The effect of x-irradiation on the functioning of adrenal auto-transplants, as measured by the response to stress
Goldman, Ralph Frederick
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Many studies have been made on the response of tissues to radiation. However, in the majority of them, only morphological alterations were investigated. The few which attempted a determination of possible physiological alterations were restricted to the irradiation of a specific area of the body and were complicated by systemic reactions resulting from the inability to confine the radiation to a specific tissue. It has been proposed that following irradiation, the adrenal gland may present alterations of a physiological nature even in the absence of any apparent morphological change. The adrenal gland of the rat, can be completely removed from the body, irradiated in vitro, and implanted into the dorsal musculature, where it will regenerate and regain some degree of functional efficiency. Moreover, the rat can be used conveniently for various tests of adrenocortical function, some of which are quantitative as well as qualitative. A review of the literature of adrenal physiology, adrenal transplantation, stress, and the biological effects of radiation is presented, with particular attention to those factors which might enter into the evaluation of the results of this study. An intensive study of the morphology of transplants, identical to those tested in the present study, was performed simultaneously in this laboratory and the histological and histochemical findings are discussed. Male Wistar rats, weighing about one hundred and twenty grams, were structured in six groups: intact normal, sham operated, immediate transplants (glands removed and implanted without delay), one hour delay transplants (stored in saline solution in vitro before implantation), irradiated transplants (2000 r. in vitro), and adrenalectomized. The animals with one hour delay transplants were the controls for those with irradiated transplants, since the combination of operative and irradiation procedures delayed implantation for one hour. The other groups were studied to establish standards for measuring relative cortical function. Fourteen days following operation all rats, except the adrenalectomized, were stressed by either histamine acid phosphate, histamine c.p., or water intoxication. Adrenalectomized rats were stressed on the tenth day after operation, since few could survive the fourteen day period. The percentage of each group surviving from the second to the fourteenth day of the postoperative period, and the weight gained during this period, was determined for each operative group. The data from the study of postoperative survival were analyzed by establishing the mean of each operative group and testing these for significant difference by means of the Student Fisher t test. The results of the weight gain study were treated similarly. The doses per hundred grams of body weight of histamine c.p. and equivalent histamine as the acid phosphate which were lethal to fifty percent of the animals of each operative type were determined by the method of Litchfield and Wilcoxon. Differences in the LD50 values were tested for statistical significance by their method. Six c.c. of water per hundred grams of body weight were administered by gavage at hourly intervals for four hours and the amount of urine excreted in an eleven hour collection period was expressed as a percentage of the total volume administered. Mean percent excretion was determined for each operative group and the differences were tested statistically by the t test. A ninety-five percent probability level was used throughout. The results of the histamine intoxication stress and the percent survival study showed thnt irradiated transplants are as efficient as their controls. However, the results of the water intoxication stress and the weight gain study reveal that the response of animals with irradiated transplants under these measures is much worse than that of their controls and, in fact, no better than that of adrenalectomized rats. A review of the factors affecting each of these measures is presented in detail, and the apparent dichotomy is explained as follows. Irradiation does not reduce the amount of protection afforded by a transplant against histamine intoxication. In fact all types of transplants provide the same amount of protection, less than that afforded by an intact gland, but of considerable value when the mortality of the adrenalectomized group is considered. This was determined using both histamine c.p. and histamine acid phosphate as stressing agents. The discussion presented leads to the conclusion that while slight differences in functional ability in meeting such an acute stress probably exist between different types of transplants, these differences are merely reflections of the variation in cell depths, and are not detectable in histamine intoxication, or any other stress which necessitates production of additional amounts of hormone for only a relatively short time. A comparison is made between histamine c.p. and histamine acid phosphate. While use of the histamine c.p. is more economical, the greater variability in response obtained with it and it s more lethal nature may render it unsatisfactory for many studies. From the discussion of survival of unstressed animals during the post operative period it may be concluded that only very small amounts of hormone are required for life maintenance. Moreover, it is concluded that irradiation does not alter the nature of the adrenal secretion, since there is no statistical difference between the survival of animals with irradiated transplants and their controls. Evidence is presented that weight gain requires a continuous supply of adequate amounts of cortical hormone. Irradiation of the gland before implantation results in a long lasting depression of mitotic activity, and reduction in the rate of maturation of cells. Fourteen days after operation, the secretory capacity of an irradiated transplant is still less than that of the controls as shown by the smaller cell depth and lower concentrations of ascorbic acid and sudanophilic lipids. The failure of the animals with irradiated transplants to gain as much weight as their controls in the fourteen day postoperative period is believed to result from a delay in reaching levels of secretion commen sura te wi th t ~e demands of the growing organism. This conclusion is supported by the observation that during a thirty day postoperative period, the animals with irradiated transplants begin to approximate the weight gain seen in the control group during a similar period. Water intoxication is shown to be a stress which requires large amounts of cortical hormone for a considerable time. It is therefore not surprising that animals with irradiated transplants, which at fourteen days contain relatively few cells and are just beginning to store reserves of hormone precursors, are apparently little better than adrenale ctomized animals in meeting the severe demands of this stress. The conclusion reached in this study is that the alterations in the function of adrenal transplants which are detectable after x-irradiation with two thousand roentgens are attributable to the reduced rate of regeneration and maturation, and not to any alteration of the nature of the secretion.
Thesis (Ph.D.)--Boston University