murdan S (2011) Assessment of gastrointestinal pH, fluid and lymphoid tissue in the guinea pig, rabbit and pig, and implications for their use in drug development. Eur J Pharm Sci 42:3–10

    Article  CAS  PubMed  Google Scholar 

  • Merchant HA, Rabbie SC, Varum FJ, Afonso-Pereira F, Basit AW (2014) Influence of ageing on the gastrointestinal environment of the rat and its implications for drug delivery. Eur J Pharm Sci 62:76–85

    Article  CAS  PubMed  Google Scholar 

  • Miller H, Zhang J, Kuolee R, Patel GB, Chen W (2007) Intestinal M cells: the fallible sentinels? World J Gastroenterol 13:1477–1486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nolte T, Brander-Weber P, Dangler C, Deschl U, Elwell MR, Greaves P, Hailey R, Leach MW, Pandiri AR, Rogers A, Shackelford CC, Spencer A, Tanaka T, Ward JM (2016) Nonproliferative and proliferative lesions of the gastrointestinal tract, pancreas and salivary glands of the rat and mouse. J Toxicol Pathol 29:1S–125S

    Article  PubMed  PubMed Central  Google Scholar 

  • NTP (2000) NTP toxicology and carcinogenesis studies of methyleugenol (CAS NO. 93-15-2) in F344/N rats and B6C3F1 mice (gavage studies). Natl Toxicol Program Tech Rep Ser 491:1–412

    Google Scholar 

  • Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W, Dorato M, Van Deun K, Smith P, Berger B, Heller A (2000) Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32:56–67

    Article  CAS  PubMed  Google Scholar 

  • Opoka W, Adamek D, Plonka M, Reczynski W, Bas B, Drozdowicz D, Jagielski P, Sliwowski Z, Adamski P, Brzozowski T (2010) Importance of luminal and mucosal zinc in the mechanism of experimental gastric ulcer healing. J Physiol Pharmacol 61:581–591

    CAS  PubMed  Google Scholar 

  • Pandiri AR (2014) Overview of exocrine pancreatic pathobiology. Toxicol Pathol 42:207–216

    Article  CAS  PubMed  Google Scholar 

  • Poh AR, O’Donoghue RJ, Ernst M, Putoczki TL (2016) Mouse models for gastric cancer: matching models to biological questions. J Gastroenterol Hepatol 31:1257–1272

    Article  PubMed  PubMed Central  Google Scholar 

  • Proctor DM, Gatto NM, Hong SJ, Allamneni KP (2007) Mode-of-action framework for evaluating the relevance of rodent forestomach tumors in cancer risk assessment. Toxicol Sci 98:313–326

    Article  CAS  PubMed  Google Scholar 

  • Qiu W, Su GH (2013) Challenges and advances in mouse modeling for human pancreatic tumorigenesis and metastasis. Cancer Metastasis Rev 32:83–107

    Article  CAS  PubMed  Google Scholar 

  • Raffa RB, Mathiasen JR, Jacoby HI (1987) Colonic bead expulsion time in normal and mu-opioid receptor deficient (CXBK) mice following central (ICV) administration of mu- and delta-opioid agonists. Life Sci 41:2229–2234

    Article  CAS  PubMed  Google Scholar 

  • Randelia HP, Lalitha VS (1988) Megaoesophagus in ICRC mice. Lab Anim 22:23–26

    Article  CAS  PubMed  Google Scholar 

  • Reindel JF, Pilcher GD, Gough AW, Haskins JR, de la Iglesia FA (1996) Recombinant human epidermal growth factor1-48-induced structural changes in the digestive tract of cynomolgus monkeys (Macaca fascicularis). Toxicol Pathol 24:669–680

    Article  CAS  PubMed  Google Scholar 

  • Reindel JF, Gough AW, Pilcher GD, Bobrowski WF, Sobocinski GP, de la Iglesia FA (2001) Systemic proliferative changes and clinical signs in cynomolgus monkeys administered a recombinant derivative of human epidermal growth factor. Toxicol Pathol 29:159–173

    Article  CAS  PubMed  Google Scholar 

  • Ruehl-Fehlert C, Kittel B, Morawietz G, Deslex P, Keenan C, Mahrt CR, Nolte T, Robinson M, Stuart BP, Deschl U, RITA Group, NACAD Group (2003) Revised guides for organ sampling and trimming in rats and mice--part 1. Exp Toxicol Pathol 55:91–106

    Article  PubMed  Google Scholar 

  • Savage NW, Barber MT, Adkins KF (1986) Pigmentary changes in rat oral mucosa following antimalarial therapy. J Oral Pathol 15:468–471

    Article  CAS  PubMed  Google Scholar 

  • Scarpelli DG (1989) Toxicology of the pancreas. Toxicol Appl Pharmacol 101:543–554

    Article  CAS  PubMed  Google Scholar 

  • Schmassmann A, Peskar BM, Stettler C, Netzer P, Stroff T, Flogerzi B, Halter F (1998) Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. Br J Pharmacol 123:795–804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seely JC (1996) Salivary glands. In: Mohr U, Dungworth DL, Capen CC, Carlton WW, Sundberg JP, Ward JM (eds) Pathobiology of the aging mouse, vol 2. ILSI Press, Washington DC, pp 261–265

    Google Scholar 

  • Shreiner AB, Kao JY, Young VB (2015) The gut microbiome in health and in disease. Curr Opin Gastroenterol 31:69–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simren M, Barbara G, Flint HJ, Spiegel BM, Spiller RC, Vanner S, Verdu EF, Whorwell PJ, Zoetendal EG, Rome Foundation Committee (2013) Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut 62:159–176

    Article  PubMed  Google Scholar 

  • Stephens LC, Ang KK, Schultheiss TE, King GK, Brock WA, Peters LJ (1986a) Target cell and mode of radiation injury in rhesus salivary glands. Radiother Oncol 7:165–174

    Article  CAS  PubMed  Google Scholar 

  • Stephens LC, King GK, Peters LJ, Ang KK, Schultheiss TE, Jardine JH (1986b) Unique radiosensitivity of serous cells in rhesus monkey submandibular glands. Am J Pathol 124:479–487

    CAS  PubMed  PubMed Central  Google Scholar 

  • Straub RH, Wiest R, Strauch UG, Harle P, Scholmerich J (2006) The role of the sympathetic nervous system in intestinal inflammation. Gut 55:1640–1649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Streett CS, Robertson JL, Crissman JW (1988) Morphologic stomach findings in rats and mice treated with the H2 receptor antagonists, ICI 125,211 and ICI 162,846. Toxicol Pathol 16:299–304

    Article  CAS  PubMed  Google Scholar 

  • Suklabaidya S, Dash P, Das B, Suresh V, Sasmal PK, Senapati S (2018) Experimental models of pancreatic cancer desmoplasia. Lab Investig 98:27–40

    Article  CAS  PubMed  Google Scholar 

  • Sundberg JP, Hanson CA, Roop DR, Brown KS, Bedigian HG (1991) Myoepitheliomas in inbred laboratory mice. Vet Pathol 28:313–323

    Article  CAS  PubMed  Google Scholar 

  • Surh I, Brix A, French JE, Collins BJ, Sanders JM, Vallant M, Dunnick JK (2013) Toxicology and carcinogenesis study of senna in C3B6.129F1-Trp53 tm1Brd N12 haploinsufficient mice. Toxicol Pathol 41:770–778

    Article  PubMed  CAS  Google Scholar 

  • Suttie AW, Masson R, Schutten M (2018) Exocrine pancreas. In: Boorman GA (ed) Boorman’s pathology of the rat. Academic Press, London/San Diego, pp 107–122

    Chapter  Google Scholar 

  • Suzuki I, Cho YM, Hirata T, Toyoda T, Akagi JI, Nakamura Y, Park EY, Sasaki A, Nakamura T, Okamoto S, Shirota K, Suetome N, Nishikawa A, Ogawa K (2016) 4-Methylthio-3-butenyl isothiocyanate (raphasatin) exerts chemopreventive effects against esophageal carcinogenesis in rats. J Toxicol Pathol 29:237–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takahashi M, Hori M, Mutoh M, Wakabayashi K, Nakagama H (2011) Experimental animal models of pancreatic carcinogenesis for prevention studies and their relevance to human disease. Cancers (Basel) 3:582–602

    Article  CAS  Google Scholar 

  • Tamamori Y, Tamura Y, Yamazaki T, Ohya K (2005) Establishment of rat model of drug-induced gingival overgrowth induced by continuous administration of phenytoin. J Pharmacol Sci 98:290–297

    Article  CAS  PubMed  Google Scholar 

  • Tsutsumi O, Taketani Y, Oka T (1993) Evidence for the involvement of epidermal growth factor in fertility decline in aging female mice. Horm Res 39 Suppl 1:32–36

    Article  CAS  PubMed  Google Scholar 

  • Ueda Y, Tsuboi M, Ota Y, Makita M, Aoshima T, Nakajima M, Narama I (2011) Gastric mucosal changes induced by polyethylene glycol 400 administered by gavage in rats. J Toxicol Sci 36:811–815

    Article  CAS  PubMed  Google Scholar 

  • Uehara T, Elmore SA, Szabo KA (2018) Esophagus and stomach. In: Boorman GA (ed) Boorman’s pathology of the rat. Academic Press, London/San Diego, pp 35–50

    Chapter  Google Scholar 

  • Valentin JP, Bialecki R, Ewart L, Hammond T, Leishmann D, Lindgren S, Martinez V, Pollard C, Redfern W, Wallis R (2009) A framework to assess the translation of safety pharmacology data to humans. J Pharmacol Toxicol Methods 60:152–158

    Article  CAS  PubMed  Google Scholar 

  • Vidal JD, Mirabile RC, Thomas HC (2008) Evaluation of the cynomolgus monkey stomach: recommendations for standard sampling procedures in nonclinical safety studies. Toxicol Pathol 36:250–255

    Article  PubMed  Google Scholar 

  • Wallig MA, Sullivan JM (2018) Exocrine pancreas. In: Wallig MA et al (eds) Fundamentals of toxicologic pathology, vol 2. Academic Press, London, pp 443–458

    Chapter  Google Scholar 

  • Ward JM, Yoon M, Anver MR, Haines DC, Kudo G, Gonzalez FJ, Kimura S (2001) Hyalinosis and Ym1/Ym2 gene expression in the stomach and respiratory tract of 129S4/SvJae and wild-type and CYP1A2-null B6, 129 mice. Am J Pathol 158:323–332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ward JM, Schofield PN, Sundberg JP (2017) Reproducibility of histopathological findings in experimental pathology of the mouse: a sorry tail. Lab Anim (NY) 46:146–151

    Article  Google Scholar 

  • Wester PW, Kroes R (1988) Forestomach carcinogens: pathology and relevance to man. Toxicol Pathol 16:165–171

    Article  CAS  PubMed  Google Scholar 

  • Whittaker P, Dunkel VC, Bucci TJ, Kusewitt DF, Thurman JD, Warbritton A, Wolff GL (1997) Genome-linked toxic responses to dietary iron overload. Toxicol Pathol 25:556–564

    Article  CAS  PubMed  Google Scholar 

  • Whittle MC, Hingorani SR (2017) Understanding disease biology and informing the management of pancreas cancer with preclinical model systems. Cancer J 23:326–332

    Article  PubMed  PubMed Central  Google Scholar 

  • Wood JD (1999) Mixing and moving in the gut. Gut 45:333–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoon YS, Shin JW, Park CB, Oh YS, Lee IS, Lee HS, Lee JS (2000) Morphological structure of accessory spleen in Chinese hamsters. J Vet Sci 1:73–75

    Article  CAS  PubMed  Google Scholar 

  • Yoshizawa K, Marsh T, Foley JF, Cai B, Peddada S, Walker NJ, Nyska A (2005) Mechanisms of exocrine pancreatic toxicity induced by oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Harlan Sprague-Dawley rats. Toxicol Sci 85:594–606

    Article  CAS  PubMed  Google Scholar 

  • Yu S, Yang M, Nam KT (2014) Mouse models of gastric carcinogenesis. J Gastric Cancer 14:67–86

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. In Vivo Animal Core, Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

    Mark J. Hoenerhoff

  2. Molecular Pathology Group, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle, NC, USA

    Arun Kumar R. Pandiri

Authors
  1. Mark J. Hoenerhoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arun Kumar R. Pandiri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arun Kumar R. Pandiri .

Editor information

Editors and Affiliations

  1. North Carolina Laboratory, Experimental Pathology Laboratories, Inc., Durham, NC, USA

    Thomas J. Steinbach

  2. Charles River Laboratories, Inc., Mattawan, MI, USA

    Daniel J. Patrick

  3. MEC Regulatory and Toxicology Consulting, LLC, Moorpark, CA, USA

    Mary Ellen Cosenza

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hoenerhoff, M.J., Pandiri, A.K.R. (2019). Pathology of the Gastrointestinal Tract and Exocrine Pancreas. In: Steinbach, T., Patrick, D., Cosenza, M. (eds) Toxicologic Pathology for Non-Pathologists. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9777-0_5

Download citation

Publish with us

Policies and ethics

Search

Navigation