Hans Meier

Part I Hereditary Primary Myopathies in Laboratory Animals: HEREDITARY MOUSE MUSCULAR DYSTROPHY WITH PARTICULAR EMPHASIS ON PATHOGENESIS AND ATTEMPTS AT THERAPY*

Muscular dystrophy or dystrophia muscularis (gene symbol dy ) occurred as a spontaneous autosomal mutation in strain 129/Re causing characteristic muscular weakness, atrophy, and reduced life-span. Since there is no evidence of abnormal patterns of innervation, muscular dystrophy is thought of as a primary myopathy. There are a number of clinical, histological, and physiological similarities to progressive juvenile pseudohypertrophic and myotonic dystrophy of man, Erb’s dystrophy, and, except for the difference in inheritance, the Duchenne type. First information on the mode of inheritance of dystrophy came from an analysis of pedigree records at The Jackson Laboratory. The incidence varied in different subcolonies of the 129/Re inbred strain, but no more than 25 per cent of the animals in a single sibship were affected (Michelson ef al., 1955). Proof for a unit recessive inheritance was derived from transplantation of ovaries from dystrophic females into ovariectomized, histocompatible ( 129/Re X DBA/2J)F1 normal females (Stevens et al., 1957). Matings between these recipient F1 hybrids and normal 129/Re produced all normal offspring in the F1 generation, 20 to 25 per cent dystrophics in the F2 generation, and 44 to 50 per cent dystrophics in backcrosses of F1 carrier males to females bearing implanted dystrophic ovaries. Since dystrophics almost never breed, the colony was maintained by repeating ovarian transplantation in each generation. Tests of the expression of the dystrophic genotype (dyldy) on a variety of different genetic backgrounds, including several heterogeneous hybrid populations and linkage crosses, showed that the proportion of dystrophics in each background was close to 25 per cent and that clinical signs were identical to the 129/Re dystrophic, except for increased vigor and longevity (Loosli e f al., 1961). By repeated crossintercross to the inbred strain C57BL/6J the dystrophy gene has been transferred to a genetically homogeneous background (Loosli et al., 1961). The best animals appear in the (129/Re-dy/ 4X C57BL/6J-dy/ 4)F1 hybrid population which segregates for especially long-lived, vigorous dystrophic animals which are essentially identical to their normal littermates except for the genes at the dy locus (Russell ef al., 1962). Clinically dystrophic mice can be identified by their abnormal behavior at about 2 weeks of age. From careful clinical observations of afflicted young, it appears that the onset of dystrophy is earlier in females than males, while the severity of symptoms seems to progress more rapidly in males than in females (Hoag & Meier, 1964, unpublished). Clinical signs are muscular weakness,

Carcinogenic effects of a single dose of diethylnitrosamine in three unrelated strains of mice: Genetic dependence of the induced tumor types and incidence

The carcinogenic effects of a single dose of diethylnitrosamine (DEN) were studied in three inbred strains of mice. The most predominant tumors observed were lung adenomas, leukemia, and liver tumors. Mice of strain AKR/J developed both leukemia and lung tumors; SWR/J mice were most susceptible to lung tumor development; and in C57BL/6J mice liver lesions including liver tumors occurred. The influence of the genetic background on the organ susceptibility to DEN-carcinogenesis is discussed.

Steroid hormones increase the growth of MuLV in rat tumor XC cells.

Abstract Ecotropic MuLV, which do not normally grow efficiently in XC cells, were found to do so under the influence of specific steroid hormones. The adsorption of virus to the cells was not facilitated by the steroids. The increase in MuLV production by XC cells involves an increased viral progeny output per cell, thereby defining an intracellular restriction by rat cells on ecotropic MuLV growth. Cell lines other than the XC were not similarly stimulated. The steroid-induced increase in MuLV growth is accompanied by enhanced XC cell fusion.

Ineffectiveness of poly ri,rc on transplanted tumors induced by methylcholanthrene.

Till now complexing agents seemed only little useful for the elimination of freshly incorporated radioactive St, since complexing agents especially the chelating agents form Stcomplexes which are less stable than the corresponding Cacomplexes [Q. Dietrich, Lehn and Sauvage [2] recently found a new type of complexing agents the cryptating agents. For the first time they received with one compound of this group, the hexaoxa-diamine macrobicycle I,

DISCUSSION OF PART II

While the frequency and types of tumors in any animal population may be due to the interactions of various factors, aspects that have been stressed by Dr. Snyder, zoo and experimental animals, provide perhaps the best animals for physicochemical studies of the environment, susceptibilities to cancer of different species and strains, under similar external conditions. Zoo animals lend themselves especially for studies of environmental (viral), dietary and genetic influences on cancerogenesis. Examples of the first relate to the feeding of cabbage and rape-seed, as well as iodine deficiency, having caused a high incidence of thyroid tumors.’ Among the second are renal carcinomas in the rhesus monkey which may be considered as familial in originz; also, in the high frequency of tumors of undulated grass parakeets, reported from the Moscow Zoological Garden, colony inbreeding could be of importance? As discussed by Dr. Jungherr, monkeys might provide insight into the possibility of a transmissible or even a contagious nature of certain kinds of cancer through artificial exposure to many infectious agents also common to man. Of course, small laboratory rodents represent the most convenient tools for studies of most aspects of cancerogenesis; particularly inbred mice and rats eliminate the difficulties arising from the heterozygosity of the substrates and also those derived from environmental dserences. However, in arriving a t accurate figures on tumor incidence, it is required that all organs be sectioned serially, a most formidable task, since grossor single-section techniques may be off as much as sixfold, as shown by Drs. Thompson and Hunt in the case of thyroid adenomas in the Sprague-Dawley rat. Dr. Hoag has presented the inbred mouse as a unique tool for research on spontaneously occurring tumors; despite the many advantages inherent to transplantable tumors, especially for chemotherapeutic purposes, they are a “far cry” from a spontaneously occurring cancerous process that appears from its inception as a systemic disease, even if the tumor occurs only at a single site. Aside from studies on a variety of now known tumor causing viruses, the greatest value of inbred strains of mice regarding spontaneous cancer lies in the relationship between aging and appearance of tumors. Barring accidents, infections, elc., lifespan is genetically determined and dependent upon the strain; another determinant is the occurrence of spontaneous cancer. Differences among inbred strains relative to these determinants provide excellent grounds for further studies. An illustration of an interesting approach follows: In testing the concept that endogeneously produced free radicals, such as HO and HOz , contribute to both the aging process and the incidence of spontaneous cancer, various reducing substances (free radical inhibitors) were incorporated into mouse diets.’J*e Antioxidants, in two experiments had been found to prolong the normal lifespan of mice. 2-Mercaptoethylamine hydrochloride (1 per cent w, incorporated into a pellet diet) prolonged the half-survival time of C3H female mice from 14.5 to 18.3 months, an increase of 26 per cent, while hydroxylamine

Statolon-therapy of spontaneous viral-caused mouse tumors

t.567 2.t26 <0.05 Thymus 0.t98 0.569 <0.0t 0.3t3 0.560 < 0.05 Spleen/body 0.008 0.015 < 0.01 Thymus/body 0.008 0.019 <0.0t 0.0t2 0.022 <0.05 peritoneal foreign body granulomas in most mice. Increased mortality from toxicity occurred in the Group 2-AKR/J mice; their lifespan was significantly decreased, and there was a highly significant weight-reducing influence on the thymus, spleen, and liver. This inhibitory effect on lymphoreticular organs was associated with a significant lowering o1 tumor occurrence. As the leukemia incidence is known to increase with age, a partial explanation is the shortened lifespan which reduced the probability of leukemia development. However, the weight of lymphoid tissues was also reduced in treated SJL/J mice in which the tumor incidence was not significantly altered. Thus, we conclude that the therapy of spontaneous tumors is more difficult than that of induced and transplanted tumors, and that the two types of tumors, leukemia and reticulum-cell sarcoma, represent different therapeutic problems.