AFIP Wednesday Slide Conference - No. 18
January 27, 1999

Conference Moderator:
LTC David G. Young
US Army Center for Health Promotion and Preventive Medicine
Directorate of Toxicology
Aberdeen Proving Ground, MD 21010-5422
NOTE: Click on images for larger views. Use browser's "Back" button to return to this page.
Return to WSC Case Menu

Case I - PV98203 (AFIP 2640100)

Signalment: Three-month-old, female, Maltese dog.
History: This puppy was presented to an emergency clinic in respiratory distress. It was purchased from a pet shop a few days before, and the owner wanted only supportive care until she could return the pup. It was quiet and anxious, with pale mucous membranes and labored respiratory effort. There was no history of trauma, nor any oral burns. The pup died after one hour of oxygen therapy, and neurogenic pulmonary edema was the tentative diagnosis.
Case 18-1. Note: Though not well visualized here, the probe extends through the aortic valve, up the aorta, through a patent ductus arteriosus, and out the pulmonary artery.
Gross Pathology: The clinician performed the postmortem examination and noted very dark, congested to hemorrhagic lungs, with abundant edema fluid in all airways. The heart was reportedly of normal size with no septal or valvular defects, and the veterinarian stressed that there was no patent ductus arteriosus. The "pluck", containing the lungs and heart, and liver, kidney and ileum were received for histopathologic processing.
Laboratory Results: None.
Contributor's Diagnoses and Comments:
1. Pulmonary arterial hypertrophy, plexiform, with alveolar edema.
2. Acute bacterial pneumonia.
The pneumonia was judged to be the result of aspiration and unrelated to the very unusual mural and intimal hypertrophy of the small pulmonary vessels. There is endothelial hyperplasia, but no mural fibrinoid necrosis. At prosection, the fixed right heart seemed hypertrophied as compared to the left, but the heart base was not further dissected.
This form of plexogenic pulmonary arteriopathy appears to be scantily represented in veterinary textbooks. In consultation with the Armed Forces Institute of Pathology, these arterial lesions were interpreted as consistent with pulmonary hypertension, either primary or secondary to a left-to-right shunt, such as a septal defect or patent ductus arteriosus (PDA). The visceral congestion, pulmonary edema and right ventricular hypertrophy support that interpretation.
Based on the assessment of the pulmonary histopathology, the fixed incised heart was retrieved and re-dissected, revealing a three millimeter patent ductus arteriosus. The probe in the submitted gross photo has been placed through the lumen from aorta to pulmonary trunk. In the case of this pup, the patent ductus must have induced significant secondary pulmonary hypertension as well as the suggestion of cor pulmonale. This is one extreme of the spectrum of lesions seen, and not all PDA's are associated with significant hypertension.
20x obj
Case 18-1. Lung. Note intimal and medial hyperplasia of small arteries which nearly or completely occlude the lumens. The adjacent interstitium is expanded by lymphocytes, anthracotic pigment, and cell debris.
AFIP Diagnosis: Lung: Arteriopathy, plexiform, multifocal, moderate, with diffuse congestion and multifocal alveolar edema, Maltese, canine.
Note: Some sections may contain minimal acute interstitial inflammation associated with bacilli.
Conference Note: Pulmonary hypertension induces a spectrum of vascular lesions in the lung, some of which have characteristic microscopic features with diagnostic significance. Although vessel changes may involve the entire arterial tree, the lesions are most prominent in arterioles and small arteries. The lesions of the pulmonary vasculature in this Maltese puppy are characterized by multifocal medial hypertrophy of small to medium-sized arterioles, loss of the internal elastic lamina, and extensive hyperplasia of the tunica intima that narrows or occludes vessel lumens. Occasionally, the hyperplastic endothelium forms tufts of small, glomerulus-like, capillary channels that span the lumens of dilated arterioles, resembling a network or web (hence, plexogenic pulmonary arteriopathy). Multifocally, there is fibrosis of the alveolar interstitium.
As noted by the contributor, the vascular lesions in this puppy represent an extreme response to prolonged pulmonary hypertension. Plexogenic pulmonary arteriopathy is an uncommon finding in domestic animals. This lesion is an end-stage arterial disease associated with a poor prognosis, even with correction of the underlying condition. Pulmonary blood pressure in humans is normally about one eighth of systemic arterial pressure, and pulmonary hypertension results when pulmonary vascular pressure reaches one fourth of systemic levels. Cardiac conditions in animals causing pulmonary hypertension include anomalies resulting in left-to-right shunts, usually a ventricular septal defect or PDA. In humans, pulmonary plexogenic arteriopathy may also occur in cases of idiopathic primary pulmonary hypertension.
Pulmonary hypertension can also result from any abnormality that restricts blood flow through the lungs; right ventricular dilatation with right-sided heart failure often follows, referred to as cor pulmonale (or pulmonary heart disease). Hypoxia can be a significant cause of pulmonary hypertension in animals, and results from any primary disease of the lung, or may occur as a consequence of reduced atmospheric oxygen, such as that found at altitudes above 7,000 feet (approximately 2,100 meters). "High altitude sickness" is most often reported in cattle. Alveolar hypoxia causes the pulmonary arterioles to constrict. Hypoxia results in acidosis which also directly induces vasoconstriction of pulmonary arterioles. Prolonged hypoxia may lead to polycythemia and increased blood viscosity, further increasing pulmonary blood pressure.
Participants identified variable numbers of bacilli in the lung, and some sections contain minimal acute inflammation in the adjacent pulmonary interstitium. In other sections, no inflammatory response was found. Participants agreed with the contributor, and interpreted the bacteria as a probable result of aspiration shortly prior to death.
Contributor: PATHVET Consultation Services, 3015 Roxanne Avenue, Long Beach, CA 90808.
1. Kolzik L, Schoen FJ: The lung. In: Robbins Pathologic Basis of Disease, 5th ed., Cotran RS, Kumar V, Robbins SL, Schoen FJ, eds., pp. 680-682, WB Saunders, Philadelphia, 1994.
2. Kuhn C III, Askin FB: Lung and mediastinum. In: Anderson's Pathology, 9th edition, Kissane JM, ed., vol. 1, pp. 954-958, CV Mosby, St. Louis, 1990.
3. Spencer H: In: Pathology of the Lung (Excluding Pulmonary Tuberculosis), 3rd edition, vol. 2, pp. 579-615, Pergamon Press, Oxford, 1979.
4. Dungworth DL: The respiratory system. In: Pathology of Domestic Animals, 4th edition, Jubb KVF, Kennedy PC, Palmer N, eds., vol. 2, pp. 588-589, Academic Press, San Diego, 1993.
5. Robinson WF, Maxie MG: The cardiovascular system. In: Pathology of Domestic Animals, 4th ed., Jubb KVF, Kennedy PC, Palmer N, eds., vol. 3, pp. 50-58, 65-66, Academic Press, San Diego, 1993.
6. Jones TC, Hunt RD, King NW: Cardiovascular system. In: Veterinary Pathology, 6th ed., pp. 983-984, Williams and Wilkins, Baltimore, 1997.

Case II - 96-3954 (AFIP 2648141)

Signalment: Three to five-month-old, grower pigs.
History: Thirteen out of 45 grower pigs, 3 to 5 months of age, kept in four different pens, died within two days after being fed a newly received batch of commercial pig ration supplied by a small feed manufacturing company. The most obvious symptoms were dog-sitting postures, posterior paresis, and loud squealing when disturbed. Death occurred within one to two days of initial appearance of clinical signs. Two pigs were presented for necropsy examination.
Gross Pathology: No significant changes were identified at necropsy. The stomach was moderately filled with fresh residual food of the same appearance and texture as the ration presented for examination.
Laboratory Results: Selenium levels as determined by mass spectrometry in blood (4.9 mg/kg), liver (6.96 mg/kg), kidney (9.07 mg/kg), residual feed in the stomach (4.89 mg/kg), and in the feed ration (10.97mg/kg) were high when compared to maximal permissible levels in blood (0.14-0.19 mg/kg)2,6, liver (<2 mg/kg)2, kidney (<2mg/kg)2 and feed according to the level approved for pigs (0.3 mg/kg) by the Food and Drug administration (FDA) in the USA1,3,8.
Contributor's Diagnosis and Comments: Motoneuronal necrosis, spinal cord, multifocal, acute, mild.
Hematoxylin and eosin stained transverse and longitudinal sections of spinal cord of the lumbosacral area are submitted. There is bilaterally symmetrical degeneration and necrosis of the motor neurons in the ventral horns of the grey matter. These changes comprise swelling, chromatolysis, increased eosinophilia, fading of nuclear membranes, and nuclear pyknosis. In the surrounding grey matter, there is marked oedema characterized by vacuolation of the neuropil, dilation of perivascular and perineuronal spaces, presence of eosinophilic fibrillar to floccular material (probably protein) in the perivascular spaces, and mild swelling of astrocytes. Small arterioles in the grey matter reveal mild swelling of endothelial cells as well as mild fibrinoid change of the walls. A few small foci of perivascular and interstitial haemorrhage can also be seen within the grey matter. In the white matter, there is marked diffuse vacuolar change with mild to moderate axonal swelling.
In contrast to myelomalacia of predominantly the lumbosacral intumescences described in the literature,3,4,5 in this outbreak, acute neuronal degeneration and necrosis were noted in the motor neurons throughout all levels of the spinal cord, from the cervical to lumbosacral region. There were no other significant histopathological changes, apart from mild to moderate generalized congestion of organs, mild to moderate cardiomyopathy, and moderate nephrosis. Chronic lesions, such as roughness of the haircoat, coronitis and sloughing of the hooves, have been reported in cases which survive for longer periods.7 Histopathological changes in such cases range from multifocal areas of poliomyelomalacia to marked gliosis with marked gitter cell infiltration, effacement of neurons, and extensive capillary proliferation.5, 7 .
Supplementation of selenium to commercial rations to prevent deficiency requires great care due to its potential toxicity when excessive quantities are added. Maximal levels approved by the Food and Drug Administration (FDA) of the United States of America have been set at 0.3 mg/kg.1, 3,6 The history of an acute posterior paralytic syndrome of sudden onset with a relatively high morbidity and mortality, toxic levels of selenium in the feed, liver and kidney, and histopathological changes of acute neuronal degeneration and necrosis in the spinal cord correspond with that described for acute selenium intoxication in swine.3, 4,7 Similar clinical signs, macroscopic, and histopathologic changes have been reproduced in pigs by experimental feeding of excessive levels of selenium.1,5,9.
Acute selenium toxicosis in pigs should also be distinguished from poisoning with 6-amininicotinamide (6-AN) which produces nicotinamide (the amide of niacin, a B complex vitamin) deficiency. A marked similarity between the clinical signs and histopathological changes within the spinal cord have been reported with this intoxication in swine. 6-amininicotinamide is believed to have a toxic effect on the glial cells of both the central and enteric nervous systems, and it has been suggested that excessive levels of selenium may antagonize niacin.
2x obj20x obj
Case 18-2. Spinal cord. Neuronal degeneration, necrosis, and loss is responsible for fragmentation & collapse of spinal cord gray matter. At 20x, neuronal cytoplasm has increased eosinophilia and nuclei are karyorrhectic.
AFIP Diagnosis: Spinal cord, ventral gray horns: Neuronal necrosis, bilaterally symmetrical, breed unspecified, porcine.
Conference Note: Excessive supplementation of selenium in rations is a potential cause of selenium toxicity in animals. Chronic exposure to environmental sources of selenium is another. Current concern about selenium bioaccumulation in wetlands from seleniferous parts of the western United States has stimulated environmental sampling and studies of waterfowl in these areas. Selenium contamination of western wetlands results from irrigation drainage from nearby farmlands. Reduced reproductive success in waterfowl and fish from selenium contaminated wetlands is the most sensitive biologic index of toxicity.
The toxicology, clinical signs, and lesions of experimentally induced selenosis in adult mallard ducks were recently described in a study that simulated environmental selenium exposure by varying the concentration of the element added to the ration. In both subchronically and chronically exposed groups, selenosis was associated with weight loss, and in several birds, lesions in the liver and integument. The primary gross lesions in the subchronic exposure group were emaciation and hepatopathy, while the most distinctive macroscopic finding in the chronic exposure group was bilaterally symmetrical alopecia of the crown and neck. Necrosis of the maxillary beak (maxillary nail) and loss of nails from the digits also occurred in some chronically exposed birds. Other lesions that have been attributed to selenium toxicosis in waterfowl include cardiac lesions, cavitary effusion, pulmonary congestion or edema, renomegaly, and atrophy of the pancreas, spleen, and thymus.
Many of the lesions caused by selenosis in waterfowl are similar to those in mammals, several of which are described by the contributor. While acute selenium toxicosis may present as central nervous system disease, chronic selenium toxicosis may initially manifest as lesions of the integument. Alopecia of the dorsal midline in pigs and of the mane and tail in horses is a characteristic feature of selenosis. Experimentally induced selenosis in cattle causes dyskeratosis of the spinous layer of hair follicles. Hoof and nail deformity and loss occurs in cattle, horses, pigs, primates, and humans in subchronic cases of selenosis. The cutaneous lesions of selenosis are thought to result from replacement of sulfur in keratin or keratin-associated proteins by selenium.
Contributor: Pathology Section, P.O. Box 12502, Onderstepoort 0110, South Africa.
1. Casteel SW, Osweiler GD, Cook WO: Selenium toxicosis in swine. J Amer Vet Med Assoc 186:1084-1085, 1985.
2. Osweiler GD: Selenium toxicosis. In: Toxicology, pp. 201-203, Williams & Wilkins Co., Philadelphia, PA, 1996.
3. Penrith M-L, Robinson JTR: Acute selenium toxicosis as a cause of paralysis in pigs. J South African Vet Assoc 66:47-48, 1995.
4. Penrith M-L, Robinson JTR: Selenium toxicosis with focal symmetrical poliomyelomalacia in postweanling pigs in South Africa. Onderstepoort J Vet Res 63:171-179, 1996.
5. Harrison LH, et al.: Paralysis in swine due to focal symmetrical poliomalacia: Possible selenium toxicosis. Vet Pathol 20:265-273, 1983.
6. Stowe HD, et al.: Selenium toxicosis in feeder pigs. J Amer Vet Med Assoc 201:292-295, 1992.
7. Summers BA, Cummings JF, De Lahunta A: Selenium poisoning. In: Veterinary Neuropathology, 1st edition, pp. 258-261, Mosby Co., St. Louis, Missouri, 1995.
8. Wilson TM, Drake TR: Porcine focal symmetrical poliomyelomalacia. Canadian J Comp Med 46:218-220, 1982.
9. Wilson TM, Scholz RW, Drake TR: Selenium toxicity and porcine focal symmetrical poliomyelomalacia: Description of a field outbreak and experimental reproduction. Canadian J Comp Med 47:412-421, 1983.
10. Wilson TM, Cramer PG, Owen RL: Porcine focal symmetrical poliomalacia: Test for an interaction between dietary selenium and niacin. Canadian J Vet Res 53:454-461, 1989.
11. O'Toole D, Raisbeck MF: Experimentally induced selenosis of adult mallard ducks: Clinical signs, lesions, and toxicology. Vet Pathol 34:330-340, 1997.

Case III - 98-3345 (AFIP 2639842)

Signalment: A nine-month-old, aborted, equine fetus.
History: Spontaneous abortion occurred during the ninth month of gestation, with no significant clinical signs in the mare.
Gross Pathology: The fetus was well-preserved. There was congestion and interlobular edema of the lungs, and pleural effusion. There was congestion of the liver and excess peritoneal fluid.
Laboratory Results: Bacterial cultures were negative. Equine herpesvirus type I was demonstrated in the thymus, lungs and liver by the fluorescent antibody technique.
Contributor's Diagnosis and Comments: Multifocal necrotizing bronchopneumonia with eosinophilic intranuclear inclusion bodies.

Etiology : Equine herpesvirus type I.

This is a good example of the lung lesions caused by equine herpesvirus. There is diffuse congestion with interlobular and subpleural edema. There are multiple foci of necrosis and hemorrhage in the pulmonary parenchyma. Cells surrounding the necrotic foci contain small eosinophilic intranuclear inclusion bodies. Necrosis of bronchial and bronchiolar epithelium is also present, with cellular debris in the lumens, and intranuclear inclusions are present in cells near the necrotic areas. Focal necrosis and intranuclear inclusions were also present in the liver, spleen and thymus.
20x obj
Case 18-3. Lung. There is diffuse bronchiolar epithelial necrosis with scattered eosinophilic intranuclear inclusions (arrowhead), and several syncytial cells in various stages of degeneration. The bronchial lumen is filled with cell debris and the pulmonary interstitium is expanded by edema, a mixed cellular infiltrate, and cellular debris.
AFIP Diagnosis: Lung: Pneumonia, broncho-interstitial, necrotizing, acute, diffuse, severe, with syncytial cells, eosinophilic intranuclear inclusion bodies, edema, hemorrhage, and fibrin, breed unspecified, equine, etiology consistent with equine herpesvirus type I.
Conference Note: Equine herpesvirus type 1 (EHV-1) is currently one of three a-herpesviruses known to produce disease in horses. EHV-1 is associated with abortion, neonatal death, respiratory disease, and neurologic dysfunction, and has been referred to as equine abortion virus. The other two equine a-herpesviruses include EHV-3, the cause of equine coital exanthema, and EHV-4, which is primarily associated with respiratory disease (equine viral rhinopneumonitis) in young horses, but may also cause abortion. Thus, both EHV-1 and EHV-4 may cause respiratory disease and abortion; however, EHV-4 more frequently causes respiratory disease, and EHV-1 is the important cause of single and multiple abortions in mares. Furthermore, EHV-1 is the only equine herpesvirus which causes neurologic disease. EHV-2 and EHV-5 are g-herpesviruses as determined by DNA fragment analysis. Both have been associated with upper respiratory disease, though the pathogenic importance of EHV-2 is questionable since antibodies are commonly found in healthy and diseased horses.
EHV-1 is a potentially serious cause of reproductive disease in mares, and both sporadic and epizootic late-term abortions and stillbirths may occur. Typically, abortion is observed between the eighth and eleventh months of gestation. The fetus is usually aborted quickly without premonitory signs in the mare, and the fetus is fresh and well-preserved. The fetus is usually alive when abortion begins, and becomes asphyxiated during delivery. Gross examination of the abortus often reveals meconium staining of the amnion and fetus due to fetal diarrhea initiated by asphyxia. The presence of meconium and squames in bronchioles and alveoli in the examined sections of lung in this case suggests an attempt to breath by the fetus, and is consistent with previous observations of EHV-1 induced abortion. The most consistent gross lesions in the fetus are severe pulmonary edema and pleural effusion. Grossly and microscopically, necrosis may be present in the lungs, liver, spleen, and lymph nodes, and inclusions often occur adjacent to necrotic areas, especially in the liver and lungs. The placenta is usually unaffected.
EHV-1 may also manifest as severe respiratory disease in newborn foals infected late in gestation, and as central nervous system dysfunction in adult horses. Most foals infected with EHV-1 are born weak and eventually die, though some reports suggest beneficial affects of early acyclovir treatment in foals surviving infection. Sporadic cases of myeloencephalitis in adult horses caused by EHV-1 infection have been identified since the early 1970's. The disease results in sudden onset of ataxia that may rapidly progress to paralysis. Adult horses acquire the virus through exposure to an aborted fetus. Histologic lesions may occur in the brain, spinal cord, meninges and ganglia, characterized by nonsuppurative vasculitis with medial and endothelial necrosis. The vascular lesions may result in poliomalacia or leukomalacia. The virus does not appear to be neurotropic, and the character of the vascular changes suggests an immune complex type disease.
Contributor: Department. of Pathology and Microbiology, Faculty of Veterinary Medicine, Univer. of Montreal, C.P. 5000, St.Hyacinthe, Quebec, Canada J2S 7C6.
1. Jones TC, Hunt RD, King NW: Diseases caused by viruses. In: Veterinary Pathology, 6th ed., pp. 230-232, Williams and Wilkins, Baltimore, 1997.
2. Murray MJ, et al.: Neonatal equine herpesvirus type 1 infection on a thoroughbred breeding farm. J Vet Intern Med 12:36-41, 1998.
3. Telford EA, et al: Equine herpesviruses 2 and 5 are g herpesviruses. Virology 195:492-499, 1993.
4. Rooney JR, Robertson J: Respiratory system and female reproductive system. In: Equine Pathology, pp. 38-39, 246-248, Iowa State Univ. Press, 1996.
5. Kennedy PC, Miller RB: The female genital system. In: Pathology of Domestic Animals, Jubb, Kennedy, Palmer, eds., 4th ed., vol. 3, pp. 436-438, Academic Press, San Diego, CA, 1993.

Case IV - 192R, 195R, 192L (AFIP 2656744)

Signalment: Nine to ten-week-old, Crl:CD (SD) BR rat.
History: This rat was part of a group of positive controls dosed with 0.8% theophylline for 36 days.
Gross Pathology: None.
Laboratory Results: No significant findings.
Contributor's Diagnoses and Comments:
1. Testis: Moderate to severe, segmental testicular degeneration with giant cell formation, tubular dilation, sperm stasis and spermatocyte necrosis.
2. Moderate to severe, multifocal vasculitis (not all sections).
3. Rete testis: Moderate to severe sperm stasis with spermatocele.
Theophylline (1,3-dimethylxanthine) is closely related to caffeine. Theophylline has been used therapeutically to treat respiratory disorders due to its ability to relax smooth muscle. When given in large quantities, theophylline has been reported to cause testicular degeneration.
The testicular changes include formation of multinucleated giant cells (derived from coalescence of spermatids), retention of spermatozoa with sperm stasis, loss of germ cells (spermatogonia and spermatocytes) and tubular dilation. Sperm stasis in the rete testis with spermatocele formation likely contributed to the tubular dilation. Tubular dilation has also been proposed to be caused by theophylline suppression of seminiferous tubular contraction.
In some sections, there is a vasculitis/perivasculitis of a testicular blood vessel. Theo-phylline has been reported to cause vasculitis in rats, primarily affecting the mesenteric vessels. However, vascular inflammation can be found in many organs of theophylline-exposed rats.
The associated epididymal sections are largely devoid of spermatozoa. In some sections, there is a mild hyperplasia of the epididymis at the junction of the caput and cauda. The thickened epididymal epithelium forms infoldings. One animal also had spermatocele formation with progression to spermatic granuloma in the epididymis.
4x obj
Case 18-4. The left photo illustrates degeneration and loss of germ cells with marked dilation of a tubule by dense aggregates of spermatozoa and secretions (spermatocele). Other tubules are filled with ill defined debris including multinucleate giant cells which are barely visible. The image on the right demonstrates vasculitis and perivasculitis with fibrinoid change.
AFIP Diagnoses:
1. Testis: Degeneration and necrosis, germ cells, with numerous multinucleate spermatitic giant cells, and multifocal spermatoceles, Crl:CD (SD) BR rat, rodent.
2. Testis: Vasculitis, chronic-active, focal, moderate, with fibrinoid change and mild multifocal pericapsular lymphoplasmacytic perivasculitis and interstitial edema.
3. Epididymis: Sperm granuloma, focal.
Some sections contain peri-epididymal edema.
Conference Note: Theophylline, a methylxanthine closely related to caffeine and theobromine, occurs in small amounts in coffee and tea. As noted by the contributor, the drug relaxes smooth muscle of the pulmonary vasculature and bronchial airways, and also acts as a cardiac stimulant and diuretic. In humans, theophylline has been used in the treatment of asthma, emphysema, and certain cardiovascular conditions. Due to concerns about potential drug-induced neoplasia in humans subjected to prolonged theophylline therapy, oral feeding studies were conducted in which rats were given high doses of theophylline, theobromine, and caffeine. While these methylxanthines did not induce neoplastic or preneoplastic changes in treated animals, several other important toxicopathologic manifestations were identified, including histopathologic changes in the testes similar to those present in this rat. The testicular changes were most pronounced in caffeine and theobromine treated rats, and less severe in animals treated with theophylline.
Marked testicular changes have also been described in rabbits fed theobromine. Lesions were characterized as degeneration and necrosis of germ cells, formation of multinucleated spermatids and spermatocytes, and hemorrhage, congestion, and interstitial edema. Additionally, myocardial degeneration and necrosis, severe hemorrhage and premature involution of the thymus were found. In contrast, the characteristic clinicopathologic finding of iatrogenically induced theobromine toxicity in dogs is right atrial cardiomyopathy. Accidental methylxanthine poisoning has been reported in animals, and is usually a result of ingestion of excessive chocolate (theobromine) or over-the-counter stimulants by pets. Accidental theobromine toxicity usually manifests as central nervous system signs which begin as restlessness, hyperactivity, and urinary incontinence, and may progress to twitching, spastic contraction of muscles, and convulsions.
Differentiating testicular lesions induced by theophylline administration from degenerative changes resulting from other causes was a topic of discussion at the conference. Testicular maturation varies among species and strains. In rabbits, there is also significant variation among individuals of the same strain and age. Spermatitic giant cells (multinucleated spermatids/giant cells) have been interpreted as a degenerative change, but also have been reported in normal rats, rabbits, mice, dogs, pigs, and men. Microscopic degenerative lesions of the testes have been reported in ten to twelve-week-old Crl:CD/BR rats used as untreated controls in oral and inhalation toxicity studies. Varying degrees of seminiferous tubule degeneration with giant cell formation was described. While the mean incidence of testicular degenerative changes in control rats used in oral studies was low (2.5%), some seminiferous tubules had advanced stages of degeneration, including tubules lined by only Sertoli cells. Further, inanition is a clinical condition that may affect germ cell maturation. Theophylline is known to cause reduced food consumption in experimental laboratory animal studies. Thus, there may be several possible causes of germ cell degeneration and giant cell formation in the testis, including hypoxia due to vascular changes, sperm stasis as a result of smooth muscle relaxation, inanition, and age, strain, or individual animal variation. In experimental studies involving the testes, all potential causes of degenerative changes should be considered.
Contributor: Pfizer Central Research, Eastern Point Road, Groton, CT 06340.
1. Friedman L, et al.: Testicular atrophy and impaired spermatogenesis in rats fed high levels of the methylxanthines caffeine, theobromine, or theophylline. J Environ Pathol Toxicol 2:687-706, 1979.
2. Lindamood C, et al.: Studies on the short-term toxicity of theophylline in rats and mice. Fundam Appl Toxicol 10:477-489, 1988.
3. Morrissey RE, Collins JJ, Lamb JC, Manus AG and Gulati DK: Reproductive effects of theophylline in mice and rats. Fundam Appl Toxicol 10:525-536, 1988.
4. Weinberger MA, et al.: Testicular atrophy and impaired spermatogenesis in rats fed high levels of the methylxanthines caffeine, theobromine, or theophylline. J Environ Pathol Toxicol 1:669-688, 1978.
5. Yuan YD, Kennedy AH and Ochoa R: Testicular toxicity of theophylline in rats. Toxicol Pathol 22:655, 1994.
6. Soffietti MG, et al.: Toxic effects of theobromine on mature and immature male rabbits. J Comp Pathol 100:47-58, 1989.
7. Lee KP, Frame SR, Sykes GP, Valentine R: Testicular degeneration and spermatid retention in young male rats. Toxicol Pathol 21:292-302, 1993.
8. Frame SR, Hurtt ME, Green JW: Testicular maturation in prepubertal New Zealand white rabbits. Vet Pathol 31:541-545, 1994.
9. Morton D, et al.: Spermatid giant cells, tubular hypospermatogenesis, spermatogonial swelling, cytoplasmic vacuoles, and tubular dilatation in the testes of normal rabbits. Vet Pathol 23:176-183, 1986.
Ed Stevens, DVM
Captain, United States Army
Registry of Veterinary Pathology*
Department of Veterinary Pathology
Armed Forces Institute of Pathology
(202)782-2615; DSN: 662-2615
* The American Veterinary Medical Association and the American College of Veterinary Pathologists are co-sponsors of the Registry of Veterinary Pathology. The C.L. Davis Foundation also provides substantial support for the Registry.
Return to WSC Case Menu