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[CANCER RESEARCH 37, 3151-3168, September 1977] Structure and Function of the Pituitary Gland in Gonadal Tumor-bearing and Normal Cyprinid Fish1 John F. Leatherland and R. A. Sonstegard2 Departments of Zoology [J. F. L.] and Microbiology ¡R.A. S.¡,College of Biological Science, University of Guelph, Guelph, Ontario, Canada SUMMARY Of particular concern with waterborne carcinogens are the reports of Harris and coworkers (12, 31), which present The F, generation hybrids of carp and goldfish exhibited a epidemiological evidence suggesting a significant relation marked hyperplasia of pars distalis basophil (gonado- ship between cancer mortality in white males and drinking trophic) cells, which first became evident in 3- to 4-year-old water that was obtained from the Mississippi River. Al fish, the age at which carp and goldfish normally become though the results of the New Orleans study cannot be sexually mature. Many of these hybrids also developed gon- considered conclusive evidence that cancer in man is adal tumors, the genesis of which also coincided with the caused by the consumption of contaminated water, these onset of gonadotroph proliferation. In these fish the baso findings must be taken into consideration. phil hyperplasia was more marked than in nontumorous hy Recently, the technology for the quantitation and qualita- brids. Tumor-bearing carp also exhibited gonadotroph hy tion of dilute organic and metallic agents in water has been perplasia similar to that in tumorous hybrids. Both tumor- rapidly improved (34). However, the problems are complex, bearing and nontumorous hybrids showed a marked reduc and the need for surveillance is acute. It is increasingly ap tion in gonadotroph cell number when fed a methallibure parent that investigations must be addressed to waterborne diet, although there was no apparent change in either the factor(s), the existence and effects of which on animal gross pathology or the histopathology of the tumors. These health are unknown. A sentinel system for the early detec findings suggest that the hyperplasia of the gonadotrophs tion and identification of waterborne environmental carcin in tumorous fish is not, ;'pso facto, responsible for the ogens is urgently needed. As an approach to this situation, maintenance of the tumors. On the contrary, since gonado we have made a survey monitoring the frequency of occur troph hyperplasia was evident in both tumorous and nontu rence of fish tumors in polluted and nonpolluted waters in morous hybrids (all of which were sterile), it may be sympto the Great Lakes to explore the potential utility of neoplasia matic of the sterile condition of the fish rather than of the in feral fish as an indicator of environmental carcinogens tumor per se. Evidence for the presence of a second gona- (36-38, 40). Epizootics of gonadal tumors in carp (Cyprinus dotrophic cell type in cyprinids is presented and discussed. carpio), goldfish (Carassius auratus), and goldfish-carp hy Other pituitary cell types were similar in structure and ultra- brids were found, and they appear to have environmental structure in carp, goldfish, and hybrids and were unaffected relevance (36-38, 40). The tumors appear to be of a Sertoli by methallibure treatment. cell origin, although some may also contain Leydig cell elements (40). The tumor incidence is as high as 100% in some age-sex groups (40). INTRODUCTION One of the characteristics of the gonadal tumor-bearing fish and also of nontumor-bearing (sterile) hybrids is a Our aquatic environments are known to be fouled with massive proliferation of pituitary basophils (40). In this pa chemicals and classes of chemicals that have carcinogenic per we report investigations undertaken to elucidate the potential (6, 24, 25, 35, 41). This area has been excellently pituitary-gonadal feedback axis in these fish. In addition, reviewed by Kraybill (18). Although there is little evidence the effect of methallibure on the number and apparent that waterborne carcinogens have produced widespread activity of the gonadotrophs was examined. In teleosts cancer problems in man, it is not difficult to envisage such a methallibure appears to act as a gonadal inhibitor by block possibility. At present, because of ground water depletion, ing gonadotropin synthesis or release (13, 19, 32), possibly many cities are processing for drinking purposes water that by inhibiting the synthesis or release of hypothalamic re may be in excess of 30% recycled (9). Many inorganic and leasing factors (26). Methallibure was given to tumor-bear organic compounds (some known carcinogens) are not re ing hybrids to determine whether the proliferation of gonad moved in current water treatment processes (5, 30). In fact, otrophs evident in these fish can be regressed in the same treatment may be producing carcinogens; i.e., chlorination way that it is in other methallibure-treated teleosts. It was may produce chloroform and carbon tetrachloride, both hoped that these experiments might provide an insight into known carcinogens (3, 15, 33). the cause(s) of the gonadotroph hypertrophy. 1 This work was supported by grants from the National Cancer Institute of Canada, Environment Canada, and the National Research Council of Can MATERIALS AND METHODS ada. 2 Research Scholar, National Cancer Institute of Canada. Received February 28, 1977; accepted June 7, 1977. Collection and Maintenance of Fish. One hundred and SEPTEMBER 1977 3151 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1977 American Association for Cancer Research. J. F. Leather/and and R. A. Sonstegard two fish were used in the study of pituitary histology, includ fluid, transferred to 70% alcohol for 48 hr, and weighed. The ing 32 carp (19 males and 13 females), 63 hybrids (38 males, data were compared by 1-way analysis of variance. Individ 23 females, and 2 hermaphrodites), and 7 goldfish (4 males, ual means were compared by least significant difference. 2 females, a 1 hermaphrodite). A further 41 fish (19 males, 19 females, and 3 of indeterminate sex) were used to deter mine the effect of methallibure on pituitary histology, and RESULTS 39 5- to 6-year-old fish were used for measurements of pituitary weight. Fish were collected by gill nets from Hamil Adult (4 Years Old) Nontumorous Carp and Goldfish. ton Harbour, Lake Ontario. Some were biopsied as they The structure of the pituitary gland was essentially similar in were removed from the nets, some were returned to Guelph nontumorous carp and goldfish (Figs. 1 and 4). The organi for biopsy, and others (to be treated with methallibure) were zation and cellular characteristics of the cell types closely returned to Guelph and acclimated for 4 to 10 weeks in 150- resembled the descriptions of goldfish pituitary given by gallon aquaria of running well water. The age of each fish other authors (2, 7, 16, 20, 21, 23, 28, 35). The rostral pars was determined at biopsy by scale ring counts. distalis (Figs. 1, 2, and 11) formed a thin anterior cap, which Methallibuie Treatment. Methallibure was administered extended dorsally from the dorsoanterior region of the pi to hybrids in 2 separate experiments. In the 1st experiment tuitary stalk and ventrally to meet the most anterior regions hybrids that displayed a distinct tumorous condition, evi of the pars intermedia. The rostral pars distalis region was denced by a distended abdomen, were chosen. They were composed of 4 cell types, an acidophil, an amphiphil (possi bly a chromophobe), and 2 basophils. The acidophils [pro- maintained in the laboratory in continuously running and aerated well water. They were fed daily with a pelleted fish lactin cells (11)] were spherical or elongated cells with diet to which had been added methallibure (I.C.I. 33,838). A spherical nuclei and prominent nucleoli. The cytoplasm was known amount of methallibure-treated diet was given so poorly granulated; the granules stained deep red with ery- throsin but only pale orange with OG (Fig. 2). The amphi- that, assuming equal food consumption, each fish received 1 mg of methallibure per kg of body weight each day. In the philic cell type [probably ACTH (16, 29)] was interspersed 1st experiment a group of 12 fish was administered the diet with the acidophils and. together with the acidophils, com for 6 weeks, and the pituitaries were fixed for light micros posed the major component of this region of the gland. The copy. Pituitaries from 5 control fish, which had been fed a amphiphils were conversely elongated cells with oval or diet identical with that of the methallibure-treated fish ex spherical nuclei but with no prominent nucleoli. Their cyto cept that methallibure had been omitted, were also fixed for plasm contained little stainable material and appeared light microscopy. chromophobic with the stains used here. In the 2nd experiment sterile and tumor-bearing hybrids In electron micrographs the prolactin (Figs. 14 and 16) were used. A group of 5 fish was randomly selected as the and ACTH cells (Figs. 15 and 16) were similar in appear ance. Both contained numerous membrane-bound elec initial control group, and the remainder of the fish were tron-dense cytoplasmic granules, and both showed signs of administered the methallibure diet. Random selections of 3 to 4 fish were made 3, 5, 10, 15, 20, and 35 days after first moderate secretory activity, as evidenced by their content giving the methallibure diet. The pituitary from each fish of mitochondria, endoplasmic reticulum, and Golgi bodies. was preserved for light microscopy. The cells differed in the diameter of the cytoplasmic gran Histology. Each fish was killed by transection of the ules, those in the prolactin cells being larger than those in spinal cord, and the pituitary was rapidly dissected from the the ACTH cells (Figs. 14 to 16) (16, 20). Interspersed among skull, cut into halves in the sagittal plane, and placed into the prolactin and ACTH cells were nongranulated cells with Bouin's Hollande sublimate.

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