Placental transfer of radioactive salts in the pregnant rabbit

0047.()740/gS $3.00 + 0.00 Copyright iD 1995 Pergamon Press Ltd

~. J. N.ucl. Med . Bioi. Vol. 12. No .5. pp. 393-396, 1985 nted 10 Great Britain. All rights reserved

Placental Transfer of Radioactive Salts in the Pregnant Rabbit E. SCHACHNER,' J. SHANI,· M. SHECHTMANt and Y. PFEIFFER Department of Pharmacology, The Hebrew University School of Pharmacy, Jerusalem and 'Assaf Harofeh Medical Center, Zerifin, Israel (Received 30 July 1984; in revised form IS April 1985)

Therisks ofradionuclidiccontamination dueto theeasy transfer of water-soluble ions from thecirculation ~f ~e pregnant woman to h~r fetus., encouraged us to study whether theease of penetration of such ions IS size-dependent. Three radlochemlcals-22NaCI 99"'TcO Na and lOlTICI were' . t d i . rabbits on the 16th day of theirpregnancy and the rabbits were killed 15 30 ~6ec eI201.v ..mtlo pregnpant each. rabbit the blo0d, hear,t kid I" , , or mm ater. rom . . I ney, rver and muscle were sampled and counted as well as placenta ammouc fluid and some fetuses. At 15 and 60min hearts and livers were excised from selected fetuse~ and blood clearance, organ-to-muscle and fetus-to-placenta ratios were calculated. The results indicate that t~e transpla~ental transfer of the small radionuclide llNa+ is faster than that of 99"'TcO- d 201TI+ reac~mg. eq~lhbnum about 3h ~f~er its injection to the pregnant rabbit. lOITI + demonst~a~:d a hi h ~ocahzatJon m the pregnant rabbits an.d fetuses' hearts and kidneys, with a similar myocardial retenli~n m both groups. Du~ to t~e concentration of lOITI +, in spite of its large diameter, into the fetuses' heart ~usc~e, careful consideration should be taken when injecting lOITICI into pregnant women for imagmg, myocardiia I

Introduction

easily and localize in the same tissues in the fetus as Internal contamination of pregnant women exposed in the pregnant mother.?' I"Ce (as citrate) has been to radionuc1ides by accident or due to diagnostic injected into female mice at different time intervals medical procedures is of great concern to radiation before mating. Its passage through the placenta safety authorities. This is because of the easy transfer was demonstrated as a Hfunction of the pre-mating of most radionuclides to the fetus, who is much more injection interval.?' 4'Ca given in drinking water sensitive to irradiation than the pregnant mother. was found in rats' embryonic tissues and 20ITl+, The current maximum permissible radioisotope when injected to pregnant mice 24 h before sacrifice, body-burden recommended by the International was detected in the heart, lung and CNS of their Commission on Radiological Protection (ICRP), offspring. The diaplacental transfer of Tl" was rapid, applies to a 70-kg standard adult . Hence, the and the authors demonstrated the existance of a sensitivity to radiation damage of a fetus during its dose-dependant barrier for Tl" in pregnant mice.!" More refined experiments along this line were embryonic development is significantly higher than performed in the rabbit, where the placental Na/K that of a 7Q-kg adult, and is a limiting factor in the radionuclidic diagnostic study of the pregnant ratio decreased gradually during gestation, until it reversed at day 16. Both total-tissue and intracellular woman.!'' calcium show a marked increase during placental It is accepted today that drugs with molecular growth, while the total placental magnesium content weight less than 600, cross the placenta easily, declines toward the end of gestation." Also, some whereas the placenta is relatively impermeable to placental localization studies with 24Na +(5) and with water-soluble drugs with molecular weights exceeding IICO were performed in humans.P' 1000. Radioactive alkaline cations such as 22Na +, In this work we compare the passage of three 2+, 8lIRb+ and 4'Ca and anions such as 18F - , t4CO~-, radiotracers: 22NaCl, 99"'TcOi and lOtTlCl from l'SCN-, IlII- or 7'SeOi2, cross the placental barrier pregnant rabbits to their pups' blood at four time intervals after injection, and discuss the possible ionic-size dependence of these radionuc1ides on their • All correspondence should be addressed to: Professor penetration through the rabbit placenta. Jashovam Shani, USC School of Pharmacy, 1985 Zonal Avenue, Los Angeles. CA 90033. U.S.A. t Dr Shechtman's participation in this work is in partial Materials and Methods fulfillment of the req~irements for a D.M.D. degree by Seventy-two female albino rabbits of the local the Faculty of Dentistry of the Hebrew University of Jerusalem, Israel. strain, weighing 2.5-3.5 kg were used in this study.

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The rabbits were mated and kept caged separately from day 4 of pregnancy. On day 16 they were injected intravenously through their marginal ear vein using 30/lCi/kg of either one of the three radionuclides, then were bled by a heart puncture and decapitated at one of the following time intervals: IS, 30,60 and 120min after injection. The animals were organized into 12 groups (four time intervals for each of the three radiotracers) and the experiment was terminated when six rabbits were accumulated in each group. From each rabbit the heart and one kidney were excised, and the liver and muscle sampled and weighed. Placentae and amniotic fluid, as well as one whole fetus were also weighed. At two time intervals (IS and 60 min) hearts and livers were excised from some selected fetuses under a dissecting microscope and weighed. All samples were counted in a Packard auto-gamma spectrophotometer, with automatic background subtraction, and the 99"'Tc count rate was corrected for decay. The dpm/g tissue was calculated for each organ based on simulated calibration standards, and organ to muscle (for the pregnant animals) or to placentae (for the fetuses) calculated subsequently. Blood clearance and fetusto-placental ratios were plotted graphically with time.

for the three radionuclides (Fig. Ib) demonstrates that while the accumulation of the lO1Tl+ and 99"'TcOi in the fetus is very slow (after the first 2 h), the accumulation of the smaller radionuc1ide-22Na +, was about 6-fold faster, indicating that equilibrium might be reached soon. These figures are given for the whole fetus, irrespective of the biodistribution of the labels in the fetuses' organs. In some selected fetuses and time intervals, where microsurgery was performed to excise the hearts and livers, heart/ muscle ratios of 9.7 (at 15min) and 5.1 (at 60min) were demonstrated for 20lTl +, as compared to 0.4-0.6 (at 15min) and 0.7--0.85 (at 60 min) for 99"'TcOi and 22Na + (data not shown). Heart-to-muscle ratios in the pregnant rabbits for lO1Tl+, 99"'TcOi and 22Na + were similar in the mothers and the fetuses (values for the pregnant mothers are given in Table I), suggesting that radionuclides differ in their rate of placental transfer, not in their ultimate biodistribution. Except for the high localization of 20lTl + in the pregnant rabbits' and fetuses' hearts-the only label concentrating in a larger organ was lO'Tl+ in the kidney (kidney/muscle of 34.6 at 1 h-see Table 1), suggesting a high affinity of lOITl + to this organ in the pregnant rabbit .

Results

Discussion

Blood clearance was similar for both 22Na+ and 99"'TcOi (Fig. la), both quicker than that of 20lTI +. When clearance values were extrapolated to time zero, it was noticed that calculated activities dropped within 2h from ,44,OOO to 17,l20dpmg (61.1% drop) for 201Tl+, from 67,050 to 12,079dpm/g (82.0% drop) for 22Na+ and from 69,000 to 10,088dpm/g (85.4% drop) for 99"'TcOi. Considering the placenta as the natural barrier between the circulation of the pregnant rabbit and its pups, we decided to study the transfer of the three radionuclides through the placenta by the . rate of their accumulation in the fetuses (Fig. Ib). Plotting the fetus/placenta values

Placental transfer is a complicated form of transmembranal transport: in the placenta there is flow of blood along both sides of the placental membrane, and transplacental transport takes place by diffusion and convection. Such transport is affected by the membrane structure and concentration difference on both sides of the membrane. In addition, the effect of charge on the transmembrane potential differences and the placental blood circulation, has to be considered. Some models for membrane structure were suggested in the literature: the bilayer model suggested by Davson and Danielli'" has been altered by Singer

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and Nicolson'" to a fluid-mosaic model, where the proteins are largely globular in shape rather then spread out as monolayers, and the lipids are thought to be in a fluid, rather than in a crystalline phase. An alternate model was developed by Solomon, (9) where the membrane contained aqueous channels that acted as a size-selective sieve. When charged molecules are present in two compartments separated by a membrane, the amount transferred will be determined by their size concentration gradient and gradient of their electrical potential. The rapid increase in cell mass in the developing conceptus creates a critical demand for various ions to be passively distributed between maternal and fetal plasma according to electrochemical gradients. Studies on transplacental potential differences in various mammals showed the presence of a positive charge on the fetal side of the placenta in the rat. The implication of this finding is that all of the reported fetal-maternal concentration relationships would require the presence of active transfer of some ions towards the fetus,'!" Such transplacental electrical potentials result probably from an electrogenic ion pump, located in the placenta. Among the three radionuclides investigated, sodium is the only physiological one, whose gradient is a basic energy-dependent property of living cells. It is a small monovalent ion, which is expected to respond to the presence of the positive charge on the fetal side of the placenta.'!" Pertechnetate 99"'TcO" has an ionic weight of 163, and is a middle-size ion, easily crossing the blood-brain and blood-placental barriers, without any reaction. Thallous is a larger monovalent ion, and is considered in humans as a blood-flow indicator"!' with extremely rapid clearance: 92% of the blood radioactivity disappears with a T I /2 of about 5 min, and the remainder with T I /2 of about 40 h.(12) The affinity of 20ITI+ to the heart muscle, perhaps as a potassium analogue, led to its use as a myocardial imaging agent. Its major route of excretion is via the kidneys, explaining why ratios as high as 34.6 for kidney-to-muscle were obtained in our study, and why it was suggested for kidney kinetic studies in patients,'!" In conclusion, our study indicate that the transplacental transfer of the small radionuclide 22Na + is faster than that of 201TI+ and 99"'TcOi, reaching equilibrium about 3 h after its injection to the pregnant rabbit. The fact that 20lTI + concentrates in the fetuses' heart at a similar organ-to-muscle ratio as in the rabbits' heart, indicates that this relatively large ion passes through the placenta, and its administration into pregnant mothers for myocardial studies should be carefully weighed against the radiation emitted to their growing fetuses. Acknowledgement-This work was supported in part by a grant from the Joint Research Fund of the Hebrew University and Hadassah, Jerusalem, Israel.

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