Accumulation and Distribution of Ions of Group-IIIA Elements in the Tissues and Eggs of the Japanese Quail

Accumulation and Distribution of Ions of Group-IHA Elements in the Tissues and Eggs of the Japanese Quail G. A. ROBINSON, D. C. WASNIDGE, and F. FLOTO Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada NIG 2W1 (Received for publication February 14, 1989)

1990 Poultry Science 69:300-306 INTRODUCTION

Many reports deal with the distribution of toxic and potentially toxic elements in mammals. The authors' laboratory examined the deposition of such elements in avian species, with the Japanese quail serving as the experimental form. The distributions of group-IIIA members among the tissues of this bird are of interest because of the marked differences seen previously among the Group-IIIB metals Gd(IH), Th(IV), and U(VI) (Robinson et al., 1984, 1986), particularly in the liver, kidneys, and bones. For diese MB elements, the percentages of distribution among the tissues in producing females were markedly different than in mature male quails. This estrogenrelated effect was induced in males given exogenous estradiol. Metals of Group IIIA have been studied extensively in mammals (reviews: Beliles, 1979; Elinder and Sjogren, 1986; Fowler, 1986; Kazantzis, 1986). Thallium, the most toxic of this subgroup (Venugopal and Luckey, 1978), has been known as an environmental contaminant of some importance for three decades (Zitko, 1975; Sherlock and Smart, 1986). Recognition is increasing of aluminium as deleterious in aquatic systems (Campbell and Stokes, 1985; Havas, 1985), soil (Horsnell, 1985), plants (de Medeiros and Haridasan, 1985), and human populations (Charhon et al., 1986). Reports on IIIA metals in birds are infrequent. Thallium-induced achondroplasia has

been reported in chick embryos (Karnofsky et al., 1950) and as being accumulated in cultured chick ventricular cells (Friedman et al., 1987). Aluminium contributed to decreased egg production, thin shells, deformed embryos, and a muscular dystrophy (Pragay, 1962; Gilani and Chatzinoff, 1981; Nyholm, 1981; Miyahara et al., 1984). But feeding aluminium sulphate to turtle doves had no marked effect (Carriere et al., 1986). No reports on the effects of gallium or indium in birds were found. In the present study, the authors compared the distributions and depositions of boron (III), aluminium (III), gallium (III), indium (III), and thallium (I) in the tissues of control and estradiol-treated male quail, laying females, and in eggs. MATERIALS AND METHODS

Japanese quail Coturnix coturnix japonica 5 to 6 mo old (males, approximately 112 g BW; females, 140 g) were housed six to eight per pen, provided with water, oyster shell fragments, and an unmedicated game-bird ration (Purina Gamebird Feeder, 20% CP, 2.5% CF) ad libitum. The birds were kept under a photoperiod of 14 h light: 10 h darkness. Each quail was given one injection of one of the IIIA ions. Two dose levels were used. For quail given the upper dose, this level was 1.5 x 10" (xmol/kg of BW, where n provided one order short of a lethal dose. The toxicity of

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ABSTRACT Solutions of salts of the five Group-IIIA elements were given, intravenously, to mature Japanese quail. By 18 h, the accumulation maxima in the major tissues were: leg bones, 20% for Ga +3 ( 67 Ga label) in estradiol-treated males; liver, 51% for Al +3 (26A1 label) in control males; kidneys, 32% for In +3 (U4m m ^ ^ 1 ) ; n estradiol-treated males; and growing oocytes plus ova, 37% for In. Accumulations of Tl +1 (201T1 label) were 6 times those for Ga or In in the brain and muscles, and. 1 times in plasma. The cumulative maxima in egg components over 8 (B; Tl) or 10 (Al; Ga; In) days were: B, 23% in albumen; Al, 38%, Ga 27%, In, 43% in yolks; Tl, 12% in shells. The accumulation of thallium in the eggshells markedly exceeded (P<.001) the deposits of the other IIIA elements in shells, Al being the next highest at .54%. (Key words: IIIA elements, Japanese quail)

GROUP-IIIA ELEMENTS IN QUAIL

Distribution Among the Tissues Thirty-four laying females (.8 to 1 egg/day, each) and 74 mature males were selected for the study. The males were given intramuscular injections of either 160 umol of estradiol-17P (E2) [l,3,5(10)-estratrien-3,17 p-diol: Steraloids, Inc., Wilton, NHJ/2.5 mL of ethanolic solution/kg (40 quail), or 2.5 mL of ethanol/kg (34 quail). At 102 h later, four quail from each of the three treatment groups (males, E2 males, females) were given intravenously (iv) one of the B, Ga, In, or Tl solutions. Six quail from each of the three treatment groups were given the Al solution. Eighteen h after giving the ions, blood was collected; the quail were killed; and the brain, digestive tract, kidneys, femora and tibiotarsi, leg muscles overlying the femora and tibiotarsi, liver, lungs, oocytes plus ova, plasma, female reproductive tract, skin plus feathers, and testes were prepared for gamma counting (Robinson et al., 1980). The protein-bound phosphorus concentrations (Chen et al., 1956; Bergink et al., 1973) and the packed-cell volumes were measured for the blood samples from the IIIAinjected quail, and for the 6 E2-injected males not given any IIIA ions. The IIIA-ion content of

each tissue was quantitated to the nearest .5 ug (approximately .3% of the dose) for boron, to a 2% level of accuracy for the 26A1, and to 1 % for the other radionuclides. The counting rates were corrected for background, expressed as the percentage of the dose per tissue or percentage per gram by reference to the counting rates or aliquots of the labelled injection solutions, and were averaged per treatment group. The effect of self-absorption on the counting rates was not significant when tested with 153Gd (Robinson et al., 1981), a nuclide emitting photons with energies equal to or less than these for the IIIA radionuclides used. Comparisons were made between differences in means using variances with n-1 weighting in the f-test for unpaired data (Steel and Torrie, 1980). The differences were tested, two means at a time, as to the percentage of depositions of ions for dosages, for egg components, and for treatment groups (males versus E2 males versus producing females). Deposition in Egg Components About 0900 h on Day 0, the laying females were given iv: B (four quail), Al (seven quail), Ga (six quail), In (six quail), or Tl (six quail) as ions in solution, .015 umol/kg of BW. Eggs were collected about 0900 h on each succeeding day for 8 to 10 days. The egg components were separated out, the radionuclide levels were expressed as die percentage per component, and the cumulative totals were calculated for each day. RESULTS AND DISCUSSION

The protein-bound phosphorus and packedcell volume values (x ± SE; n = 34) for each treatment were: females, .129 ± .001 mg/mL and .391 ± .007, respectively; E2-treated males, 1.061 ± .067 mg/mL and .267 ± .006; ethanol-treated males, .018 ± .002 mg/mL and .403 ± .011. The difference in the packed-cell volume values for females versus the ethanoltreated males was not significant. The P values for all other combinations were <.001. The increased values for plasma protein-bound phosphorus concentration and the decreased values for packed-cell volume in males verified the effectiveness of E2 in terms of stimulating vitellogenesis (Gibbins and Robinson, 1982). Aluminium apparently did not interfere with phosphorylation during vitello-

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the metal ions was tested, two males per solution, beginning with 150 umol/kg. Injections were done slowly, taking 4 to 5 s each. The criterion of acceptability was that the quail lived for 18 h after being given a test solution. Thus, the upper dose levels for the distribution study were: B, 150 umol/kg (as boric acid in an aqueous solution); Al, 150 umol/kg; Ga, 15 umol/kg; In, 15 umol/kg (as chlorides in .03M HCl solution); and Tl, 1.5 umol/kg (as sulphate in .015Af H2SO4 solution). For quail given the lower dose level, the dosage was .015 umol/kg. The tracers were: 1.9 Bq of 26A1 (ICN, Irvine, CA)/kg of BW (Bq = bequerel = 1 disintegrations per second); 280 kBq of 67 Ga (NEN, Boston, MA)/kg; 56 kBq of U 4 m In (metastable indium-114, NEN)/kg; and 280 kBq of 201T1 (NEN)/kg. The analytical method for B (neutron-activation analysis, Neutron Activation Services, McMaster University, Hamilton, Ontario, Canada) and the specific concentration of the 26A1 were barely adequate for quantitation at the dosage level of 150 umol/kg; so for these nuclides, no .015 umol/ kg groups were attempted.

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FIGURE 1. Deposition of IIIA elements in tissues of the Japanese quail. Mature male quail were given, intramuscularly, either 160 umol of estradiol-17p72.5 mL of ethanolic solution/Teg (solid bars) or 2.5 mL ethanol/kg of BW (hatched bars). At 102 h later, these males, together with untreated producing females (.8 to 1 egg/day, each; open bars), were given, intravenously, solutions of H3BO3 (natural abundance for B), AICI3 (26A1 label), GaCl3 ( 67 Ga label), InCl3 ( 114m In label), or TINO3 (201T1 label). Means (± SE; n = 4 quail per bar except 6 for Al), 18-h accumulations, expressed as percentages of the dose given. Oocytes plus ova values were for the rapidly growing (yellow) oocytes in the ovaries plus ova found in the reproductive tract.

genin synthesis or with the transport of the finished vitellogenin, although the solubility of aluminium phosphate is slight (Handbook of Chemistry and Physics, 1983-84). In the E2treated males given aluminium, the mean protein-bound phosphorus level (.904 ± .122 mg/mL; n = 6) was not different (P>.05) than that for the group of E2-treated males not given aluminium (.788 ± .064 mg/mL; n = 6). Further, the daily egg production and yolk weights for the six laying females given aluminium were maintained over the 10-day period. The assay values for boron and aluminium exceeded the lower levels of detection only in the kidneys, leg bones, livers, and oocytes (Figure 1). The quantities of 67Ga, 114m In, and

201

T1 used were sufficient to label all of the tissue groups selected for study (Figures 1, 2, 3 and 4). Other than as shown in Figure 1, the differences (P<.05 to .001) between the percentage deposition values occurred in the brain and plasma of the three treatment groups and in the muscles for the female and E2-male groups (Figure 2). Differences for the other tissues studied did not present a consistent pattern (Figure 3). The depositions of the Group-IIIA elements in the bones of male Japanese quail were slight (Figure 1), a surprise in view of the reported affinity of aluminium, gadolinium, and indium for bone in mammals (Venugopal and Luckey, 1978; Manzo et al, 1983). Lie et al. (1960) did not find a marked affinity for thallium in

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Dosage ( u m o l / kg ,

GROUP-IIIA ELEMENTS IN QUAIL

the tissues of the rat, other than the kidneys. The percentage accumulations for IIIA ions in the leg bones were similar to those for gadolinium and thorium (Robinson et al, 1984). The estradiol-stimulated deposition of aluminium, gallium, and indium in bones is a response reported (Robinson et al, 1986) for

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uranium but not seen for gadolinium or thorium. Estradiol markedly decreased the deposition of aluminium in the liver, thereby providing some protection for the liver from any toxic effects of aluminium accumulation. Levels of IIIA labels in the kidneys were as found previously for gadolinium, except for indium where the accumulations approximated the 30% found for uranium (Robinson et al, 1986). Where two dose levels were used, the distribution of the near-toxic dose was similar to that for the smaller dosage, as has been reported for mice (Castronovo and Wagner, 1971). This result was in contrast with that seen for uranium, where large doses increased the percentage deposition in the kidneys (Kupsh and Robinson, 1989). Aluminium, gallium, and indium were deposited in the oocytes to a greater extent (P<.05 to .001) than for boron or thallium. Such a response may be expected since B was present as the anion; Al, Ga, and In, as +3 cations; and Tl, as the +1 cation. The retention of thallium in muscle (Figure 2) would support the view (Gehring and Hammond, 1967; Cavanagh et al., 1974) that thallium behaves much as does potassium in many biochemical reactions. The plasma levels of thallium were .1 (P<.01, except not significant for low-dose Ga versus Tl in males and E2-males) of the values for gallium and indium; thus, the greater affinity of brain and muscle tissue for thallium was not attributable to a greater concentration in the plasma present in those tissues. The deposition of label in the other tissues showed no consistent pattern among the percentage of dose values (Figure 3). Deposition levels in the egg components are shown in Figure 4. The maxima and SE for daily collections were: B, albumen, 3.96 ± .20%, Day 7; Al, yolks, 10.9 ± 2.0%, Day 3; Ga, yolks, 7.88 ± .47%, Day 3; In, yolks, 11.97 ± 1.41%, Day 3; Tl, shells, 8.63 ± 0.84%, Day 1. Comparing the percentage of the dose deposited in each component, the albumen contained more B (P<.01 for Day 8) than did the yolks or shells; the yolks contained more In = Al = Ga (P<.001 for Day 10) than did the albumen or shells; and the shells contained more Tl (P<.001 for Day 8) than did the albumen or yolks. The low percentage of accumulations for boron and thallium in the yolks (Figure 4) were as seen previously for uranium (Robinson

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D o s a g e (.umol / kg ) FIGURE 3. Tissues showing small or no differences among percentage accumulations of Ga, In, and Tl. Boron and Al were below the lower detectable limits._Solid bars = estradiol-treated males; hatched bars = ethanol-injected males; open bars = laying females. Values are x ± SE.

et al., 1984). The boron and thallium, in whatever chemical form they are present in the plasma, do not appear to bind to vitellogenin to the same extent as calcium, gadolinium, or thorium. Aluminium, gallium, and indium transfer into the yolk; yet the crystal ionic radii (.51, .62, .81 pm; Handbook of Chemistry and Physics, 1983-84) are similar to or less than that for U(VI) at .80 pm but are markedly different than the values for gadolinium (.94), thorium (1.02), or calcium (.99). Coordinate numbers may be more appropriate for comparisons than are ionic radii (Panson and Charles, 1977; Martin and Richardson, 1979). The shells of eggs laid 24 h after labelling the hens (eggshells for Day 1) acquired 8.63 ± .84% (n = 6) of the 201T1 dose (Figure 4). The total accumulation for the 8 days of egg collection was 12.1 ± 1.4%. These percentages were greater (P<.001) than for any of die omer four Group-IIIA elements. Barclay et al. (1953) did find 9.45% of a 204T1 label was

associated with chicken eggshells, but that label was given directly into the egg through a hole in the shell and is not seen as analogous to a hen-to-shell transfer. In the present study, oxidation of the T1(I) ions to Tl(III) may have occurred as the shell gland shows oxidative activity (Pearson and Goldner, 1974); but no grains of thallium oxide similar to those found in yeast mitochondria (Lindegren and Lindegren, 1973) were seen in die wall of the shell gland or in the formed shell. The Tl2(CC<3)2, if such exists, may be indistinguishable from CaC03 under the microscope. Autoradiography was unsuccessful for the 204Tl-labelled eggshells (hens, 1.5 umol Tl/kg; shells from Day 1, 8.15 ± .21% of dose, n = 8), in an attempt to find which layer of shell (Sturkie, 1976) contained the label. The diffusion disc for the .764 MeV negations far exceeded die thickness of the shell pieces. The ionic radius of .95 for Tl(III) is similar to that for calcium, so thallium in an

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GROUP-IIIA ELEMENTS IN QUAIL

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Collection period (days) FIGURE 4. Deposition of IIIA elements in eggs of Japanese quail. Dosages were .015 umol/kg of BW given intravenously on Day 0. Each datum point represents the cumulative total as of the date of egg collection for the percentage of total dose present in the egg component named as, Y = yolks, A = albumen, S = shells plus membranes. Totals for B, Ga, or In in the shells and for Ga or In in albumen were <.3%. The SE limits are shown where such limits exceed .5%.

oxidized form could have been deposited along with calcium during shell formation. The ratio of thallium to calcium in the shells, as estimated from the ^ T l counting rates and from approximately 40% of an avian shell being calcium, was 1:40,000 (low dosage) to 1:500 (high dosage). Perhaps the thallium deposition in the shells is just a case of coprecipitation, rather than of any formation and active deposition of Tl(III). In a general sense, the "typical" forms Al(III), Ga(III), and In(III) of the IIIA elements, as compared with the "atypical" forms of borate and T1(I), were deposited in the livers of all three treatment groups (females, estradiol-treated males, ethanol-treated males) of Japanese quail and in the leg bones of the estrogen-containing females and estradioltreated males. The deposition of indium in the kidneys of these quail was markedly greater than for the other IIIA elements. The extent of depositions in the growing oocyte and, thus, appearing in the egg yolk was In > Al > Ga > Tl = B. In other tissues, the thallium levels in tissues from the brain and leg muscle were approximately 6 times those for gallium and indium; whereas in plasma, the levels of

gallium and indium were approximately 10 times that for thallium. Thallium deposition in eggshells was 25 times those for the other IIIA elements. To postulate what effect environmental thallium has on the shell-gland function and on shell formation is inappropriate at this stage. ACKNOWLEDGMENT

The authors thank the Ontario Ministry of Agriculture and Food for supporting the present project. REFERENCES Barclay, R. K., W. C. Peacock, and D. A. Karnofsky, 1953. Distribution and excretion of radioactive thallium in the chick embryo, rat, and man. J. Pharmacol. Exp. Ther. 107:178-187. Beliles, R. P., 1979. The lesser metals. Pages 547-615 in: Toxicity of Heavy Metals in the Environment, Part 2. F. W. Oenme, ed., Marcel Dekker, Inc., New York, NY. Bergink, E. W„ H. J. Kloosterboer, M. Gruber, and G. AB, 1973. Estrogen-induced phosphoprotein synthesis in roosters. Kinetics of induction. Biochim. Biophys. Acta 294:497-506. Campbell, P.G.C., and P. M. Stokes, 1985. Acidification and toxicity of metals to aquatic biota. Can. J. Fish. Aquat. Sci. 42:2034-2049.

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Response of lucerne to phosphate as Poultry Sci. 60:563-568. affected by calcium and potassium sulfates and soil Sherlock, J. C , and G. A. Smart, 1986. Thallium in foods aluminum levels. Aust. J. Exp. Agric. Anim. Husb. 25: and the diet. Food Addit. Contain. 3:363-370. 557-561. Steel, R.G.D., and J. H. Torrie, 1980. Page 106 in: Principles Kamofsky, D. A., L. P. Ridgway, and P. A. Patterson, 1950. and Procedures of Statistics. 2nd ed. McGraw-Hill Production of achondroplasia in the chick embryo with Book Company, New York, NY. thallium. Proc. Soc. Exp. Biol. Med. 73:255-259. Sturkie, P. D., 1976. Reproduction in the female and egg Kazantzis, G., 1986. Thallium. Pages 549-567 in: Handbook production. Chapter 16. Page 320 in: Avian Physioloon the Toxicology of Metals. Volume II: Specific gy. Edited by the author. Springer-Verlag, New York, Metals. L. Friberg, G. F. Nordberg, and V. B. Vouk, NY. ed. Elsevier/North Holland, Amsterdam, The Nether- Venugopal, B., and T. D. Luckey, 1978. Toxicity of group lands. III metals. Pages 101-127 in: Metal Toxicity in Mammals. 2. Chemical Toxicity of Metals and Metalloids. Kupsh, C. C , and G. A. Robinson, 1989. Linearity of the Edited by the authors. Plenum Press, New York, NY. accumulation of various dosages of uranium in the major organs of the mature male Japanese quail. Effect Zitko, V., 1975. Toxicity and pollution potential of thallium. of various doses of estradiol-17(3. Comp. Biochem. Sci. Total Environ. 4:185-192.