(Mesocricetus auratus) - Hereditary Hydrocephalus in Laboratory-reared Golden Hamsters
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Vet Pathol 43:523–529 (2006)
Hereditary Hydrocephalus in Laboratory-reared Golden Hamsters
(Mesocricetus auratus)
J. F. EDWARDS, S. GEBHARDT-HENRICH, K. FISCHER, A. HAUZENBERGER, M. KONAR, AND A. STEIGER
Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences,
Texas A&M University, College Station, TX (JFE); and Institute of Animal Genetics,
Nutrition and Housing, Division of Animal Housing and Welfare (SG-H, KF, AH, AS)
and Vetsuisse Faculty, Division of Clinical Radiology (MK), Bern, Switzerland
Abstract. A colony of golden hamsters had an ongoing problem with hydrocephalus. In an attempt
to clear the colony of the problem, new breeders from another supplier had been purchased. At
termination of a behavioral study, the brain was collected from 35 animals (four of which had died with
hydrocephalus during the study) and was examined macroscopically and by light microscopy. Although
no animals manifested obvious behavioral changes, 31 of 35 (88.6%, 13/15 males and 18/20 females in
control and manipulated groups) had hydrocephalus. Twenty-five animals had macroscopically
identifiable hydrocephalus, and six had hydrocephalus identified microscopically. Neither teratogenic
concentrations of metals nor mycotoxins were detected in tissues or food, and sera from breeders tested
negative for antibodies to Sendai virus, reovirus 3, and lymphocytic choriomeningitis virus. Trial
matings of breeders expected to produce hydrocephalic offspring resulted in affected offspring, and
mating of breeders expected to produce normal offspring resulted in normal or less-affected offspring.
Hydrocephalus was confirmed retrospectively in some breeders. Hereditary hydrocephalus appears to be
widespread in hamster stocks in Central Europe. Affected animals do not manifest signs of disease and
usually die without obvious premonitory signs. Despite severe hydrocephalus, the animals can breed,
and animal handlers do not identify motor deficits or abnormal behavioral activity. This entity is unlike
the previously described, hereditary hydrocephalus of hamsters that is phenotypically identifiable and
usually is lethal before they attain breeding age.
Key words: Cerebrospinal fluid; hamsters; hereditary hydrocephalus.
Hydrocephalus is an accumulation of cerebro- also was one of the first laboratory animal species
spinal fluid (CSF) that is the result of an imbalance studied for experimental induction of hydrocepha-
between its synthesis and absorption in the central lus via intracerebral inoculation with several
nervous system (CNS).12,16 With few exceptions, it pathogens.5,8,10,11,13,14,18,19,21 Additionally, in utero
is the result of increased resistance to absorption. exposure to several metals and chemicals has been
Often, it is the result of obstruction to CSF flow associated with hydrocephalus in hamster off-
within the ventricular system: noncommunicating spring.1,6,7
or obstructive hydrocephalus. Hydrocephalus can A university pathology diagnostic service was
be of a communicating type when meningitis, contacted to evaluate an ongoing problem of
subarachnoidal neoplasia, or trauma external to hydrocephalus in the university’s hamster colony.
the ventricular system increases resistance to CSF Over a year-long period, sporadic cases of hydro-
flow. Hydrocephalus may be congenital or ac- cephalus had been diagnosed in animals of the
quired. In humans, where it is diagnosed in almost colony that died. Despite buying new breeding
one of every 1,000 births, most causes of congenital stock from a second, commercial supplier, cases of
hydrocephalus are unknown. Hydrocephalus is hydrocephalus continued to be detected. We de-
a common malformation and has been described scribe the findings of a study of spontaneous,
in several domestic and laboratory animal spe- hereditary hydrocephalus in golden hamsters.
cies.16,17 Although the condition may be hereditary,
a number of infectious, chemical, and physical Materials and Methods
agents have been documented to cause hydroceph- All observations were done on golden hamsters raised
alus. The golden hamster (Mesocricetus auratus) in the Institute of Animal Genetics, Nutrition and
not only has a heritable form of hydrocephalus, but Housing, Division of Animal Housing and Welfare,
523524 Edwards, Gebhardt-Henrich, Fischer, Hauzenberger, Konar, and Steiger Vet Pathol 43:4, 2006
Bern, Switzerland. Hamsters were reared using standard Table 1. Hamster test matings to study hereditary
practices, and all handling followed guidelines approved hydrocephalus.
by the Institution’s Animal Welfare Committee.
When a pathologist became involved for a more in- Degree of Hydrocephalus
depth study of the problem, a group of 31 (17 female, 14
Litter
male) golden hamsters in a study were scheduled for
termination. These animals had been selected from nine Mating Dam Sire Female Male
litters. The remaining littermates of these nine litters had
been used in other studies and were not available for A S* S 3S 2S
examination. Four hamsters (one male and three females) B N{ N 2N, 1M{ 1N
had already died acutely of hydrocephalus during the C M S1 5M 1S, 2M
D S S1 1S, 2UI 3S
experiment. The parents of the experimental animals were
derived from animals purchased from two suppliers. S* 5 severe hydrocephalus, macroscopically obvious; N{ 5
The hamsters had been weaned and placed on a 12- not affected; M{ 5 mild hydrocephalus, microscopically
week, behavioral experiment. For that experiment, they obvious; S15 sire diagnosed by ultrasonography prior to
mating; UI 5 unknown status; live animals not examined.
had been housed singly in cages of various sizes and with
a variable depth of litter to observe the effect of these
variables on behavior. Animals were videotaped princi- tested for antibodies to reovirus 3, lymphocytic chor-
pally during their nocturnal, active phase, and their time iomeningitis virus (LCMV), and Sendai virus (MICRO-
spent in various behaviors was monitored and quanti- BIOS Gmbh, Münchenstein, Switzerland). Liver sam-
fied (time spent chewing, grooming, climbing). Their ples from the same two animals were tested for
running activity on an in-the-cage, running wheel was concentrations of Cu, Cr, Zn, Pb, Cd, and Hg, and
continuously monitored. They were euthanized when feed was assayed for fumonisin and ochratoxin A
they were 15 weeks old, and were examined for (Interlabor Belp Ag, Belp, Switzerland).
macroscopic lesions. The brain and samples of liver, Parents of the animals in the behavior experiment
lungs, kidneys, and heart were fixed in buffered formalin were still alive, but resources to examine all animals by
and processed in routine manner for light microscopic ultrasonography or MRI were not available. Assuming
examination of 5 mm-thick, HE-stained sections of that the problem was heritable, several matings were
paraffin-embedded tissues. One section of each visceral done to help elucidate transmission of the hydrocephalic
organ and four coronal sections of each brain were trait. Results of necropsy of the original 35 experimental
examined. Brain coronal sections were at the level of the animals were used to predict the lesion status of the
cranial portion of the caudate nucleus, the nucleus parents. The following matings were done (Table 1):
habenularis, the rostral colliculus, and the cerebellar mating A, repeat mating of two hamsters that produced
roof nuclei. Brains were graded as normal, mildly affected offspring in the original experiment (the female
hydrocephalic (if lesions were barely visible macroscop- ultimately was found to be severely hydrocephalic and
ically or only noted histologically), or severely hydro- the male was mildly hydrocephalic); mating B, mating of
cephalic (if lesions were macroscopically obvious). two hamsters that had produced clinically normal
One male animal in the colony was observed to be offspring in the original experiment (both breeders
smaller than all males of the same age. It was ultimately were found to be normal); mating C, severely
anesthetized (inhalation isoflurane), and the brain was affected male (diagnosed by ultrasonography) bred to
examined by use of ultrasonography (Aloka Prosound a mildly affected female; and mating D, the known,
SSD 5500, Zug, Switzerland). This male was found to severely affected male of mating C bred to a severely
have hydrocephalus and was used for later breeding hydrocephalic female. These mated females delivered
studies. Another 30-day-old male in the colony was their offspring, which were euthanatized and examined
observed to have poor balance and possible doming of at weaning. Permission was given to euthanize all
the skull. Prior to euthanasia, it was anesthetized parents mated to produce the litters of hamsters used
(ketamine hydrochloride [1 mg/kg of body weight] and for the behavioral experiment, and the brain and viscera
medetomine [0.15 mg/kg]). After confirming that the from breeders and offspring were examined as described
animal had hydrocephalus by use of magnetic resonance previously.
imaging (MRI; Hitachi AIRIS II, Tokyo, Japan), One-
hundred microliters of gadodiamid (Omniscan; Results
0.005 mmol/ml) was inoculated into the right lateral During the behavioral experiment, none of the
ventricle, and the MRI procedure took 30 minutes to
animals, including the four that died before the
complete. Sequences performed included: a T2-weighted
fast spin echo in transverse orientation, a dorsal, scheduled termination date, manifested obvious
completely balanced, steady-state, free precision type clinical signs of disease. Phenotypically, none of the
sequence, and a dorsal T1-weighted, field echo plane 35 experimental animals had domed skull or were
after intraventricular contrast application. identified as lagging behind littermates in growth
Sera from two dams of the litters, one clinically rate. Of the 35 experimental hamsters, 25 (71.4%,
normal dam and one with severe hydrocephalus, were 12/15 males and 13/20 females) had severe,Vet Pathol 43:4, 2006 Hamster Hereditary Hydrocephalus 525 macroscopically visible hydrocephalus. However, 31 of 35 (88.6%, 13/15 males and 18/20 females) had hydrocephalus macroscopically visible or histologically detectable (Fig. 1). Four animals had asymmetrically affected lateral ventricles (Fig. 2). It was determined histologically that only the lateral ventricles were dilated. In affected animals, the periventricular parenchyma was rarified sub- jacent to broken ependymal linings, but inflamma- tion, periventricular diverticulae or clefts, necrosis, hemosiderosis, vascular abnormalities, and gitter cells were not observed. The ventricular lining was intact in most areas, but segments of ependymal cells were attenuated or missing (Fig. 3). The choroid plexuses were judged not to be atrophic. Histologic examination of sections did not reveal overdistention, absence, or obstruction of the third or fourth ventricular system or the mesencephalic aqueduct. Usually, the lining of the nondistended mesencephalic aqueduct was folded, and the aqueduct profiles were often flat or star-shaped (Fig. 4). Because the brain lacked obstructive lesions and the third and fourth ventricles were not dilated, it was concluded that these hamsters had a communicating hydrocephalus. With the exception of one male with a urolith and hematu- ria, other lesions were not seen macroscopically or Fig. 1. Brain; hamster. Cross sections from three microscopically in visceral organs. hamsters with differing degrees of hydrocephalus. The A small male in the colony was observed and, section on the right has barely perceptible, macroscopic using ultrasonography, severe hydrocephalus was hydrocephalus. Bar 5 1 cm. detected. This male recovered from anesthesia Fig. 2. Brain; hamster. Hydrocephalus of the later- unremarkably and was used in subsequent breeding al ventricles is asymmetric. Bar 5 0.5 cm. studies before it was euthanized, after which severe hydrocephalus was confirmed by necropsy and histologic examination. Another male in the colony a litter of three clinically normal pups and one with mild ataxia was observed to have a slightly pup with histologically detectable hydrocephalus. domed skull, and hydrocephalus was diagnosed by The mating of the ultrasonographically diagnosed use of MRI. Gadodiamid injected into the right affected male with a female with mild hydroceph- ventricle was observed to travel from the right alus (mating C) resulted in a litter of eight pups, lateral ventricle into the left ventricle, down the one with severe and seven with mild hydrocephalus. third ventricle and aqueduct, and into the fourth Mating of the same affected male with a severely ventricle. This hamster was euthanized after the affected female (mating D) resulted in six offspring, injection study, and severe hydrocephalus typical of four of which had severe hydrocephalus. The other that in other hamsters of the colony was observed. two offspring of this litter were retained for future Remating of two parents (severely affected study, and although not examined to date, they female and mildly affected male), the previous have produced severely affected offspring. Affected mating of which had produced severely affected animals of either sex were produced from all animals used in the behavior experiment (Table 1, matings of affected parents. mating A), resulted in a litter of five pups, all with The 35 experimental animals were selected from severe hydrocephalus. One male of this litter was nine litters. Examination of the parents of the stunted and had a domed skull (Fig. 5). Mating of experimental group indicated that three of nine two clinically normal parents that had previously dams had hydrocephalus (one mild and two produced some clinically normal offspring used in severe), and that three of five sires had mild the behavior experiment (mating B) produced hydrocephalus. Four matings of phenotypically
526 Edwards, Gebhardt-Henrich, Fischer, Hauzenberger, Konar, and Steiger Vet Pathol 43:4, 2006 Fig. 3. Cerebral cortex; hydrocephalic hamster. Fig. 3a. The thinned, hydrocephalic cortex has a rarified subependymal parenchyma, but lacks inflammation and gliosis. HE. Bar 5 150 mm. Fig. 3b. The lining of the ventrolateral aspect of the ventricle is intact (large arrow) on one side of the cavity, but attenuated and broken
Vet Pathol 43:4, 2006 Hamster Hereditary Hydrocephalus 527
normal parents had resulted in only two clinically Several viruses can induce hydrocephalus in
normal offspring and 11 affected animals (seven of hamsters; however, to experimentally induce hy-
which were severely affected). Mating of mildly drocephalus, the viruses are inoculated intracere-
affected animals to clinically normal animals had brally into newborn animals.5,8,11,13,14,18 Hydroceph-
resulted in two clinically normal and eight alus can be induced rapidly in neonatal hamsters,
affected offspring. One litter from a mildly affected but mature hamsters usually are not susceptible to
male mated to a severely affected female resulted in viral-induced hydrocephalus.13,18 Animals with
only severely affected offspring. Severely affected virus-induced hydrocephalus often develop domed
animals had not been mated to each other to skulls, manifest neurologic impairment, and com-
provide animals for the original experiment. Un- monly are physically stunted. Hamsters that re-
fortunately, not all offspring from the initial nine cover from viral infection may maintain motor
litters were used in this study and were available for deficits, and depending on the virus, have residual
study. histologic lesions such as periventricular gliosis,
Antiviral antibodies to reovirus 3, Sendai virus, spongiosis, inflammation, or hemosiderosis. None
or LCMV were not detected in sera, and Zn, Cu, of these lesions were present in the hamsters of this
Cd, Pb, Cr, and Hg were not detected in toxic study; rather, the only lesion noted was patchy,
amounts in the liver samples. The tested food was multifocal disruption or attenuation of the epen-
negative for ochratoxin A and fumonisin. dymal lining, with subjacent neuropil edema.
Because ependymal cells replicate little if any after
Discussion birth, any process causing necrosis or tearing of the
The lesions do not provide evidence of an ependyma could result in the lesions seen in the
obvious cause or pathogenesis for this form of ependymal lining.2,4,15,20
hydrocephalus. When examined, the process in the Support for an infectious cause would have come
brain appeared inactive without inflammation or from the demonstration of circulating antibodies to
any of the lesions associated with chronic hydro- viral pathogens that cause hydrocephalus in
drocephalus. The lack of doming in most affected hamsters. Although only two animals were tested,
animals suggests that the condition may have viral antibodies were not detected in their serum.
developed after suture lines closed,16 and the Usually, circulating antibodies in recovered breed-
dilatation was limited to the lateral ventricles, ers would be expected to protect the fetus by
suggesting that the condition was the result of preventing viremia in the parents, providing
aqueductal stenosis. The mesencephalic aqueduct lactogenic immunity in colostrum, and preventing
(of ‘‘Sylvius’’) is the site obstructed in more than shedding of virus to newborn pups. Although
two thirds of human cases of noncommunicating, LCMV can persist in recovered hosts, there was
congenital hydrocephalus,12,16 but blockage, focal no serologic or histologic evidence of LCMV in
gliosis, or forking of the aqueduct was not evident members of the colony. Ultimately, it was conclud-
in these hamsters. The closed, folded, or star- ed that the hydrocephalus was not induced by an
shaped aqueduct profiles might be interpreted as infectious agent.
collapse of aqueducts that were dilated in the live A toxic cause of hydrocephalus was considered.
animal. However, aqueducts of nonperfused brains Some toxins and metals can induce hydrocephalus
tend to appear slightly more collapsed than those if the developing fetus is exposed in utero, and we
of perfused brains. Even normal hamster brains in tested for several of these teratogens.6,7,12 Although,
this study had folded aqueduct linings. Still, it only two liver samples were tested, metals associ-
might be that the folded lining represents a form of ated with in utero induction of hydrocephalus in
dysplasia of variable severity in these related hamsters and rats were not detected. Food likewise
hamsters, and only when it is sufficiently severe tested negative for fungal toxins that can cause
does it lead to obstruction and hydrocephalus. hydrocephalus in hamsters.
r
(short arrow) on the other side. HE. Bar 5 100 mm.
Fig. 4. Brain, mesencephalic aqueduct profiles; hamster. Fig. 4a. Hydrocephalic hamster with a folded
aqueduct having a collapsed lumen. Fig 4b. Clinically normal hamster with a folded, star-shaped, aqueductal lining.
HE. Bar 5 100 mm.
Fig. 5. Litter of hamsters from the test mating of two hydrocephalic hamsters. One (center) of five animals, all
of which had hydrocephalus, is stunted and has a dome-shaped skull.528 Edwards, Gebhardt-Henrich, Fischer, Hauzenberger, Konar, and Steiger Vet Pathol 43:4, 2006 Evidence that this is a hereditary condition came with any lesion that suggests aqueduct stenosis or from the results of test matings. The litters from malformation. However, unlike our hamster con- these test matings were small, presumably because dition, affected H-Tx rats routinely develop domed of the advancing age of the breeders and not skull, and affected animals do not thrive. Most because of fetal death. Initial litters from which affected H-Tx rats die within 14 weeks after birth. experimental pups had been selected were of The histologic lesions of both conditions are normal size for the colony (data not shown). The similar. Similar to the hamster condition, H-Tx is reproduction of a litter with severe hydrocephalus not sex linked and backcrosses of normal animals using affected breeders (matings A and D) was result in affected offspring. The analysis of the strong evidence that the problem was not infectious. inheritance of the H-Tx mutant suggested that H- Despite exposure to the same housing conditions, Tx is a monogenic, recessive, autosomal condition feed, and water, reduction in the occurrence and with incomplete penetrance. severity of lesions resulted from mating normal These animals’ ability to thrive and perform parents (mating B) in the same colony. A genetic normal motor tasks during the behavioral study basis for the condition was further supported despite severe loss of cerebral tissue was surprising. because reduced severity of the lesions resulted from In rats with kaolin-induced (K-I) hydrocephalus, mating of less affected animals (mating C). Analysis there appears to be a threshold of ventricle size of all of the data of this study does not permit only beyond which functional changes are de- conclusions regarding mode of inheritance or the tected.4 In K-I hydrocephalus in hamsters, clinical- presence or absence of a major locus or single gene ly observed, neurologic deficits are seen immedi- controlling the condition. Information regarding the ately after kaolin injection and persist for at least parents of the original breeding animals and the 15 days even though the kaolin causes less di- phenotype of all siblings in the litters was not latation of ventricles and cortical loss, compared available. More generations of animals and more with that in the hamsters of the present study.1 Of specific backcrosses are needed to characterize the course, in the K-I hydrocephalus model, kaolin is pattern of inheritance. This heritable problem is not injected into the brain stem and would affect sex associated and most probably is an autosomal different areas of the brain. recessive trait. Such a defect with variable penetrance More work on antemortem diagnosis of this would explain why breeding phenotypically normal heritable hydrocephalus using non-invasive tech- animals had resulted in many severely as well as niques is warranted. The condition may remain mildly affected offspring. Because breeding pheno- latent in a colony because many hydrocephalic typically normal animals may result in affected animals result from breeding of clinically normal offspring, the condition will be difficult to detect in parents. Genetic markers would facilitate identify- colonies. ing carriers. If the colony experience of the present Significant differences are apparent between the study is typical, one may expect occasional deaths previously reported, hereditary hydrocephalus de- in affected colonies, and if necropsy is performed scribed in golden hamsters and the condition on unscheduled deaths in a colony, the condition observed in the hamsters of this study.21 In the could be detected. The fact that affected animals or published descriptions of hereditary hamster hy- carriers were provided by two commercial suppliers drocephalus, all hydrocephalic hamsters were suggests that the condition is widespread. Hydro- stunted and had a characteristic domed skull. cephalus is reported sporadically in hamsters. One Those animals usually did not survive to breeding study of a movement disorder of hamsters (the dstz age. For the most part, the external phenotype of mutant) initially associated the signs of the disease the hamsters of the present study was normal, and with hydrocephalus; however, the researchers all animals lived to breed successfully. Additional- discovered they had hydrocephalus in their control ly, the three animals identified as affected because animals as well.19 Perhaps, the conclusions of past of slower growth, domed skull, or balance prob- studies using hamsters and having hydrocephalus lems had better survivability than those with the as an endpoint should be reexamined in light of the published form of hereditary hydrocephalus. The use of adequate controls and the incidence of histologic lesions of the described, hereditary, spontaneous hydrocephalus. hamster hydrocephalus have not been published; At the time of this study, funding was not thus, further comparison is not possible. available to investigate the problem further. The condition resembles the H-Tx hydrocepha- Permission to examine the breeders provided lus mutation in rats.3,9 The H-Tx mutation only important information, but the pathogenesis of affects the lateral ventricles and is not associated the lesion remains uncharacterized. By the time the
Vet Pathol 43:4, 2006 Hamster Hereditary Hydrocephalus 529
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