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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

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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 22-25C (71.6-77.0F), and the ambient temperature should not exceed 33C (91.4F). 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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148 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 -70C; 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. REFERENCES . . ~ Abbey, H. 1979. Survival characteristics of mouse strains. Pp. 1-18 in Development of the Rodent as a Model System of Aging, Book II, D. C. Gibson, R. C. Adelman, and C. Finch, eds. DHEW Pub. No. (NIH) 79-161. Washington, D.C.: U.S. Department of Health, Education, and Welfare. Albert, T. F., A. L. Ingling, and J. N. Sexton. 1976. Permanent outdoor housing for wood- chucks, Marmota monax. Lab. Anim. Sci. 26:415-418. Altman, P.L., and D.D. Katz, eds. 1979a. Inbred and Genetically Defined Strains of Labora (

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