Inbred Hamsters as Animal Models of Disease

T h e terms “animal model,” “animal model of hum a n disease,” “animal model in biomedical research,” etc., have different meanings to different individuals. Some c h o o s e primates as the best model of human disease bec a u s e of the closeness of the a p e s and monkeys to hum a n s in the evolutionary scale; others prefer rodents bec a u s e of ease of handling, fecundity in reproduction, and . short life span. T h e widespread and most naive definition is that of the mouse as “a little man who lives his seventy years in two.” In a much broader sense , however, any biological system from viruses to primates can be a model for human disease because the fundamental disease processes may take place in microorganisms, as well as in more complex structures. Perhaps the best, and certainly one of the most important models, h a s been the sweet pea which produced for Mendel, the laws of Mendelian genetics which prevail for man and animal. The Syrian hamster, about which this discussion centers, entered the research laboratory in 1941, having been earlier caught and domesticated in Syria by biologists of Jerusalem University (1). T h e development of inbred strains is even more contemporaneous and w a s initiated by workers such as Billingham, Robertson, Whitney, and Nixon. The last two n a m e s were both associated with Bio-Research Institute, a n d it is to their efforts that w e owe our present 27 inbred strains. T h e s e inbred strains are kept in our foundation stock at Cambridge where additional inbred lines a r e worked o n by C.H. Yoon under a resources grant from NIH. Basic research at Bio-Research Institute centers around the further definition of these inbred strains of hamsters, and s o m e are being developed for commercial production by Bio-Research Consultants, Inc., of Cambridge, a n d its subsidiary, TELACO, Bar Harbor, ME. Table I lists t h e s e strains and summarizes their characteristics. It is noticeable from that table that a rather simple parameter like life expectancy varies markedly and significantly between strains even though, in s o m e cases of shorter survival, t h e c a u s e of earlier death has not yet been ascertained. Recently described mutations discovered in inbred Syrian hamsters are hydrocephalus (2) and retinal degeneration (3). A list of the disease models, in addition to t h e mutations mentioned, is contained in Table II, and s o m e of these models will now be discussed in more detail. Cystic prostatic hypertrophy or hyperplasia (Fig. 8) w a s described by Homburger and Nixon (4) in 1970. At that time, six strains were investigated and classed in two groups of a g e s , namely, up to 115 days and beyond. Among the older animals, two lines showed marked hypertrophy of t h e prostate as expressed in its weight, and the histological examination showed a cystic hyperplasia of the prostate gland in these affected lines, namely, the 2.4 and 87.20 lines. Schaffner (5) has used the 87.20 line to study the effects of various factors on this type of prostatic disease, and h e found in his animals that the older animals all suffered from a hyperplastic prostate. T h e s a m e situation h a s prevailed in our colonies, whereas in the colony of the Ciba-Geigy Corp., in Ardsley, NY (6), Steinetz found that in the 2.4 line 6 months or older, marked testicular atrophy occurred but no hyperplasia of the prostate w a s present. This contradiction h a s not as yet been fully explained although it would appear as a possible explanation that, in the absence of females in the surroundings of the animals, the aging male does undergo testicular atrophy. In our colony, the animals were kept-the s e x e s separated-but nevertheless there were always females in the environment, whereas Steinetz’s colony may have been limited to males only. Another interesting model is that of obesity (Fig. 2) which still is largely unexplored. This was observed in an inbred line with frequent spontaneous adrenal tumors, described by Homburger and Russfield in 1970 (7). Obesity occurred relatively late in life-more frequently and with greater severity in females than in males-and w a s not related to the presence or absence of adrenal tumors. Hind-leg paralysis (Fig. 1) has been described by Nixon and Connelly in 1968 (8) as a sex-linked, recessive characteristic, and in the view of Manuelidis, constitutes a model for amyotrophic lateral sclerosis, whereas Nauta h a s felt that there is also present a peripheral demyelinizing disorder. (Personal communication from Manuelidis a n d Nauta on their studies of a few animals.) Spontaneous seizures are unkown in rodents where the classical example of a possible model for epilepsy is the audiogenic seizures of mice and rabbits. Yoon and co-workers (9) described spontaneous seizures in Golden’ hamsters which appear to be transmitted as a simple recessive. The condition maintains itself throughout the youth of the hamsters until about a g e 60 days when the seizures disappear. Myopathy and cardiomyopathy (Figs. 3-7) are conditions transmitted by a recessive autosomal gene in inbred Syrian hamsters, and are perhaps the most intensively studied of all disease models available in this species. More than 60 papers have been published on the subject of cardiomyopathy in Syrian hamsters since it w a s first described in 1962 by Homburger (10). The disease is characterized by serum enzyme changes, increases especially in serum phosphocreatine kinase (which occur quite early and vary with age), and histological lesions of muscular dystrophy. The behavior of the cardiac muscle has been especially well studied. In the original strain, which w a s designated as BIO 1.50 and has since been lost, the life expectancy w a s around 200 days, and death w a s from cardiac failure with classical edema and other diseases of cardiac decompensation. In the BIO 14.6 line, which w a s derived from the 1.5 line by outcrossing to another line and crossing the F2:generation’s affected offspring with each other, the life expectancy is