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OCR for page 121
8
Rodents that Require
Special Consideration
Rodents with a wide variety of valuable genetic characteristics are avail-
able for use in many kinds of research (Altman and Katz, 1979a, 1979b;
Festing, 1993; Festing and Greenhouse, 1992; Hansen et al., 1981; Hedrich
and Adams, 19901. Most are easily maintained with the husbandry techniques
discussed in Chapter 5. However, some important research models, especially
those with deleterious mutations, require special care. Some such as mice
that carry the homozygous mutation scid (severe combined immune deficiency),
some strains of mice that carry the homozygous mutation nu (nude), and
rodents exposed to sublethal irradiation are so severely immunodeficient that
contact with infectious agents of even low pathogenicity can cause severe
illness and death, and they require isolation for survival (NRC, 1989~. Others
have specific requirements for the presentation of food and water; for ex-
ample, food pellets must be placed on the cage floors and longer than normal
sipper tubes are necessary for rodents with mutations that cause dwarfing, and
soft diets are essential for mice and rats with mutations in which the incisors
fail to erupt (Marks, 19871. Many mutants are subfertile or sterile and require
special breeding techniques to maintain the mutation.
A detailed description of the unique husbandry and breeding requirements
for each model is beyond the scope of this book. Mating strategies for propa-
gating lethal, sterile, or deleterious mutations have been described (Green,
1981~. Those wishing to use mutant rodents should discuss with the investiga-
tor or company providing the animals whether there are special requirements
for the animals' care and breeding. This chapter will address selected research
121
OCR for page 122
122
RODENTS: LABORATORY ANIMAL MANAGEMENT
models: immunodeficient rodents, wild rodents, rodents used for studying
aging, mouse and rat models for type I (insulin-dependent) diabetes mellitus,
and transgenic mice. Those models are relatively commonly used in research,
and information on their husbandry is often difficult to find.
IMMUNODEFICIENT RODENTS
Rodents whose immune systems have been altered through spontaneous
mutation, transgenic manipulation, or the application of immunosuppressive
drugs or other treatments have long been useful models in biomedical re-
search. However, the immunologic deficiencies that make these animals use-
ful as models often render them susceptible to a host of opportunistic and
adventitious infectious agents that would produce few or no effects in immu-
nologically competent animals (Powles et al., 1992; Soulez et al., 1991~. The
recommendations in this report that cover various rodent species generally
apply to immunologically compromised rodents, but much more stringent housing
conditions are often required to ensure the health of immunodeficient rodents.
Husbandry
In general, the cages or other implements used to house immunodeficient
rodents should be capable of being adequately disinfected or sterilized on a
regular basis. The housing systems should be capable of eliminating airborne
contamination of the animals and should be capable of being manipulated
without exposing the animals to microbiologic contamination during experi-
mentation and routine husbandry procedures. In determining housing and
husbandry requirements for maintaining immunodeficient rodents, it is impor-
tant to consider the effects of various opportunistic and adventitious microor-
ganisms on the type of research being conducted. The length of the study and
the research goals will influence the attention to detail needed to prevent
infection with such organisms. Maintaining animals in an axenic or microbio-
logically associated (defined-flora) state might involve a level of effort that is
too great and techniques that are too complex for most experimental studies.
Plastic Cages with Filter Tops
This housing system consists of a shoebox cage usually constructed of
transparent autoclavable plastic and a separate filter top a plastic cap with a
removable filtration surface in the top. The cap and cage fit together snugly
but do not necessarily form a perfect seal. A stainless-steel wire-bar top keeps
animals from gaining access to the filter top and provides a food hopper and a
holder for a water bottle. An opaque cage can be used, but a transparent cage
facilitates routine animal observation without the need to open the cage except
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RODENTS THAT REQUIRE SPECIAL CONSIDERATION
for feeding and watering, sanitation, and experimentation.
123
Cages and filter
tops and all food, water, and bedding used in those cages should be sterilized.
All changing and manipulation of animals should be done in a laminar-
flow work station using aseptic technique. Sterile gloves or disinfected for-
ceps should be used to manipulate animals in any individual cage, and all
experimental manipulations should be done so as to minimize or eliminate
contamination of the animals. The successful maintenance of animals with
this housing system depends directly on rigid adherence to aseptic technique
in all aspects of animal and cage manipulation. Although the initial purchase
cost of this housing system might seem relatively low compared with that of
other systems for housing immunodeficient rodents, the requirement for lami-
nar-flow change stations, sterile supplies, and other operating expenses leads
to a substantial continuing cost. Moreover, only minimal mechanical safe-
guards are built into this system, and success depends absolutely on technique.
A major drawback to using plastic cages with filter tops is that there is
a low rate of air exchange between the cage and the room. As a result,
bedding might have to be changed more frequently to minimize the buildup
of toxic wastes and gases and keep relative humidity appropriately low.
Individually Ventilated Plastic Cages with Filter Tops
This housing system uses plastic cages with filter tops that are constructed
and maintained like those previously described. However, an air supply has
been introduced into each cage with a special coupling device similar in ap-
pearance to the fittings used for automatic watering. Air is supplied to a cage
under positive pressure and is exhausted through the filter top. Other ventila-
tion options with respect to positive and negative pressure, as well as a sepa-
rate exhaust, are also available. Usually, the air supplied to these cages is
filtered with a high-efficiency particulate air (HEPA) filter. This system has
advantages over the nonventilated plastic cages, but its principal disadvantage
is the potential for contamination of the fittings that are used to introduce air
into the cages. Rigorous attention must be paid to disinfection of these fit-
tings. The efficiency of this system in protecting immunodeficient animals
from infectious agents has not been extensively evaluated.
Isolators
Large isolators capable of housing many rodent cages are commercially
available. As discussed elsewhere in this report, isolators are ideal for
excluding microorganisms in that they rely very little on individual tech-
nique for many husbandry procedures or experimental manipulations. Tra-
ditionally, they have been used for housing axenic or microbiologically
associated animals. Many varieties of isolators are available; the most
common are those made of a flexible bag of vinyl or other plastic material,
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24
RODENTS: LABORATORYANIMAL MANAGEMENT
such as polyurethane. Modern isolators are relatively easy to use and pro-
vide investigators and animal-care technicians with easy access to the ani-
mals. Special precautions are not needed, because all manipulation is done
through built-in glove sleeves with attached gloves. All supplies provided
to the isolator are sterilized and are introduced through a port; a chemical
sterilization and disinfection procedure is used to decontaminate the outside
of the items that have been previously sterilized and wrapped with plastic or
other materials that can withstand chemical sterilization or disinfection.
Air into and out of the isolator is usually highly filtered. As opposed to
plastic cages with filter tops, the isolator offers an advantage in health
assessment, in that a large number of animals are maintained as a single
biologic unit. Isolators made of rigid plastic with a flexible front offer
additional advantages, such as integrated racking, individual lighting, lower
operating air pressures, and conservation of space.
Recent advances in construction coupled with the availability of vacuum-
packed and irradiated supplies have made isolators for housing immuno-
logically compromised animals a cost-competitive alternative to cages with
plastic filter tops.
HEPA-Filtered Airflow Systems
These systems have a variety of forms, including modular chambers,
hoods, and racks that are designed to hold cages under a positive flow of
HEPA-filtered air. In some instances, plastic cages with filter tops have
been used in laminar airflow racks that supply a steady stream of HEPA-
filtered air across the cage tops to facilitate air diffusion through the filters.
The design of such racks usually involves a blower that pushes air across a
HEPA filter and then into a large space (or plenum) that contains thousands
of small holes. The holes are designed to permit air to be blown across
shelves on which cages are placed. Because many cages must fit on the
shelves, there is considerable eddying or turbulence of air across the tops of
the cages. Once the cages are pulled forward 10-20 cm beyond the lip of a
shelf, the air no longer flows laminarly and mixes with room air. Another
system consists of a flexible-film enclosure in which HEPA-filtered air is
supplied under positive pressure to a standard rack or group of racks con-
taining filter-topped cages. For both systems, all manipulations must be
made in a laminar-flow work station using aseptic technique.
Environmental Considerations
Immunodeficient rodents have been successfully maintained at rec-
ommended room temperatures for rodents (NRC, 1996 et seq.~. Several
theoretical considerations suggest that some immunodeficient rodents,
specifically those lacking hair or thyroid glands, might require a higher
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RODENTS THAT REQUIRE SPECIAL CONSIDERATION
125
ambient temperature because of hypothyroidism and poorly developed
brown adipose tissue, which reduce the capability for nonshivering
thermogenesis (Pierpaoli and Besedovsky, 1975; Weihe, 1984~. In practice,
such temperatures are not necessary and in fact can be detrimental be-
cause they tend to create husbandry problems, including increased de-
composition of feed and bedding, increased rate of growth of environ-
mental bacteria, and an uncomfortable working environment for animal-care
personnel. In addition, because housing of immunocompromised ani-
mals generally requires systems that restrict airflow and heat transfer,
temperatures in the animal cages tend to be higher than ambient tem-
perature; therefore, increasing the room temperatures is generally not
necessary.
Humidity and ventilation should be consistent with recommendations in
the Guide (NRC, 1996 et seq.~. It is important to remember that many of
the containment systems result in increased relative humidity and restrict
ventilation. Therefore, animal density, bedding-change frequency, and the
relative humidity of incoming air should be adjusted to compensate for
some of these differences.
Food and Bedding
Food and bedding for immunocompromised animals should be steril-
ized or pasteurized to eliminate vegetative organisms. Depending on the
method of sterilization selected, fortification of feed with vitamins might be
required. Steam sterilization can drastically reduce concentrations of some
vitamins and can accelerate the decomposition of some vitamins during
storage. Other treatments, such as irradiation, result in much less destruc-
tion of these nutrients and so might not require the same degree of fortifica-
tion of feed before or after sterilization. Adequate validation of the steril-
ization process is essential to ensure that food or bedding does not serve as
a source of contamination.
Water
The water supplied to immunodeficient animals must be free of micro-
biologic contamination. Sterilization of water is the only sure method of
eliminating such contamination. Sterilization can be accomplished by heat
treatment, zonation, or filtration. All those processes must be adequately
controlled and validated. Other water treatments have been advocated for
use with immunocompromised animals, including acidification, chlorina-
tion, chloramination, and the use of antibiotics and vitamins. The principal
purpose of adding treatment materials to water is to reduce bacterial growth
and hence the likelihood of cross contamination in case bacteria are intro
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126
RODENTS: LABORATORYANIMAL MANAGEMENT
duced into the water supply The treatments are not without effects, which
can include alteration of bacterial flora, alterations in macrophage and lym-
phocyte function, reduction in water consumption, and exposure to chlori-
natedhydrocarbons(Fidler, 1977;Halletal., 1980;Hermanetal., 1982;
McPherson, 1963; Reed and Jutila, 19729. In general, the use of the treat-
ments is not an adequate substitute for sterilization of water and should be
used only as an adjunct.
Health Monitoring
Many immunodeficient rodents are susceptible to a greater range and
incidence of diseases caused by microorganisms than are immunocompetent
animals. The lack of a completely functioning immune system often results
in more dramatic clinical signs and pathologic changes than would be seen
in immunocompetent animals. Because some immunodeficient animals of-
ten lack the ability to produce antibodies in the presence of microorgan-
isms, serology is often not useful for diagnosis. Screening for such agents
might require the use of immunocompetent sentinel animals of the appropri-
ate microbiologic status. Most commonly, soiled bedding is used as a
means of exposing sentinel animals to the immunocompromised animals,
and a period of 4-6 weeks of exposure is often required before samples can
be taken. Sentinels must be housed under the same environmental condi-
tions and microbiologic barriers as the immunocompromised animals. Health
monitoring of animals maintained in individual plastic cages with filter tops
is complicated by the potential for contamination of individual cages, as
opposed to large groups of cages, with a particular microorganism. Be-
cause frequent screening of every cage is not economically feasible, statisti-
cal schemes for sampling or batching soiled bedding for exposure of senti-
nel animals is often required. That is less of a problem with the use of
isolators in which large numbers of cages are kept in the same microbio-
logic space.
Purchase of animals from commercial sources or transfer of animals
from other institutions entails some risk with respect to immunocompromised
animals. Health status can be compromised during packing, transport, un-
packing, and housing of animals. It is important to provide adequate quar-
antine and stabilization time to allow assessment of the health status of
these animals before they are used in experimental procedures. Appropriate
precautions should be taken to disinfect the outside of transport containers
and to examine them for integrity. Specialized containers have been devel-
oped for transport of immunocompromised rodents and should be used whenever
possible.
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RODENTS THAT REQUIRE SPECIAL CONSIDERATION
WILD RODENTS
127
A large number of rodent species have been maintained and bred in a
laboratory environment. Wild rodents are used in many fields of research,
including genetics, reproduction, immunology, aging, and comparative physio-
logy and behavior. Hibernating rodents, such as woodchucks (Ma rmota
monax) and 13-lined ground squirrels (Spermophilus tridecemlineatus), are
used to study control of appetite and food consumption, control of endo-
crine function, and other physiologic changes associated with hibernation.
Woodchucks are also used as models to study viral hepatitis and virus
induced carcinoma of the liver.
Wild rodents can be obtained by trapping or, in a few instances, from
investigators who are maintaining them in the laboratory. Trapping is the
simplest way to acquire wild rodents. However, a collector's permit is re-
quired in most states, and it is also important to confirm that the species to be
trapped, as well as other species in the trapping area, are not threatened or
endangered. It is best to begin trapping with an experienced mammalogist.
A search of the literature will locate investigators who maintain feral
rodents in a laboratory environment; however, these scientists usually do
not maintain enough animals to permit distribution of more than a few.
Colonies of wild rodents are listed in the International Index of Laboratory
Animals (Festing, 1993), in Annotated Bibliography on Uncommonly Used
Laboratory Animals: Mammals (Fine et al., 1986), and in the Institute of
Laboratory Resources (ILAR) Animal Models and Genetics Stocks Data
Base (contact: ILAR, 2101 Constitution Avenue, Washington, DC 20418;
telephone, 1-202-334-2590; fax, 1-202-334-1687; URL: http://www2.nas.edu/
ilarhome/~. Several species of the genera Mus and Peromyscus are more
widely used and are available from laboratory-bred sources.
Hazards
Wild-trapped rodents commonly carry pathogens and parasites that are
usually not found in or have been eliminated from animal facilities; there-
fore, appropriate precautions must be taken to prevent disease transmission
between feral and laboratory stocks (see Chapter 63. The primary hazard to
personnel is getting bitten. Personnel should always wear protective gloves
when handling wild rodents. Mice can be handled with cotton gloves (Dewsbury,
1984) or can be moved from place to place in a tall, thin bottle (Sage,
19811. Metal meat-cutter's gloves can be worn under leather gloves for
handling larger, more powerful species, such as black rats (Rattus rattus)
(Dewsbury, 19841. Elbow-length protection, such as leather gloves and
gauntlets, should be worn for handling woodchucks because the animals can
turn rapidly and bite the inside of the handler's forearm.
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128
RODENTS: LABORATORYANIMAL MANAGEMENT
Wild rodents can carry zoonotic diseases, such as leptospirosis and
lymphocytic choriomeningitis, that are not usually encountered in labora-
tory-bred rodents (Redfern and Rowe, 19761. Personnel should be offered
immunization for tetanus, and anyone that is bitten should receive prompt
medical attention. Wild-caught mastomys tPraomys (Mastomys) natalensis]
cannot be imported into the United States, because it is a host for the
arenavirus that causes the highly fatal Lassa fever.
Care and Breeding
Many small species can be housed in standard mouse and rat cages
(Boice, 1971; Dewsbury, 1974a); solid-bottom cages with wood shavings or
other bedding are preferred (Dewsbury, 1984~. Most small wild rodents are
much quicker than domesticated rodents and can easily escape if the han-
dler is not careful. It is advisable to open cages inside a larger container,
such as a tub or deep box, to avoid escapes (Dewsbury, 1984; Sage, 19811.
Most species do well if given ad libitum access to water and standard rodent
diets; however, voles do better on rabbit diets (Dewsbury, 1984; Fine et al.
1986~. General guidelines for caring for wild rodents have been published
(CCAC, 1984; Redfern and Rowe, 19761. Fine et al. (1986) have summa-
rized and provided references for laboratory care and breeding of kangaroo
rats (Dipodomys spp.~; grasshopper mice (Onychomys spp.~; dwarf, Sibe-
rian, or Djungarian hamsters (Phodopus sungorus); Chinese hamsters (Cricetulus
barabensis, also called C. griseus or C. barabens~s griseus); common, black-
bellied, or European hamsters (Cricetus cricetus); white-tailed rats (Mystromys
albicaudatus), fat sand rats (Psammomys obesus), voles (Microtus spp.),
four-striped grass mice (Rhabdomys pumilio), and degus (Octodon degus).
Guidelines on laboratory maintenance of hystricomorph (Rowlands and Weir,
1974; Weir, 1967, 1976) and heteromyid (Eisenberg, 1976) rodents have
been published. Mammalogists and other investigators experienced in working
with specific species are also excellent sources of information.
Breeding of many wild species is similar to that of domesticated ro-
dents. Some (e.g., voles and deer mice) breed almost as well in captivity as
do domesticated species (Dewsbury, 19841. Others (e.g., four-striped grass
mice) require special conditions (Dewsbury, 1974b; Dewsbury and Dawson,
1979~. A few investigators have reported that breeding of wild Mus species
is difficult unless running wheels are provided; exercise (up to 10-15 miles/
day) apparently causes females to come into estrus and begin a normal
breeding cycle (Andervont and Dunn, 1962; Schneider, 1946~. Others have
not had this problem (Sage, 1981~. Pheromones are extremely important in
the reproduction of some wild rodents; too frequent bedding changes pre-
clude successful reproduction. A nesting enclosure might be appropriate
and should be constructed of a durable material that is easily sanitized, such
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RODENTS THAT REQUIRE SPECIAL CONSIDERATION
129
as plastic or corrosion-resistant metal. Nesting material might improve
neonatal survival.
Peromyscus
Peromyscus maniculatus (the deer mouse) and P. Ieucopus (the white-
footed mouse) can be maintained with the same husbandry procedures as
laboratory mice. A maximum of seven can be housed in 7 x 10 inch plastic
cages. Standard rodent feed and water should be give ad libitum. Rabbit or
guinea pig feed should not be used, nor should such supplements as fresh
vegetables, raisins, and sunflower seeds. Except for breeding, sexes should
be housed separately. Peromyscus are reasonably cold-tolerant; the sug-
gested temperature is 22-25°C (71.6-77.0°F), and the ambient temperature
should not exceed 33°C (91.4°F).
For breeding, single male-female pairs are formed at the age of about
90 days and remain together throughout life.
_~J ~ ~ ^ ~_~^A_^ ~ ~ The estrous cycle is 5 days
(Clark, 19841. Females caged alone or with other females will not come
into estrus. The average reproductive life of Peromyscus is 18-36 months.
Females should be checked regularly for pregnancies. Copulatory plugs are
not a reliable indication of mating, because they are inconspicuous. Light-
ing is very important in breeding. A 16:8-hour light:dark ratio is generally
satisfactory. Continuous light will produce anestrus, and breeding difficul-
ties can sometimes be overcome by reducing the light cycle to a light:dark
ratio of 12:12 hours and gradually increasing it to 16:8 over a 3-week
period (W. D. Dawson, Peromyscus Stock Center, unpublished). Introduc-
tion of a strange male into a cage with a pregnant female can block the
pregnancy (Bronson and Eleftheriou, 1963~. Gestation is 22 days, except in
lactating females, in which it is delayed by 4-5 days. Females enter post-
partum estrus about 12 hours after delivery and then remate; therefore,
serial litters are produced at 26- to 27-day intervals. Litter size is usually
three to six and rarely exceeds eight. Males provide some of the care for
the young. Additional information on the care and breeding of Peromyscus
can be obtained from the Peromyscus Stock Center, Department of Biology,
University of South Carolina, Columbia, SC 29208 (telephone, 803-777-
3107; fax, 803-777-4002~.
-
Woodchucks
Woodchucks (Marmota monox) have been successfully housed indoors
in standard cat, dog, or rabbit cages (Snyder, 1985; Young and Sims, 1979)
and outdoors in pens or runs (Albert et al., 1976). Enclosures must be
carefully secured because a woodchuck can squeeze through any hole large
enough to admit its head (Young and Sims, 1979). Each animal should be
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30
RODENTS: LABORATORY ANIMAL MANAGEMENT
provided with a nesting box and nesting material, especially if it is housed
under conditions that will induce hibernation, for example, in a cold room
or, in a cold climate, outdoors in an unheated enclosure. Very thin wood-
chucks will not survive hibernation (Young and Sims, 1979~. Usually, adult
females are housed in small groups, and males are housed individually
except during breeding season. However, young males and females can be
kept together through their first year (Young and Sims, 1979~. Food and
water should be made available ad libitum. Water should be provided in
heavy porcelain bowls. Standard bottles and sipper tubes are not satisfac-
tory, because the animals grip the tubes in their teeth and shake them until
they are dislodged from the bottles (Snyder, 1985; Young and Sims, 19791.
Woodchucks do well on commercial rabbit diet (Young and Sims, 19791.
AGING COHORTS
Mice and rats have been favored by mammalian gerontologists as ex-
perimental models because of their relatively short and well-defined life
spans, small size, comparatively low cost, and the large and growing store
of information on their genetics, reproductive biology, physiology, biochemistry,
endocrinology, neurobiology, pathology, microbiology, and behavior. However,
the term comparatively low cost is used advisedly. The true cost in 1994 of
producing one 24-month-old rat was approximately $200 and a similarly
aged mouse $95; the cost for producing one 36-month-old rat was approxi-
mately $350 and a similarly aged mouse $175 (Dewitt Hazzard, National
Institute on Aging, National Institutes of Health, Bethesda, Maryland, un-
published). The cost to investigators is slightly more than half that amount
because production is subsidized by the National Institute on Aging (NIA).
A problem faced by investigators who use aged animals is periodic short-
ages in older cohorts of some strains.
General Considerations
Strictly speaking, aging can refer to all changes in structure and function
of an organism from birth to death; however, mammalian gerontologists gen-
erally confine their experiments to alterations that occur after the onset of
sexual maturity and the transition from the juvenile to the young adult pheno-
type. In sampling for some measure of aging or accruing pathologic condi-
tions, 6-month-old animals will usually provide a normal baseline, and sam-
pling should be carried out at 6-month intervals. Many investigators consider
a 24-month-old rodent to be "old"; however, age-related changes in a number
of characteristics are often more pronounced in still older animals.
The mean life span (MnLS) of ad libitum-fed (AL-fed), hybrid strains
of specific-pathogen-free (SPF) mice or rats is often around 30 months,
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RODENTS THAT REQUIRE SPECIAL CONSIDERATION
131
whereas that for calorically restricted (CR) animals, depending on the regi-
men used, can be 30 percent longer (see Figures 8.1 and 8.2~. Because
caloric restriction retards or eliminates common forms of chronic renal dis-
ease and a variety of neoplasms, some gerontologists believe that such
nutritional management should be the norm. Comparative changes in AL-
fed versus CR rodents are increasingly used to test the validity of putative
biologic markers of aging rates.
Survivorship in any colony used for gerontologic research should be de-
termined repeatedly. Survival curves for SPF mice and rats should exhibit a
classic "rectangularization pattern," that is, a survival curve should nearly
parallel the X axis close to the 100-percent survival level for a prolonged
period and then decline sharply as the population nears the species' maximum
life span (MxLS), which is defined as the age at which only 10 percent of the
animals are surviving. A linear survival curve indicates a problem in the
population (e.g., exposure to infectious disease). Patterns of age-related pa-
thology within a colony should be repeatedly evaluated through systematic
sampling and necropsy of cohorts of various ages (including histologic exami-
nation of the major organs). Any animal euthanatized during the course of a
study on aging should be necropsied to determine whether the cause of death,
such as a specific lesion or neoplasm, could seriously affect the interpretation
of the experimental data. For example, the occurrence of lymphoma involving
primarily the spleen of old mice of some strains not only decreases survival,
but might cause death before other expected findings can occur; this limits the
value of these strains in some studies of age-related immunology. A good deal
of information is now available on the pathology of aging cohorts of com-
monly used laboratory mice and rats (Altman, 1985; Bronson, 1990; Burek,
1978; Myers, 1978; Wolf et al., 1988~.
Laboratory Mice
There are obvious advantages to using genetically defined strains for
research on aging. Inbred or F1 hybrid strains provide a reproducible gene
pool, and so permit a more rigorous evaluation of environmental variables,
such as caloric restriction. However, in some circumstances, such as longi-
tudinal studies with markers of aging or searches for longevity-assurance
genes, the widest possible allelic variability might be desired. For those
purposes, systematically outbred animals might suffice, although in the de-
velopment of such lines, including so-called Swiss mice, the tendency to
select breeding pairs for docility and breeding efficiency has resulted in a
loss of genetic heterogeneity. An alternative approach is to develop an 8-
or 16-way cross between established inbred lines (van Abeelen et al., 1989~.
Recombinant inbred mice can also be useful for aging research because
they provide a reassortment of linked parental genes (see Chapter 31. Re
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RODENTS: LABORATORYANIMAL MANAGEMENT
unpredictable interactions between the transgene and other host genes (e.g.,
insertional mutagenesis), altered responses to microorganisms or other envi-
ronmental variables, compromised fertility, and possible instability of transgene
expression through generations. Depending on the presence and severity of
those characteristics, barrier maintenance might be advisable. Filter-top
caging systems are usually sufficient if proper precautions are taken. Flex-
ible-film or rigid isolator systems, however, permit the most complete con-
trol of the physical and microbiologic environment. Microbiologic status
should be monitored regularly and should include testing for standard mu-
rine infectious agents. Both transgenic and sentinel mice should be evalu-
ated if the integration or expression of a foreign gene alters immune compe-
tence.
Transgenic mice should be observed daily, and all visible clinical events
should be recorded. Animal-care technicians should be trained to recognize
clinical events and to report their occurrences with appropriate descriptive
terminology. Unexpected deaths should be discussed with an animal-health
professional, such as an animal pathologist, to determine whether necropsy
and histologic examination are warranted. It is imperative that deceased
animals be collected and preserved properly as soon as they are discovered.
Corpses can be placed in fixative, refrigerated, or frozen, depending on the
specific postmortem procedures that are planned.
Management of a transgenic-mouse facility includes special require-
ments for embryo donors, embryo recipients, and offspring. In many transgenic
facilities, embryo collection and culture, DNA introduction, and embryo
transfer are performed outside the barrier; therefore, the embryos and em-
bryo-transfer recipients might no longer be SPF and should not be returned
to the barrier.
Embryo Donors
Embryos into which DNA will be introduced to generate founder mice
are obtained by administering exogenous gonadotropin hormones intraperi-
toneally to virgin females. The hormones elicit synchronized ovulation of a
relatively large cohort of mature oocytes (i.e., superovulation); therefore,
fertilization and later preimplantation development will also be synchro-
nized. Very young females 28-40 days old, depending on the stock or
strain usually respond best to superovulatory hormones. Outbred mice
were originally used as embryo donors; more recently, inbred FVB mice
have also been used. FVB mice are highly inbred, they respond well to
superovulatory hormones, and their embryos have large pronuclei (Taketo
et al., 1991).
Males should be individually housed; females can be group-housed be-
fore mating. Breeding is most effective if a 3- to 8-month-old male that is a
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RODENTS THAT REQ UIRE SPECIAL CONSIDERATION
149
proven breeder is paired and bred with one or two females every 2 or 3
days. Mating should always occur in the cage of the male.
An uninterrupted dark phase of the lighting cycle is critical for efficient
superovulatory breeding; a light:dark ratio of 14 to 10 hours is effective.
Two gonadotropin hormones, pregnant mare serum gonadotropin (PMSG)
and human chorionic gonadotropin (HCG), are each administered 7-9 hours
before the beginning of the dark cycle, but PMSG is administered 2 days
before HCG. Pronuclear embryos are generally collected 14-17 hours after
the beginning of the dark cycle. For example, if the dark cycle begins at 10
p.m., PMSG would be administered between 1 and 3 p.m. 2 days before the
day of mating, HOG would be administered between 1 and 3 p.m. on the
day of mating, and pronuclear embryos would be collected between noon
and 3 p.m. the next day.
Embryo Recipients
Group-housed females are used; outbred or hybrid mice generally make
the best dams. Good choices of stocks to carry transferred embryos include
outbred ICR mice (if a white coat is desiredJ and C57BL/6 x DBA/2 F1
(B6D2F1) hybrid mice (if a colored coat is desired). Housing strategies
that avoid synchronization of estrus in group-housed females have been
described (Gordon, 1993~.
A colony of vasectomized males is required. It is preferable for the
males to be test mated to ensure sterility; however, if 5- to 6-week-old
males are vasectomized, there is no sperm yet in the vas deferens, and test
mating is not necessary. Even if test mated, males used to produce pseudopregnant
females should be a different color from the embryo donor so that "acciden-
tal" offspring of males that have recovered their fertility can be distin-
guished from transgenic offspring.
Embryo-donor females should be 0-1 day more advanced in the repro-
ductive cycle than pseudopregnant females. Early (one or two cells) em-
bryos are transferred into the oviduct of the embryo recipient; morula and
blastocyst embryos are transferred directly into the uterus. Recipient fe-
males should be used only once.
Ofi~spring
Individual litters should be separated by sex at weaning and housed in
cages that clearly indicate the litter number, date of birth, lineage, and
parental identities. In general, fewer than 25 percent of live-born pups that
receive transgene DNA as embryos will have integrated transgenes; 10 per-
cent is considered average if microinjection is used. Most transgenic mice
are identified by Southern blotting or polymerase chain reaction (PCR) analysis
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150
RODENTS: LABORATORYANIMAL MANAGEMENT
of DNA extracted from tissue taken from the tip of the tail; approximately 1
cm of tissue is sufficient. Rarely, it is possible to identify transgenic mice
by detecting gene products from the introduced DNA.
Breeding Transgenic Mice
Once a mouse is identified as transgenic, it should be bred to verify that
the transgene has been integrated into its germ cells. The development of a
colony of mice homozygous for the transgene is achieved by standard breeding
and test-mating procedures. Homozygous transgenic mice will produce 100
percent transgenic progeny on mating with a nontransgenic mate, whereas
hemizygotes will produce both transgenic and nontransgenic offspring. It is
recommended that multiple test litters be analyzed before the homozygosity
of a breeder is considered established. Transgenic inheritance patterns do
not always conform to classical Mendelian patterns, because the integration
and expression of a transgene can affect implantation, in utero develop-
ment, and postnatal survival. When mice are not homozygous for the transgene,
all offspring must be screened for the transgene.
Reproductive performance of transgenic mice can differ substantially
from that of the nontransgenic parental or background strains. Insertional
phenomena can compromise fertility and affect embryo survival. Although
breeding mice to homozygosity for the transgene is often desirable, ho-
mozygotes might be inviable, infertile, or subfertile. If fertility problems
are encountered in homozygotes, whether caused by transgene expression or
insertional mutagenesis, the problem can often be effectively managed by
maintaining the transgene in the hemizygous state. Even in hemizygous
mice, however, the effects of transgene integration, transgene expression, or
both can be detrimental to survival and reproduction, and investigators and
animal-care personnel should be alert to the necessity for establishing ag-
gressive breeding programs. In extreme cases, assisted-reproduction tech-
nologies (e.g., superovulation and in vitro fertilization) might be helpful.
Identification, Records, and Genetic Monitoring
Identity, breeding, and pedigree records must be fastidiously kept be-
cause breeding errors in transgenic colonies are difficult to detect. For
example, classic genetic monitoring will not necessarily distinguish between
different transgenic lines on the same background strain. Even direct ex-
amination of the transgenic DNA sequence (e.g., with Southern blotting or
PCR analysis) might not definitively identify a specific mouse. It is recom-
mended that a combination of methods for identification and genetic moni-
toring be used in a colony of transgenic mice. Purified DNA samples from
important animals can be frozen and stored at -70°C; these might be useful
for future analyses, especially if DNA rearrangement is suspected.
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R ODENTS THA T REQ UIRE SPECIAL CONSIDERA TI ON
151
Individual animals can be marked rapidly and inexpensively by tattooing,
clipping ears, or using ear tags. The most reliable, albeit most expensive,
system for identifying an individual animal is subcutaneous implantation of a
transponder encoded with data on the animal. Transponder identification chips
are durable for the life of the animal and suitable for computerized data-
handling. Whatever method is chosen should be used in conjunction with a
well-maintained cage-card system. One issue that arises in colonies of geneti-
cally engineered animals that does not arise in other colonies is confidentiality
specifically related to patentability of the animals; information displayed on
cage cards should be reviewed with the principal investigator.
The identity of each transgene-bearing breeder should be verified be-
fore mating Imnortant information on the transgenic parent includes tran
~ vat ~ '''~''^~4t~ ~ ~ ~-~~ ~ ~~^ ~ ~ - ^ ~ ^~~ ~~ ~ ~~ ~ ~~ ~~~ ~ ~- ~~--- (~ - ~
spender code or other identification code, lineage, date of birth, date of
pairing, administration of exogenous hormones (if any), and date of separa-
tion of breeding pair. If mice escape, all unidentifiable animals should be
euthanatized, and recaptured identifiable females should be isolated for at
least 3 weeks to determine whether they are pregnant. Litters derived from
questionable or unverified matings should be euthanatized.
Embryo Cryopreservation
Because each transgenic line is unique, embryo cryopreservation might
be considered. In general, cryopreservation issues relevant to transgenic
lines are the same as those relevant to other rodents (see Chapter 41. How-
ever, some lines cannot be made homozygous, are reproductively compro-
mised, or both, so it might be prudent to freeze more embryos than would
be necessary for preservation of an inbred strain.
Data Management
A large amount of data accumulates in a transgenic colony and must be
managed efficiently. ~ ~ ~
Daily or weekly records Include data on oreeolng
birth, weaning, death, and laboratory analyses; they also include documen-
tation of observations on such things as characteristics that are possibly
related to gene manipulation, pathologic conditions, and unusual behaviors.
Shipment and Receipt of Transgenic Rodents
In general, it is not necessary to use extraordinary containment proce-
dures for shinning trans~enic mice.
'' ~ ~ To reduce the risk of loss, shipments
can be split so that accidents or errors during transit do not compromise the
entire shipment. The following information should accompany transgenic
mice shipped from a facility and be requested for transgenic mice brought
into a facility:
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52
RODENTS: LABORATORY ANIMAL MANAGEMENT
.
genetic identity, including the species and strains from which the
transgene originated, the designations of all transgene components, the an-
cestry of the transgenic founder, and the exact lineage designation and gen-
eration number of each mouse;
.
· standardized transgene symbol (see NRC, 1993);
individual identification numbers accompanied by an explicit de-
scription of the identification method (e.g., subcutaneous transponders, 16-
digit codes, or an ear-marking scheme with a drawn key);
· description of the predicted phenotype and relationship of transgene
expression to such factors as age, sex, pregnancy, and lactation;
· identification of potential human health hazards related to transgene
expression (e.g., active expression of intact virus particles or potentially
immunogenic viral structural proteins);
· general health status of the mice and probable morbidity or mortal-
ity associated with transgene expression, including available data on sero-
logic, bacteriologic, and parasitologic screening: and
.
' ' ' .L ~' (J ~
information important to maintenance and breeding, such as breed-
ing strategies, pregnancy rates, gestation times, litter sizes, and sex distribu-
tion within litters.
Human Health Hazards
Consideration must be given to possible zoonotic hazards posed by
transgenic mice. For example, viral replication has been demonstrated in
mice carrying the entire hepatitis B virus genome (Araki et al., 1989~. Pre-
liminary banking of employees' sera should be considered (see Chapter 2~.
Administrative Issues
In maintaining colonies of transgenic animals, all relevant legal re-
quirements must be addressed. Examples include laws governing patent
applications or awards, international regulations governing the importation
or exportation of genetically engineered animals, and quarantine laws.
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OCR for page 158
Representative terms from entire chapter:
life span
