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Effects of Cobalt Chloride, Nickel Chloride, and Nickel Subsulfide upon Erythropoiesis in Rats* AGNETA OSKARSSON, P h .D., MARILYN C. REID, B.S., and F. WILLIAM SUNDERMAN J r ., M .D.f Departments of Laboratory Medicine and Pharmacology, University of Connecticut School o f Medicine, Farmington, CT 06032
ABSTRACT The erythropoietic effects of sustained intraperitoneal (i.p.) administra tion of CoCl 2 and NiCl 2 were compared with the effects of a single intrarenal (i.r.) injection of aN i 3 S2 in female Fischer-344 rats. Infusion of NiCl2 by osmotic minipumps (0.85 mg Ni per day, i.p., for 24 days; total dose = 20 mg Ni per rat) did not alter the blood hematocrit or reticulocyte count during six weeks of observation. Under identical conditions, i.p. infusion ofCoCl2 (0.85 mg Co per day, i.p., for 24 days; total dose = 20 mg Co per rat) caused significant erythrocytosis (hematocrit at six weeks = 62 ± 4 percent, P < 0 . 0 0 1 versus 50 ± 3 percent in controls) and reticulocytosis (reticulocyte count at three weeks = 2.5 ± 1.5 percent, P < 0.005 versus 0.8 ± 0.7 percent in controls). Administration of aN i 3 S2 to rats as a single i.r. injection (7 mg Ni per rat) caused pronounced erythrocytosis (hematocrit at six weeks = 79 ± 2 percent, P < 0.001 versus controls) and reticulocytosis (reticulocyte count at three weeks = 2.8 ± 1.2 percent, P < 0.005 versus controls). This study demonstrates that i.p. infusion of Ni[II] is ineffective in stimulating erythro poiesis in rats, and that salient differences exist betw een the enhanced erythropoiesis that occurs in rats following i.p. infusion of Co[II] and that produced by i.r. injection of aN i 3 S2. Introduction
effects, such as g a stro in testin al d is turbances, hypothyroidism , and deaf n ess . 3 , 1 ° ’ 2 4 , 2 8 ' 3 8 F ish er and L angston , 8 Goldwasser et al , 1 2 and Smith and Fisher 4 2 showed that administration of CoCl 2 to rats in creases ren al p ro d u ctio n of erythropoietin. Necas and coworkers3 1 ’ 3 2 deduced that Co[II] causes local ischemia of renal re ceptors that control erythropoietin pro duction in rats or, alternatively, that Co[II] alters the responsiveness of these recep tors to oxygen. Fisher et al 9 demonstrated that Co[II] also causes direct stimulation of erythropoiesis in the bone marrow of isolated, perfused, hind limbs of dogs. Adam son and H e rb e rt , 1 H u n te r and Jackson , 1 7 Leisy et al , 2 7 and Schulman et al 3 9 found that Co[II] stimulates in vitro synthesis of globin by reticulocytes. Clin ical observations suggest that the extrarenal effects of C o[II] may be of paramount importance, since cobalt en hancement of erythropoiesis in anephric patients is equal to that in patients with functioning kidney s . 3 , 5 , 7 , 4 9 That nickel subsulfide (aN i 3 S2) stimu lates erythropoiesis in rats was discovered by Jasm in 1 8 in 1973 and has been con firmed in several subsequent studies . 1 3 , 1 4 15, 16, 19, 2 0 , 2 1 , 2 2 , 2 3 , 3 0 , 45 , 47 , 48
P r o n O U n C e d
erythrocytosis, reticulocytosis, increased erythrocyte incorporation of 5 9 Fe, and expanded blood volume occur in rats from one to five months after an intrarenal (i.r.) injection of aN i 3 S 2 . 1 6 , 2 1 , 2 2 , 3 0 Under identi cal conditions, i.r. injection of cobalt sul fide (CoS) or metallic Co dust does not stim ulate erythropoiesis in rats . 2 1 The erythrocytosis that is induced by i.r. injec tion of aN i 3 S2 is apparently mediated by enhanced renal production of erythro poietin, since plasma erythropoietin activ ity is increased, and the erythrocytosis re gresses following resection of the injected kidney . 1 4 , 4 5 Administration of aN i 3 S2 to rats by intravenous, intrahepatic, or in tram uscular injections does not affect erythropoiesis . 2 1 , 2 2 , 2 3 , 4 8
In the present study, the erythropoietic effects of sustained parenteral administra tion of CoCl 2 and NiCl2 were compared with the effects of a single i.r. injection of aN i 3 S2 in rats. The experiment was ac complished by intraperitoneal (i.p.) im plantation of osmotically driven m ini pumps which infuse solutions at a steady rate of 1.0 fil per hour . 4 , 4 1 , 5 0 As will be described, i.p. infusion of NiCl 2 did not alter the blood hematocrit or reticulocyte count; u nder identical conditions, i.p. infusion o f C o C l 2 caused significant erythrocytosis and reticulocytosis. The erythrocytosis that was produced by con tinuous infusion of CoCl 2 for 24 days was less than that produced by a single i.r. injection of aN i 3 S2. Materials and Methods T est C om po un ds
Nickel subsulfide (aNi 3 S2, median par ticle diameter 1.3 ¡xm) was provided by INCO Ltd.* The aN i 3 S 2 was analyzed for cobalt, alum inum , copper, and m an ganese by emission spectroscopy,! con tamination by each of these metals was less than 0.01 percent by weight. The identity of the aN i 3 S 2 crystals was con firmed by X-ray diffractometry. \ Ultrapure nickel chloride (NiCl2 • 3H 2 0 ) and cobalt chloride (CoCl2 • 6H 2 0 ) were also obtained." E x p e r im e n t a l A n im a l s
Female rats of the Fischer-344 strain § were housed in polystyrene cages, two to three rats per cage, and fed laboratory rat * Toronto, Ontario, Canada. t Performed by Dr. Stuart Warner, Gordon Re search Laboratory, INCO Ltd., Clarkson, Ontario, Canada. | Performed by Dr. Edward Kostiner, Institute of Materials Science, University of Connecticut, Storrs, CT. 11Alpha Inorganics Division, Ventron Corporation, Beverly, MA. § C harles River B reeding Laboratories, Inc., North Wilmington, MA.
E R Y T H R O P O IE S IS IN D U C E D BY C O B A L T A N D N IC K E L
chowll and tap water ad libitum. At the beginning of the experim ent, the rats were approximately four months old; their body weights averaged 179 g (SD ± 10 g, range = 156 to 207 g, n = 28). The rats were randomly distributed into four ex perimental groups; each group contained seven rats. I m p l a n t a t io n
M in ip u m p s
Osmotic minipumps** were used for continuous i.p. infusion of 0 . 2 ml of test solutions at a constant rate of 1 . 0 /xl per hour. Each rat in Group A, B, and C was anesthetized with diethyl ether and a one cm incision was made in the right side of the abdom en for i.p. insertion of the minipump. The peritoneum and abdomi nal muscles were closed with sutures, and the skin incision was closed with surgical clips. The minipumps were replaced on days 8 and 16. Rats in Group A (controls) received i.p. infusion of NaCl solution (0.15 mol per liter, adjusted to pH 5.4) at a rate of 0.085 mg Na per day for 24 days, (total close = 2 mg Na per rat). Rats in Group B received i.p. infusion of NiCl2 solution (0.60 mol per liter, pH 5.6) at a rate of 0.85 mg Ni per day for 24 days, (total dose = 20 mg Ni per rat). Rats in Group C received i.p. infusion of CoCl2 solution (0.60 mol per liter, pH 5.1) at a rate of 0.85 mg Co per day for 24 days, (total dose = 20 mg Co per rat). I n t r a r e n a l I n je c t io n
Each rat in Group D was anesthetized with diethyl ether and the right kidney was exposed by subcostal lumbar inci sion. By use of a one ml tuberculin syringe with # 25 gauge needle, a suspension of 10 mg of aN i 3 S2 in 0.2 ml of sterile NaCl solution (0.15 mol per liter) was injected into the cortex of the cephalad pole of the U Ralston Purina Co., St. Louis, MO. ** “Alzet” pumps, model 2001, Alza Corporation, Palo Alto, CA.
kidney (total dose = 7 mg Ni per rat). The musculature was sutured and the skin in cision was closed with surgical clips. H e m a t o l o g ic a l M e a s u r e m e n t s
Blood samples (80 ¿il) were collected from each rat on days 0, 3, 7,14,21,28,35, and 42. The blood samples were obtained by incising the tip of the tail with a scal pel; the samples were withdrawn into cap illary tu b e s th a t co n tain ed d rie d sodium h ep arin ( 1 0 0 units p er tube). Measurements of microhematocrit were performed by the method of Strumia et al . 4 6 Reticulocyte counts were performed as described by M iale 2 9 on days 3, 7, 14, 2 1 , and 28. St a t i s t i c a l A n a l y s e s
Student’s “t” test 5 2 was used to assess the statistical significance of differences betw een the mean values (± SD) of blood hem atocrits, reticulocyte counts, and body weights for rats in Groups B, C, and D versus the corresponding values for control rats (Group A). Results B l o o d H e m a t o c r it Va l u e s
Measurements of blood hematocrit are summarized in figure 1. In NiCl2-treated rats (Group B), mean hematocrit values did not change significantly during the observation period, compared to corre sponding values in control rats (Group A). In CoCl2-treated rats (Group C), signifi cant increases in blood hematocrits oc curred from three weeks until the end of the experiment at six weeks. Although i.p. infusion of CoCl2 was terminated at 24 days, the blood hematocrit values con tinued to increase throughout the obser vation period, reaching 62 (SD ± 4) per cent at six weeks (P < 0.001 versus 50 ± 3 percent in Group A and 48 ± 4 percent in Group B). In aN i 3 S2-treated rats, signifi-
OSKARSSON, R E ID , A N D SU N D E R M A N JR .
F i g u r e 1. Blood h e matocrit in rats at intervals following initiation of the ex p erim en t. G roup A (controls, upper left) re ceiv ed i.p. in fu sio n of NaCl solution (0.15 mol per liter) at a rate of 0.085 mg Na per day for 24 days (total dose = 2 mg Na per rat). Group B (upper right) received i.p. infusion of NiCl2 solution (0.60 mol per liter) at a rate of 0.85 mg Ni per day for 24 days (total dose = 20 mg Ni per rat). Group C (lower left) received i.p. infusion of CoCl2 solution (0.60 mol per liter) at a rate of 0.85 mg Co per day for 24 days (total dose = 20 mg Co per rat). Group D (lower right) received a single intraren al (i.r.) in jectio n of PERIOD OF OBSERVATION (weeks) aN i3S2 (7 mg Ni per rat). The vertical lines denote the standard deviations. P < 0.005 versus corresponding value in Group A, • P < 0.001 versus corresponding value in Group A. The shaded areas denote the reference range for blood hematocrit in rats of the Fischer-344 strain.15
cant increases in hematocrits occurred from one week after the i.r. injection until the end of the experiment. At six weeks, blood hematocrit values in N i 3 S2-treated rats averaged 79 ± 2 percent (P < 0.001 versus th e c o rresp o n d in g values in Groups A, B, and C). B l o o d R e t ic u l o c y t e C o u n t s
As shown in figure 2, blood reticulocyte counts did not change significantly in rats of Group B during or after i.p. infusion of NiCl2, compared to corresponding values in control rats (Group A). In CoCl2-treated rats (Group C), reticulocyte counts were significantly increased in two weeks, and reached a maximum of 2.5 ± 1 .5 percent at three weeks (P < 0.005 versus 0.8 ±0.7 in Group A, and 0.7 ±0.5 in Group B). In aN i 3 S 2 treated rats (Group D), reticulo cyte counts were significantly increased in one week and reached a maximum of 2.8 ± 1 .2 percent at three weeks (P < 0.005
versu s th e co rresp o n d in g values in Groups A and B). B o d y W e ig h t s
M easurements of body weight at one, three, and six weeks after the beginning of the experiment are illustrated in figure 3. No significant changes in body weight oc curred at these intervals. All of the rats lived until the end of the experiment; they ap p eared health y except for signs of erythrocytosis (intensely red ears, eyes, noses, feet, and tails) in rats of Groups C and D.
Discussion This study demonstrates that sustained i.p. infusion of NiCl 2 does not cause eryth rocytosis in rats, whereas i.p. infusion of C o C l 2 cau ses m arked erythrocytosis under identical experimental conditions.
E R Y T H R O P O IE S IS IN D U C E D BY C O B A L T AND N IC K E L
F i g u r e 2. Blood reticu locyte count in rats at in tervals following initia tion of the experim ent. The dosages and routes of adm inistration of NaCl, NiCl2, CoCl2, and «Ni3S2 are given in the legend for figure 1. § P < 0.05 versus corresponding value in Group A. * P < 0.005 ver sus corresponding value in Group A. • P < 0.001 versus co rresponding value in Group A. The shaded areas denote the reference range for blood reticulocyte count in rats of the Fischer-344 strain.15 PERIOD OF OBSERVATION (weeks)
Following i.v. administration of NiCl 2 and CoCl2 to rats, both metal ions are rapidly accumulated by the kidney and excreted in urine . 3 3 , 3 4 , 3 5 The results of the present study are consistent with previous com parisons of the erythropoietic effects of Ni[II] and Co[II]. Orten et a l 3 6 reported that addition of an unspecified nickel salt
to a milk diet (enriched with Fe and Cu) had no effect upon blood hem oglobin concentration, hematocrit, or erythrocyte count in rats, while similar addition of CoCl2 to the milk-Fe-Cu diet resulted in pronounced erythrocytosis. Goldwasser et al 1 2 administered NiCl 2 and CoCl 2 to rats by single subcutaneous (s.c.) injection
F i g u r e 3. Body weight of rats at intervals follow ing initiation of the ex p erim en t. T he dosages and routes of administra tio n of N aCl, N iC l2, C oC l2, and aN i3S2 are given in the legend for figure 1.
PERIOD OF OBSERVATION (weeks)
O SK A R SSO N , R E ID , A N D SU N D E R M A N JR .
(6.7 mg Ni per rat or 3.4 mg Co per rat) and collected plasma samples 18 hours later for erythropoietin assay. Mean eryth ropoietin activity in plasmas of N iCl2treated rats did not differ significantly from that of NaCl-treated controls. On the other hand, mean erythropoietin activity in plasmas of CoCl2-treated rats averaged 2.6-times that of the controls. Smith and coworkers 4 3 , 4 4 isolated the lysosome-rich, light mitochondrial fraction (LMF) from renal tissue of rats following s.c. injection of CoCl 2 or NiCl*. The LM F of CoCl2 treated rats was susceptible to in vitro os motic release of arylsulfatase activity; in NiCl2-treated rats, the release of arylsul fatase from LM F was equal to that of controls. Smith et al 4 4 hypothesized that Co[II] differs from Ni[II] in its capacity to derange the membrane integrity of the lysosome-rich LMF; they proposed that damaged lysosomes of CoCl2-treated rats release a renal erythropoietic factor (REF) that subsequently interacts with a plasma p ro te in su b strate to g en erate ery th ropoietin. Necas and N euw irt 3 1 showed that Co[II]-stimulation of erythropoietin p ro d u ctio n in rats is su p p resse d by hyperoxia; on the other hand, Sunderman (unpublished observation) found that aN i 3 S 2 induced erythrocytosis in rats is not affected by hyperoxia. The results of the present study and the previous investigations that have been cited indicate that salient differences exist betw een the enhanced erythropoiesis that occurs following an i.r. injection of aN i 3 S2 and that produced by systemic adminis tration of Co[II] salts. Perhaps the most significant difference is that i.r. injection of aN i 3 S2 frequently leads to induction of renal cancer , 2 1 , 4 7 whereas there is no evi dence th a t C o[II]-induction of ery th rocytosis is associated with neoplasia. The present authors speculate that enhanced renal production of erythropoietin after i.r. injection of aN i 3 S2 may constitute an oncodevelopmental marker of neoplastic dedifferentiation, similar to the release of
alpha-fetoprotein which occurs during hepatocarcinogenesis in rats treated with N -2-fluorenylacetam ide . 4 0 Experim ents to test this proposition are underway in our laboratory. Acknowledgments The authors are grateful to Sidney Hopfer, Ph.D., Edward E. Morse, M.D., Samuel K. Shen, Ph.D., and Leo Delaney, B.S. for advice and assistance.
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cinom as and erythrocytosis in rats following intrarenal injection of nickel subsulfide. Lab. Invest. 35:71-78, 1976. J a s m in , G. and S o l y m o s s , B.: Polycythem ia induced in rats by intrarenal injection o f nickel subsulfide, aN i3S2- Proc. Soc. Exp. Biol. Med. 148:774-776, 1975. J a s m in , G. and S o l y m o s s , B.: T he topical ef fects of nickel subsulfide on renal parenchym a. Inorganic and N utritional Aspects of Cancer. Schrauzer, G. N., ed. N ew York, P lenum Press, 1978, pp. 69-83. Ka s a n e n , A., Ku l o n e n , M., and F o r r s t r o m , J.: Oral cobalt therapy in renal anem ia. Ann. M ed. Intern. F enn. 52:43-48, 1963. K a t o , K . Iron-cobalt treatm ent of physiologic and nutritional anem ia in infants. J. Pediat. 77:385-396, 1937. Kr is s , J. P., C a r n e s , W. H., and G r o s s , R. T.: H ypothyroidism and thyroid hyperplasia in pa tients treated w ith cobalt. J. Am. M ed. Assoc.
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