- Email: [email protected]
Use of 1α-Hydroxyvitamin D3 in Prevention of Bovine Parturient Paresis. 8. Maternal and Neonatal Plasma Calcium, Parathyroid Hormone, and Vitamin D Metabolites Concentrations1
Use of l~-Hydroxyvitamin 03 in Prevention of Bovine Parturient Paresis. 8. Maternal and Neonatal Plasma Calcium, Parathyroid Hormone, and Vitamin D Metabolites Concentrations 1 A, BAR, S. STRIEM, R. PERLMAN, and M. SACHS 2 Institute of Animal Science Agricultural Research Organization The Volcani Center Bet Dagan, Israel
ABSTRACT
Plasma Ca and 1,25-hydroxyvitamin D were higher in calves of treated cows than in the respective controls. A high concentration of la-hydrovitamin D3 was observed in the plasma of calves of treated cows. However, 24 h after birth, the plasma concentration of la-hydroxyvitamin D3 became undetectable and plasma 1,25-hydroxyvitamin D concentration was similar to that of the calves of the control cows. Plasma Ca remained high for at least an additional 10 d in calves of treated cows.
Thirteen Israeli Friesian cows (3.71 average calvings) in the second or later lactation, fed a daily diet containing 90 g of c a and 50 g of P, were injected once intramuscularly with 700 ~g l a - h y d r o x y vitamin D3 in order to investigate its placental transfer and its subsequent metabolism in the neonate. The injection of the vitamin 96 to 24 h before calving slightly increased plasma Ca at parturition, whereas uninjected controls displayed a prominent hypocalcemia. On the 10th and 20th d after calving, difference in the plasma Ca concentration of the two groups was not significant. At parturition, plasma parathyroid hormone concentration was significantly higher and plasma 1,25-dihydroxyvitamin D lower in the control than in the treated
INTRODUCTION
COWS.
At parturition the plasma concentrations of Ca, parathyroid hormone, hydroxyproline, and 24,25-hydroxyvitarain D were higher in the calves than in their dams. Plasma concentrations of 25hydroxyvitamin D were markedly higher and 1,25-hydroxyvitamin D was slightly higher in cows than in their offsprings.
Received May 13, 1987. Accepted April 19, 1988. 1Contribution from the Agricultural Research Organization, The Volcani Center, Bet Dagen, Israel, Number 2045-E, 1987 series. This research was supported by grants from the US-Israel Binational Agricultural Research and Development Fund (BARD 352-81). 2,,Haklait,,, Veterinary Clinical Services, Netanya, Israel. 1988 J Dairy Sci 71:2723-2729
Bovine parturient paresis is the result of a severe hypocalcemia at parturition (20, 26). Hypocalcemia at parturition is accompanied by elevated plasma concentrations of parathyroid hormone [PTH] (19, 20) and 1,25-dihydroxyvitamin D [1,25-(OH)2D], the active hormonal form of vitamin D. The latter increases plasma Ca (1, 19, 20, 21). la-Hydroxyvitamin D3 (la-OHD3) is used to prevent bovine parturient paresis (27, 28, 29). The la-OHD3 is hydroxylated rapidly in the liver (11, 16) to form 1,25-(OH)2D3. In cows, plasma concentration of 1,25-(OH)2D peaks 24 to 48 h after the intramuscular injection of lo~-OHD3. The increase in plasma 1,25(OH)2D is followed by a rise in plasma Ca, apparently as a result of increased intestinal Ca absorption (6, 21). Plasma 1,25-(OH)2D decreased rapidly in the injected animals, whereas plasma Ca remained elevated for an additional few days (1). At 3 to 4 d postpartum, plasma Ca was still elevated in the la-OHD3-treated cows, whereas plasma 1,25-(OH)2D was lower than in the uninjected animals (1). Due to the high plasma concentrations of Ca and vitamin D metabolites, with its subsequent depression of
2723
2724
BAR ET AL.
PTH secretion, the formation o f 1,25-(OH)2D in the kidney might have been inhibited (10, 25). Although the response of the cow to exogenous 1-hydroxylated derivatives of vitamin D has been studied extensively, the response of the neonate to this treatment is not yet known. A t birth, neonatal 1,25-(OH)2D concentration is not correlated with that of the dam, whereas other vitamin D metabolites are highly correlated (4, 13, 30). Neonate plasma Ca is thought to be dependent on the maternal concentration of 1,25-(OH)2D (13). Because la-OHD3 treatment increases maternal plasma concentrations o f I~-OHD3 and 1,25-(OH)2D (1), neonate Ca and vitamin D metabolism will also likely be affected. The objectives of the present study were: 1) to determine the changes in vitamin D and Ca metabolism in the neonate as the result of administering 10~-OHD3 to the dam, and 2) to investigate the placental transfer o f la-OHD3 and its subsequent metabolism in the neonate. For this purpose, we assessed the changes in the neonate plasma concentrations of vitamin D metabolites.
glycol. Blood samples were taken from the treated cows at time of injection. Seven nontreated controls were bled 71 to 32 h before parturition. All cows were bled 0 to 2 h, 3, 10, and 20 d after parturition. Their calves were bled at parturition prior to drinking colostrum. None of the animals suffered from metabolic disorders or dystocia. Trial 2
This trial compared the changes in plasma la-OHD3, 1,25-(OH)2D, and Ca following parturition in control calves and in calves of cows given a single injection of I&-OHD3. Eleven dry pregnant cows of the same breed, age, and weight (milk production of 5320 to 9825 4% FCM, milking twice a day) and which had calved at least twice (average 4.1 -+ 1.5), on the same feeding schedule as in trial 1, were assigned to the 2nd trial. Six cows were injected i.m. 43 + 18 h before calving with 700 gtg 10t-OHD3. Five uninjected cows served as controis. All cows were bled at parturition. Their calves were bled at birth, before drinking colostrum, and at 24, 48, and 240 h postpartum. No animal suffered from metabolic disorders or dystocia.
MATERIALS AND METHODS Analytical Procedures Trial 1
This trial was to 1) compare the changes in plasma vitamin D metabolites, PTH, and Ca following parturition in control cows and in cows given a single injection of I~-OHD3; and 2) compare plasma vitamin D metabolites, PTH, Ca, and hydroxyproline (HPRO) at parturition in control and treated cows and in their offspring. Fourteen dry pregnant Israeli Friesian cows (600 to 700 kg b o d y weight; milk production of 5708 to 8109 4% FCM, milking twice a day), which had calved at least twice (average was 3.4 + 1.1 SD), were fed a ration for 6 to 7 wk before calving, consisting of wheat silage, vetch hay, concentrates, and minerals containing approximately 90 g of Ca and 50 g of P/d. After parturition, the cows consumed 20 to 22 kg DM of compound milk test ration containing 1.68 Mcal NE 1 and 16.6% CP/kg DM. At 96 to 48 (average 85 + 17) h before calving, seven cows were injected i.m. into the neck (Serratus muscle) with 700 /ag I~-OHD3 in propyleneJournal of Dairy Science Vol. 71, No. 10, 1988
All blood samples were taken in heparinized tubes and centrifuged as described previously (29). Plasma samples were analyzed for Ca (29) and HPRO (7). Plasma PTH concentrations was determined using commercial radioimmunoassay kit [lmmuno Nuclear Corp., Stillwater, MN; (22)] for C-terminal PTH. This kit used chicken antihuman C-terminal PTH with crossreactivity of 100% with bovine PTH 1-84 (22). Plasma samples (3 to 4 ml) were extracted and chromatographed as by Bar et al. (2). 25Hydroxyvitamin D, 24,25-(OH)2D, and 1,25(OH)2D were determined as described elsewhere (2, 5). The concentration of 10~-OHD3 was estimated by the nonequilibrium binding assay (1) using calf thymus cytosol. This assay was modified slightly (4), and HPLC-purified extracts of control cows plasma were added to the incubation tubes containing the standards. Statistical Methods
Means, standard deviations, standard errors (trials 1 and 2), factorial analysis of variance
CALVES OF l a - H Y D R O X Y V I T A M I N D3-TREATED DAMS
2725
At parturition, plasma PTH concentration increased (P<.01) in the controls, but n o t in the l~-OHD3-treated cows. A slight (P>.05) increase in plasma PTH was observed in the treated cows 3 d after calving. Plasma PTH was not (P>.05) different in either group 3 d before or 10 and 20 d after claving. Plasma 25-hydroxyvitamin D (25-OHD) tended to decrease after parturition. Differences between the control and treated cows were not significant (P<.05). Plasma 24,25(OH)2D did not change (P>.05) in the control cows, but increased markedly after parturition in the treated ones. Differences in plasma 24,25-(OH)2D were significant (P<.01) 3 and 10 d after parturition. At parturition, plasma Ca was higher (P<.01) in the calves than in their dams (Table 1). Plasma Ca was higher in treated cows and in
(trial 2), Student's t test, regressions, and correlations (for vitamin D metabolites assays) were computed according to standard procedures (3D. R ESU L T S
Trial 1
At parturition the control cows showed (Figure 1) typical hypocalcemia (7.8 + .5 rag/ dl). Injection of I~-OHD3 96 to 48 h before calving (one cow 48, the other six 84 to 96 h) prevented periparturient hypocalcemia and slightly increased (P<.01) plasma Ca (9.7 -+ .4). Three days after calving, plasma Ca in the treated cows was still higher (P<.01) than in the controls. Plasma Ca concentration was not different (P>.05) between the two groups at the 10th and 20th d after calving.
IlllJ0ilJl,
l
2.5
~70
~2.o c
"1I--
o_ 1.5 !
1.0 -4
I
I
I
0
4
8
I
I
I
50
I I
1
..I
4 0 4 8 12 16 20 AVERAGE TIME AFTER PARTURITION
I
I
I
12
16
20
Figure 1. Changes in plasma concentrations (means +- SE) o f calcium, parathyroid h o r m o n e (PTH), 25hydroxyvitamin D (25-OHD), and 24,25-dihydroxyvitamin D [24,25-(OH)2D] o f seven cows injected 96 to 48 h before parturition with 700/zg of lc~-hydroxyvitamin D s [I~-OHD 3 ] (o); and of seven control cows (o). Journal o f Dairy Science Vol. 71, No. 10, 1988
2726
BAR ET AL.
TABLE 1. Plasma concentrations of calcium, parathyroid hormone (PTH), hydroxyproline (HPRO), and vitamin D metabolites 1 in la-hydroxyvitamin D 3 [la-OHD3]-treated or control cows and in their offspring at parturition.2 Calves Concentration
SE Calcium, mg/dl PTH, ng/ml HPRO, ~tg/ml 25-OHD, ng/ml 24,25-(OH)2D, ng/ml 1,25-(OH)2D , pg/ml
Cows
Control
11.8 4.1 11.6 34.2 14.0 75
.3 a .4 a 1.3 a 1.8 a 3.0 a 12 a
Treated .~ 12.9 4.1 9.4 25.7 11.4 205
SE .4 a .4 a .6 a 4.6 a 3.3 a 23 b
Control .X
SE
7.8 2.4 2.8 76.8 3.7 132
.5 c .3 b .2 b 4.5 b 1.4 b 24 a
Treated X
SE
9.6 1.5 2.1 72.2 6.4 227
.5 b .4 b .2b 9.7 b 2.8 h 7b
a'b'CMeans with different letters within rows differ (P<.01). 1Metabolites are 25-hydroxyvitamin D (25-OHD), 24,25-dihydroxyvitamin D [24,25-(OH)2D], and 1,25dihydroxyvitamin D [1,25-(OH)~D]. Means ± SE of six or seven animals.
their offspring than in the controls. This difference was significant (P<.01) in cows only. Plasma PTH was higher (P<.01) in t h e calves than in their dams. Plasma PTH was lower (P<.01) in treated than in control cows. Calves PTH c o n c e n t r a t i o n was n o t affected ( P > . 0 5 ) by the l a - O H D 3 t r e a t m e n t . Plasma H P R O was higher (P<.01) in the calves than in their dams; l a - O H D 3 t r e a t m e n t did n o t influence ( P > . 0 5 ) plasma H P R O in the dams or in their offspring. Plasma 25-OHD was lower and plasma 24,25(OH)2D was higher (P<.01) in the calves than in their dams. T r e a t m e n t w i t h l a - O H D 3 did n o t affect plasma 25-OHD and 24,25-(OH)2D either in dams at parturition or in their offspring. Due to technical difficulties, plasma 1,25-(OH)2D was d e t e r m i n e d in plasma samples of o t h e r 5 to 6 animals treated similarly. Plasma 1,25(OH)2D was higher (P<.01) in the l a - O H D 3 treated cows and in their offspring than in the respective controls (1). Trial 2
Plasma l a - O H D 3 , 1,25-(OH)2D, and Ca concentrations of calves are s h o w n in Figure 2. The l a - O H D 3 was detectable only in the plasma of calves at birth (P<.01), t h e n disappeared within 24 h, and reappeared 10 d later ( P > . 0 5 ) . Plasma 1,25-(OH)2D was higher in calves of la-OHD3-treated cows than in the controls, but this difference disappeared 24 h p o s t p a r t u m . Plasma Ca was higher in calves of treated cows Journal of Dairy Science Vol. 71, No. 10, 1988
than in the controls ( P > . 0 5 ) t h r o u g h o u t the entire period. Ten days postpartum, plasma l a - O H D 3 was higher ( P > . 0 5 ) than after 1 or 3 d, apparently as a result of a nonspecific interference.
DISCUSSION
The hypocalcemia at parturition probably induced the secretion of PTH (Figure 1) (15, 17). The latter peaked at parturition and returned to p r e p a r t u m c o n c e n t r a t i o n within 3 d. A t the same time, plasma Ca was lower than before calving. The high plasma PTH after parturition, t o g e t h e r with the decrease in plasma Ca, appear to account for the increased k i d n e y p r o d u c t i o n o f 1,25-(OH)2D (10) and for its a c c u m u l a t i o n in the plasma. As shown b y us previously (1, 28), a single injection of 700/.tg l a - O H D 3 prevented the h y p o c a l c e m i a at parturition. The present results indicate that the t r e a t m e n t also prevented the increase in plasma PTH (Figure 1). Plasma Ca o f treated cows was still elevated 3 d p o s t p a r t u m but returned to the p r e t r e a t m e n t c o n c e n t r a t i o n 10 d after calving. A l t h o u g h at 3 d p o s t p a r t u m plasma Ca approached preinjection values (Figure 1), increase in plasma PTH was significant in the treated animals. If this finding is confirmed in further e x p e r i m e n t a t i o n , then the involvement of an additional regulator of PTH secretion should be considered.
CALVES OF lce-HYDROXYVITAMIN D~-TREATED DAMS
o 250 -
Q.
"-" 50
-6 --9
_
I
i
t 0 2z, a8 TIME AFTER
240
PARTURITION.h
Figure 2. Changes in plasma la-hydroxyvitamin D3 [la-OHD~], 1,25-dihydroxyvitamin D [1,25(OH)~D], and Ca concentrations (means -+SE)of five control calves (e) and six calves of cows injected with 700 ~g of la-OHD~ (o).
The values obtained in the present study for plasma 25-OHD and 24,25-(OH)2D were higher than those obtained in studies (4, 13, 17) carried out in other countries under different environmental or nutritional conditions. Our values were validated by including known plasma samples containing 15 to 25 and 1 to 3 ng/ml of 25-OHD and 24,25-(OH)2D in the assays. A few samples were also analyzed in a different laboratory (9) with the same results. Although the maternal plasma 25-OHD concentration was not affected by the I~-OHD3 treatment, the concentration of 24,25-(OH)2D was markedly increased postpartum in the treated cows. These results coincide with earlier ob-
2727
servations indicating that a single injection of I~-OHD3 to dry, pregnant cows inhibited kidney 25-OHD-1-hydroxylase and induced 25OHD-24-hydroxylase activity for up to 8 d postinjection (25). In the treated animals, plasma 24,25-(OH)2D peaked 10 d postpartum whereas plasma Ca, PTH (Figure 1), I~-OHDa and 1,25-(OH)2D had returned to concentrations similar to that of controls. This could be either a delayed response to the hypercalcemia associated with elevated plasma 1,25-(OH)2D at parturition or a result of the improved Ca balance caused by increased intestinal Ca absorption, which peaked 2 to 6 d after injection (6, 21). Similar to other species (8, 14, 24), plasma Ca concentration of neonatal calves at parturition is higher than maternal concentration (Table 1) (4, 13). In spite of neonatal hypercaleemia, plasma PTH was also higher than the maternal one. These results support the suggestion made by Keaton et al. (23) that the plasma Ca concentration, below which increases in PTH secretion are observed, is set at a higher concentration in the neonate. The concentrations of 25-OHD and of 1,25-(OH)2D are lower and the concentration of 24,25-(OH)2D is higher in the neonatal calf than in the mother (Table 1) (4, 13, 30). A1though neonatal and maternal 25-OHD are correlated (13, 30), the concentration in neonatal calves is low, apparently as a result of their lower liver vitamin D-25-hydroxylase (12). At parturition, the concentrations of 25OHD and 24,25-(OH)2D were slightly (P>.05) lower in the plasma o f offspring of controls (Table 1). However, a high concentration of plasma la-OHD3 was observed (Figure 2) in the offspring of dams treated with the drug and their plasma concentration of 1,25-(OH)2D was higher than that of the respective controls. Within 24 h postpartum, the plasma concentration of la-OHD3 in calves of clams treated with the drug became undetectable and the concentration of 1,25-(OH)2D decreased and reached the same values as observed in the control calves. These results suggest that la-OHD3 is transferred from the maternal to the fetal plasma. However, at parturition an efficient mechanism (possibly liver 25-hydroxylation) removes the la-OHD3 from neonate circulation. The results provide additional evidence that in cattle, unlike humans (18), neonatal and Journal of Dairy Science Vol. 71, No. 10, 1988
BAR ET AL.
2728
m a t e r n a l 1,25-(OH)2D plasma c o n c e n t r a t i o n s are n o t c o r r e l a t e d (13, 30). T h e high plasma 1,25-(OH)2D c o n c e n t r a t i o n o b s e r v e d in calves o f l a - O H D 3 - t r e a t e d c o w s could result f r o m its 2 5 - h y d r o x y l a t i o n in t h e calf liver r a t h e r t h a n f r o m its placental transfer. Plasma Ca c o n c e n t r a t i o n in t h e o f f s p r i n g o f t r e a t e d d a m s was slightly higher t h a n t h a t o f t h e respective controls. Results w e r e similar f o r sheep (8). This increase in p l a s m a Ca is likely to b e t h e result o f higher m a t e r n a l plasma 1,25(OH)zD and its e f f e c t o n t h e placental transp o r t o f Ca (8). This suggestion is s t r e n g t h e n e d b y t h e fact t h a t , prior to d r i n k i n g c o l o s t r u m , n e o n a t e s have no o t h e r s u p p l y o f Ca. H o w ever, a direct e f f e c t o f t h e n e o n a t a l high plasma vitamin D 1 - h y d r o x y l a t e d m e t a b o l i t e s o n t h e k i d n e y , o r b o n e , s h o u l d be c o n s i d e r e d . ACKNOWLEDGMENTS
T h e a u t h o r s t h a n k M. Uskokovic o f Hoffman-La R o c h e Inc., Nutley, NJ for t h e crystalline 24,25-(OH)2D3 and 1,25-(OH)2D3. T h e lt~-OHD3 was g e n e r o u s l y s u p p l i e d b y Teva Ltd., Jerusalem, Israel. The t e c h n i c a l assistance o f Ms. N. Britzy is gratefully a c k n o w l e d g e d . REFERENCES
1 Bar, A., R. Perlman, and M. Sachs. 1985. Observation on the use of lcz-hydroxyvitamin D 3 in the prevention of bovine parturient paresis: the effect of a single injection on plasma l~-hydroxyvitamin D~, 1,25-dihydrovitamin D3, calcium, and hydroxyproline. J. Dairy Sci. 68:1952. 2 Bar, A., J. Rosenberg, and S. Hurwitz. 1984. The lack of relationships between vitamin D 3 metabolites and calcium binding protein in the eggshell gland of laying birds. Comp. Biochem. Physiol. 78B:75. 3 Bar, A., M. Sachs, and R. Perlman. 1986. Observation on the use of la-hydroxyvitamin D 3 in the prevention of bovine parturient paresis. 6. Lack of effect on the concentrations of vitamin D metabolites and on the vitamin Dz equivalence of the milk. J. Dairy Sci. 69:2810. 4 Barlet, J.-P., T. M. Nguyen, M.-J. Davicco, C. Dardillat, J. Lefaivre, and M. Garabedian. 1981. Plasma levels of vitamin D metabolites in the bovine species during the perinatal period. Reprod. Nutr. Dev. 21:127. 5 Bishop, J. E., A. W. Norman, J. W. Coburn, P. A. Roberts, and H. L. Henry. 1980. Studies on the metabolism of calciferol. XVI. Determination of the concentration of 25-hydroxyvitamin D, 24,25dihydroxyvitamin D and 1,25-dihydroxyvitamin D in a single two-milliliter of plasma sample. Miner. Electrolyte Metab. 3 : 181.
Journal of Dairy Science Vol. 71, No. 10, 1988
6 Braithwaite, G. D. 1980. The effect of dose rate of la-hydroxycholecalciferol on calcium and phosphorus metabolism in sheep. Br. J. Nutr. 44:183. 7 Dabev, D., and H. Struck. 1971. Microliter determination of free hydroxy proline in blood serum. Biochem. Med. 5:17. 8 Durand, D., G. D. Braithwaite, and J.-P. Baler. 1983. The effect of la-hydroxycholecalciferol on the placental transfer of calcium and phosphate in sheep. Br. J. Nutr. 49:475. 9 Edelstein, S., M. Charman, D.E.M. Lawson, and E. Kodicek. 1974. Competitive protein-binding assay for 25-hydroxycholecalciferol. Clin. Sci. Mol. Med. 46:231. 10 Fraser, D. R. 1980. Regulation of the metabolism of vitamin D. Physiol. Rev. 60:551. 11 Fukushima, M., Y. Nishii, M. Suzuki, and T. Suda. 1978. Comparative studies on the 25-hydroxylation of cholecalciferol and la-hydroxycholecalciferol in perfused rat liver. Biochem. J. 170:495. 12 Gascon-Barre, M., V. Plourdo, P. Haddad, and J. Martial. 1985. Fetal and neonatal uptake and microsomal C-25 hydroxylation of [aHlvitamin D~ by the rat liver. Page 654 in Vitamin D. Chemical, biochemical and clinical update. A. W. Norman, K. Schaefer, H.-G. Grigolt, and D. V. Herra, h, ed. de Gruyter, Berlin, 13 Goff, J. P., R. L. Horst, and E. T. Littledike. 1982. Effect of maternal vitamin D status at parturition on the vitamin D status of the neonatal calf. J. Nutr. 112:1387. 14 Golf, J. P., R. L. Horst, and E. T. Littledike. 1984. Effect of sow vitamin D status at parturition on the vitamin D status of the neonatal piglets. J. Nutr. 114:163. 15 Habener, J. F., M. Rosenblatt, and J. T. Potts, Jr. 1984. Parathyroid hormone: biochemical aspects of biosynthesis, secretion, action, and metabolism. Physiol. Rev. 64:985. 16 Holick, M. F., T. E. Tavela, S. A. Holick, H. K. Schnoes, H. F. DeLuca, and B. M. GaUagher. 1976. Synthesis of 1 hydroxy[6-aH]vitamin D3 and its metabolism to 1,25-dihydroxy[6-3H] vitamin Dz in the rat. J. Biol. Chem. 251:1020. 17 Hollis, B. W., H. H. Draper, J. H. Burton, and R. J. Etches. 1981. A hormonal assessment of bovine parturient paresis: evidence for a role of oestrogen. J. Endocrinol. 88:161. 18 Hollis, B. W., and W. B. Pittard, III. 1984. Evaluation of the total fetomaternal vitamin D relationships at term: evidence for racial differences. J. Clin. Endocrinol. Metab. 59:652. 19 Horst, R. L., N. A. Jorgensen, and H. F. DeLuca. 1978. Plasma 1,25-dihydroxyvitamin D and parathyroid hormone levels in paretic dairy cows. Am. J. Physiol. 235:E634. 20 Horst, R. L., and T. A. Reinhardt. 1983. Vitamin D metabolism in ruminants and its relevance to the periparturient cow. J. Dairy Sci. 66:661. 21 Hove, K. 1984. Effects of 1-hydroxylated metabolites of cholecalciferol on intestinal radiocalcium absorption in goats. Br. J. Nutr. 51:157. 22 lmmuno Nuclear Corp. 1986, Methods and reagents: C-terminal PTH by RIA.
CALVES OF lc~-HYDROXYVITAMIN D~-TREATED DAMS 23 Keaton, J. A., J. A. Barto, M. P. Moore, J. B. Gruel, and G. P. Mayer. 1978. Altered parathyroid response to calcium in hypercalcemic neonatal calves. Endocrinology 103:2161. 24 Kurdoba, E., T. Okano, N. Mizuno, T. Kobayashi, S. Kodama, M. Minomiya, Y. Morishita, and T. Matsuo. 1981. Plasma levels of 25-hydroxyvitamin Dz and 25-hydroxyvitamin D~ in maternal, cord and neonatal blood. J. Nutr. Sci. Vitaminol. 27:55. 25 Littledike, E. T., G. W. Engstrom, and M. Sachs. 1986. Methods for sequential sampling and analysis of renal 25-hydroxyvitamin D~ 1-, 24-, and 23hydroxylase activities of dairy cows and calves injected with la-hydroxyvitamin D~. J. Dairy Sci. 69:990. 26 Littledike, E. T., J. W. Young, and D. C. Beitz. 1981. Common metabolic diseases in cattle: ketosis, milk fever, grass tetany, and downer cow complex. J. Dairy Sci. 64:1465. 27 Marquardt, J. P., M. F. Holick, R. L. Horst, N. A.
28
29
30
31
2729
Jorgenson, and H. F. DeLuca. 1974. Efficacy of la-hydroxyvitamin D 3 on prevention of parturient paresis, J. Dairy Sci. 57:106. Sachs, M., A. Bar, R. Cohen, Y. Mazur, E. Mayer, and S. Hurwitz. 1977. Use of la-hydroxycholecalciferol in the prevention of bovine parturient paresis. Am. J. Vet. Res. 38:2039. Sachs, M., A. Bar, O. Nir, O. Ochovsky, B. Machani, E. Meir, B. Z. Weiner, and Z. Mazor. 1987. The efficacy of la-hydroxyvitamin D~ in the prevention of bovine parturient paresis. Vet. Rec. 10:39. Smith, P. N., and F. A. Kallfelz. 1985. Abnormalities in the regulation of vitamin D metabolism associated with bovine parturient paresis (milk fever), Page 630 m Vitamin D. Chemical, biochemical and clinical update. A. W. Norman, K. Schaefer, H.-G. Grigolt, and D. V. Herrath, ed. de Gruyter, Berlin. Snedecor, G. W., and W. G. Cochran. 1968. Statistical methods. 6th ed. Iowa State Univ. Press, Ames.
Journal of Dairy Science Vol. 71, No. 10, 1988
ABSTRACT
Plasma Ca and 1,25-hydroxyvitamin D were higher in calves of treated cows than in the respective controls. A high concentration of la-hydrovitamin D3 was observed in the plasma of calves of treated cows. However, 24 h after birth, the plasma concentration of la-hydroxyvitamin D3 became undetectable and plasma 1,25-hydroxyvitamin D concentration was similar to that of the calves of the control cows. Plasma Ca remained high for at least an additional 10 d in calves of treated cows.
Thirteen Israeli Friesian cows (3.71 average calvings) in the second or later lactation, fed a daily diet containing 90 g of c a and 50 g of P, were injected once intramuscularly with 700 ~g l a - h y d r o x y vitamin D3 in order to investigate its placental transfer and its subsequent metabolism in the neonate. The injection of the vitamin 96 to 24 h before calving slightly increased plasma Ca at parturition, whereas uninjected controls displayed a prominent hypocalcemia. On the 10th and 20th d after calving, difference in the plasma Ca concentration of the two groups was not significant. At parturition, plasma parathyroid hormone concentration was significantly higher and plasma 1,25-dihydroxyvitamin D lower in the control than in the treated
INTRODUCTION
COWS.
At parturition the plasma concentrations of Ca, parathyroid hormone, hydroxyproline, and 24,25-hydroxyvitarain D were higher in the calves than in their dams. Plasma concentrations of 25hydroxyvitamin D were markedly higher and 1,25-hydroxyvitamin D was slightly higher in cows than in their offsprings.
Received May 13, 1987. Accepted April 19, 1988. 1Contribution from the Agricultural Research Organization, The Volcani Center, Bet Dagen, Israel, Number 2045-E, 1987 series. This research was supported by grants from the US-Israel Binational Agricultural Research and Development Fund (BARD 352-81). 2,,Haklait,,, Veterinary Clinical Services, Netanya, Israel. 1988 J Dairy Sci 71:2723-2729
Bovine parturient paresis is the result of a severe hypocalcemia at parturition (20, 26). Hypocalcemia at parturition is accompanied by elevated plasma concentrations of parathyroid hormone [PTH] (19, 20) and 1,25-dihydroxyvitamin D [1,25-(OH)2D], the active hormonal form of vitamin D. The latter increases plasma Ca (1, 19, 20, 21). la-Hydroxyvitamin D3 (la-OHD3) is used to prevent bovine parturient paresis (27, 28, 29). The la-OHD3 is hydroxylated rapidly in the liver (11, 16) to form 1,25-(OH)2D3. In cows, plasma concentration of 1,25-(OH)2D peaks 24 to 48 h after the intramuscular injection of lo~-OHD3. The increase in plasma 1,25(OH)2D is followed by a rise in plasma Ca, apparently as a result of increased intestinal Ca absorption (6, 21). Plasma 1,25-(OH)2D decreased rapidly in the injected animals, whereas plasma Ca remained elevated for an additional few days (1). At 3 to 4 d postpartum, plasma Ca was still elevated in the la-OHD3-treated cows, whereas plasma 1,25-(OH)2D was lower than in the uninjected animals (1). Due to the high plasma concentrations of Ca and vitamin D metabolites, with its subsequent depression of
2723
2724
BAR ET AL.
PTH secretion, the formation o f 1,25-(OH)2D in the kidney might have been inhibited (10, 25). Although the response of the cow to exogenous 1-hydroxylated derivatives of vitamin D has been studied extensively, the response of the neonate to this treatment is not yet known. A t birth, neonatal 1,25-(OH)2D concentration is not correlated with that of the dam, whereas other vitamin D metabolites are highly correlated (4, 13, 30). Neonate plasma Ca is thought to be dependent on the maternal concentration of 1,25-(OH)2D (13). Because la-OHD3 treatment increases maternal plasma concentrations o f I~-OHD3 and 1,25-(OH)2D (1), neonate Ca and vitamin D metabolism will also likely be affected. The objectives of the present study were: 1) to determine the changes in vitamin D and Ca metabolism in the neonate as the result of administering 10~-OHD3 to the dam, and 2) to investigate the placental transfer o f la-OHD3 and its subsequent metabolism in the neonate. For this purpose, we assessed the changes in the neonate plasma concentrations of vitamin D metabolites.
glycol. Blood samples were taken from the treated cows at time of injection. Seven nontreated controls were bled 71 to 32 h before parturition. All cows were bled 0 to 2 h, 3, 10, and 20 d after parturition. Their calves were bled at parturition prior to drinking colostrum. None of the animals suffered from metabolic disorders or dystocia. Trial 2
This trial compared the changes in plasma la-OHD3, 1,25-(OH)2D, and Ca following parturition in control calves and in calves of cows given a single injection of I&-OHD3. Eleven dry pregnant cows of the same breed, age, and weight (milk production of 5320 to 9825 4% FCM, milking twice a day) and which had calved at least twice (average 4.1 -+ 1.5), on the same feeding schedule as in trial 1, were assigned to the 2nd trial. Six cows were injected i.m. 43 + 18 h before calving with 700 gtg 10t-OHD3. Five uninjected cows served as controis. All cows were bled at parturition. Their calves were bled at birth, before drinking colostrum, and at 24, 48, and 240 h postpartum. No animal suffered from metabolic disorders or dystocia.
MATERIALS AND METHODS Analytical Procedures Trial 1
This trial was to 1) compare the changes in plasma vitamin D metabolites, PTH, and Ca following parturition in control cows and in cows given a single injection of I~-OHD3; and 2) compare plasma vitamin D metabolites, PTH, Ca, and hydroxyproline (HPRO) at parturition in control and treated cows and in their offspring. Fourteen dry pregnant Israeli Friesian cows (600 to 700 kg b o d y weight; milk production of 5708 to 8109 4% FCM, milking twice a day), which had calved at least twice (average was 3.4 + 1.1 SD), were fed a ration for 6 to 7 wk before calving, consisting of wheat silage, vetch hay, concentrates, and minerals containing approximately 90 g of Ca and 50 g of P/d. After parturition, the cows consumed 20 to 22 kg DM of compound milk test ration containing 1.68 Mcal NE 1 and 16.6% CP/kg DM. At 96 to 48 (average 85 + 17) h before calving, seven cows were injected i.m. into the neck (Serratus muscle) with 700 /ag I~-OHD3 in propyleneJournal of Dairy Science Vol. 71, No. 10, 1988
All blood samples were taken in heparinized tubes and centrifuged as described previously (29). Plasma samples were analyzed for Ca (29) and HPRO (7). Plasma PTH concentrations was determined using commercial radioimmunoassay kit [lmmuno Nuclear Corp., Stillwater, MN; (22)] for C-terminal PTH. This kit used chicken antihuman C-terminal PTH with crossreactivity of 100% with bovine PTH 1-84 (22). Plasma samples (3 to 4 ml) were extracted and chromatographed as by Bar et al. (2). 25Hydroxyvitamin D, 24,25-(OH)2D, and 1,25(OH)2D were determined as described elsewhere (2, 5). The concentration of 10~-OHD3 was estimated by the nonequilibrium binding assay (1) using calf thymus cytosol. This assay was modified slightly (4), and HPLC-purified extracts of control cows plasma were added to the incubation tubes containing the standards. Statistical Methods
Means, standard deviations, standard errors (trials 1 and 2), factorial analysis of variance
CALVES OF l a - H Y D R O X Y V I T A M I N D3-TREATED DAMS
2725
At parturition, plasma PTH concentration increased (P<.01) in the controls, but n o t in the l~-OHD3-treated cows. A slight (P>.05) increase in plasma PTH was observed in the treated cows 3 d after calving. Plasma PTH was not (P>.05) different in either group 3 d before or 10 and 20 d after claving. Plasma 25-hydroxyvitamin D (25-OHD) tended to decrease after parturition. Differences between the control and treated cows were not significant (P<.05). Plasma 24,25(OH)2D did not change (P>.05) in the control cows, but increased markedly after parturition in the treated ones. Differences in plasma 24,25-(OH)2D were significant (P<.01) 3 and 10 d after parturition. At parturition, plasma Ca was higher (P<.01) in the calves than in their dams (Table 1). Plasma Ca was higher in treated cows and in
(trial 2), Student's t test, regressions, and correlations (for vitamin D metabolites assays) were computed according to standard procedures (3D. R ESU L T S
Trial 1
At parturition the control cows showed (Figure 1) typical hypocalcemia (7.8 + .5 rag/ dl). Injection of I~-OHD3 96 to 48 h before calving (one cow 48, the other six 84 to 96 h) prevented periparturient hypocalcemia and slightly increased (P<.01) plasma Ca (9.7 -+ .4). Three days after calving, plasma Ca in the treated cows was still higher (P<.01) than in the controls. Plasma Ca concentration was not different (P>.05) between the two groups at the 10th and 20th d after calving.
IlllJ0ilJl,
l
2.5
~70
~2.o c
"1I--
o_ 1.5 !
1.0 -4
I
I
I
0
4
8
I
I
I
50
I I
1
..I
4 0 4 8 12 16 20 AVERAGE TIME AFTER PARTURITION
I
I
I
12
16
20
Figure 1. Changes in plasma concentrations (means +- SE) o f calcium, parathyroid h o r m o n e (PTH), 25hydroxyvitamin D (25-OHD), and 24,25-dihydroxyvitamin D [24,25-(OH)2D] o f seven cows injected 96 to 48 h before parturition with 700/zg of lc~-hydroxyvitamin D s [I~-OHD 3 ] (o); and of seven control cows (o). Journal o f Dairy Science Vol. 71, No. 10, 1988
2726
BAR ET AL.
TABLE 1. Plasma concentrations of calcium, parathyroid hormone (PTH), hydroxyproline (HPRO), and vitamin D metabolites 1 in la-hydroxyvitamin D 3 [la-OHD3]-treated or control cows and in their offspring at parturition.2 Calves Concentration
SE Calcium, mg/dl PTH, ng/ml HPRO, ~tg/ml 25-OHD, ng/ml 24,25-(OH)2D, ng/ml 1,25-(OH)2D , pg/ml
Cows
Control
11.8 4.1 11.6 34.2 14.0 75
.3 a .4 a 1.3 a 1.8 a 3.0 a 12 a
Treated .~ 12.9 4.1 9.4 25.7 11.4 205
SE .4 a .4 a .6 a 4.6 a 3.3 a 23 b
Control .X
SE
7.8 2.4 2.8 76.8 3.7 132
.5 c .3 b .2 b 4.5 b 1.4 b 24 a
Treated X
SE
9.6 1.5 2.1 72.2 6.4 227
.5 b .4 b .2b 9.7 b 2.8 h 7b
a'b'CMeans with different letters within rows differ (P<.01). 1Metabolites are 25-hydroxyvitamin D (25-OHD), 24,25-dihydroxyvitamin D [24,25-(OH)2D], and 1,25dihydroxyvitamin D [1,25-(OH)~D]. Means ± SE of six or seven animals.
their offspring than in the controls. This difference was significant (P<.01) in cows only. Plasma PTH was higher (P<.01) in t h e calves than in their dams. Plasma PTH was lower (P<.01) in treated than in control cows. Calves PTH c o n c e n t r a t i o n was n o t affected ( P > . 0 5 ) by the l a - O H D 3 t r e a t m e n t . Plasma H P R O was higher (P<.01) in the calves than in their dams; l a - O H D 3 t r e a t m e n t did n o t influence ( P > . 0 5 ) plasma H P R O in the dams or in their offspring. Plasma 25-OHD was lower and plasma 24,25(OH)2D was higher (P<.01) in the calves than in their dams. T r e a t m e n t w i t h l a - O H D 3 did n o t affect plasma 25-OHD and 24,25-(OH)2D either in dams at parturition or in their offspring. Due to technical difficulties, plasma 1,25-(OH)2D was d e t e r m i n e d in plasma samples of o t h e r 5 to 6 animals treated similarly. Plasma 1,25(OH)2D was higher (P<.01) in the l a - O H D 3 treated cows and in their offspring than in the respective controls (1). Trial 2
Plasma l a - O H D 3 , 1,25-(OH)2D, and Ca concentrations of calves are s h o w n in Figure 2. The l a - O H D 3 was detectable only in the plasma of calves at birth (P<.01), t h e n disappeared within 24 h, and reappeared 10 d later ( P > . 0 5 ) . Plasma 1,25-(OH)2D was higher in calves of la-OHD3-treated cows than in the controls, but this difference disappeared 24 h p o s t p a r t u m . Plasma Ca was higher in calves of treated cows Journal of Dairy Science Vol. 71, No. 10, 1988
than in the controls ( P > . 0 5 ) t h r o u g h o u t the entire period. Ten days postpartum, plasma l a - O H D 3 was higher ( P > . 0 5 ) than after 1 or 3 d, apparently as a result of a nonspecific interference.
DISCUSSION
The hypocalcemia at parturition probably induced the secretion of PTH (Figure 1) (15, 17). The latter peaked at parturition and returned to p r e p a r t u m c o n c e n t r a t i o n within 3 d. A t the same time, plasma Ca was lower than before calving. The high plasma PTH after parturition, t o g e t h e r with the decrease in plasma Ca, appear to account for the increased k i d n e y p r o d u c t i o n o f 1,25-(OH)2D (10) and for its a c c u m u l a t i o n in the plasma. As shown b y us previously (1, 28), a single injection of 700/.tg l a - O H D 3 prevented the h y p o c a l c e m i a at parturition. The present results indicate that the t r e a t m e n t also prevented the increase in plasma PTH (Figure 1). Plasma Ca o f treated cows was still elevated 3 d p o s t p a r t u m but returned to the p r e t r e a t m e n t c o n c e n t r a t i o n 10 d after calving. A l t h o u g h at 3 d p o s t p a r t u m plasma Ca approached preinjection values (Figure 1), increase in plasma PTH was significant in the treated animals. If this finding is confirmed in further e x p e r i m e n t a t i o n , then the involvement of an additional regulator of PTH secretion should be considered.
CALVES OF lce-HYDROXYVITAMIN D~-TREATED DAMS
o 250 -
Q.
"-" 50
-6 --9
_
I
i
t 0 2z, a8 TIME AFTER
240
PARTURITION.h
Figure 2. Changes in plasma la-hydroxyvitamin D3 [la-OHD~], 1,25-dihydroxyvitamin D [1,25(OH)~D], and Ca concentrations (means -+SE)of five control calves (e) and six calves of cows injected with 700 ~g of la-OHD~ (o).
The values obtained in the present study for plasma 25-OHD and 24,25-(OH)2D were higher than those obtained in studies (4, 13, 17) carried out in other countries under different environmental or nutritional conditions. Our values were validated by including known plasma samples containing 15 to 25 and 1 to 3 ng/ml of 25-OHD and 24,25-(OH)2D in the assays. A few samples were also analyzed in a different laboratory (9) with the same results. Although the maternal plasma 25-OHD concentration was not affected by the I~-OHD3 treatment, the concentration of 24,25-(OH)2D was markedly increased postpartum in the treated cows. These results coincide with earlier ob-
2727
servations indicating that a single injection of I~-OHD3 to dry, pregnant cows inhibited kidney 25-OHD-1-hydroxylase and induced 25OHD-24-hydroxylase activity for up to 8 d postinjection (25). In the treated animals, plasma 24,25-(OH)2D peaked 10 d postpartum whereas plasma Ca, PTH (Figure 1), I~-OHDa and 1,25-(OH)2D had returned to concentrations similar to that of controls. This could be either a delayed response to the hypercalcemia associated with elevated plasma 1,25-(OH)2D at parturition or a result of the improved Ca balance caused by increased intestinal Ca absorption, which peaked 2 to 6 d after injection (6, 21). Similar to other species (8, 14, 24), plasma Ca concentration of neonatal calves at parturition is higher than maternal concentration (Table 1) (4, 13). In spite of neonatal hypercaleemia, plasma PTH was also higher than the maternal one. These results support the suggestion made by Keaton et al. (23) that the plasma Ca concentration, below which increases in PTH secretion are observed, is set at a higher concentration in the neonate. The concentrations of 25-OHD and of 1,25-(OH)2D are lower and the concentration of 24,25-(OH)2D is higher in the neonatal calf than in the mother (Table 1) (4, 13, 30). A1though neonatal and maternal 25-OHD are correlated (13, 30), the concentration in neonatal calves is low, apparently as a result of their lower liver vitamin D-25-hydroxylase (12). At parturition, the concentrations of 25OHD and 24,25-(OH)2D were slightly (P>.05) lower in the plasma o f offspring of controls (Table 1). However, a high concentration of plasma la-OHD3 was observed (Figure 2) in the offspring of dams treated with the drug and their plasma concentration of 1,25-(OH)2D was higher than that of the respective controls. Within 24 h postpartum, the plasma concentration of la-OHD3 in calves of clams treated with the drug became undetectable and the concentration of 1,25-(OH)2D decreased and reached the same values as observed in the control calves. These results suggest that la-OHD3 is transferred from the maternal to the fetal plasma. However, at parturition an efficient mechanism (possibly liver 25-hydroxylation) removes the la-OHD3 from neonate circulation. The results provide additional evidence that in cattle, unlike humans (18), neonatal and Journal of Dairy Science Vol. 71, No. 10, 1988
BAR ET AL.
2728
m a t e r n a l 1,25-(OH)2D plasma c o n c e n t r a t i o n s are n o t c o r r e l a t e d (13, 30). T h e high plasma 1,25-(OH)2D c o n c e n t r a t i o n o b s e r v e d in calves o f l a - O H D 3 - t r e a t e d c o w s could result f r o m its 2 5 - h y d r o x y l a t i o n in t h e calf liver r a t h e r t h a n f r o m its placental transfer. Plasma Ca c o n c e n t r a t i o n in t h e o f f s p r i n g o f t r e a t e d d a m s was slightly higher t h a n t h a t o f t h e respective controls. Results w e r e similar f o r sheep (8). This increase in p l a s m a Ca is likely to b e t h e result o f higher m a t e r n a l plasma 1,25(OH)zD and its e f f e c t o n t h e placental transp o r t o f Ca (8). This suggestion is s t r e n g t h e n e d b y t h e fact t h a t , prior to d r i n k i n g c o l o s t r u m , n e o n a t e s have no o t h e r s u p p l y o f Ca. H o w ever, a direct e f f e c t o f t h e n e o n a t a l high plasma vitamin D 1 - h y d r o x y l a t e d m e t a b o l i t e s o n t h e k i d n e y , o r b o n e , s h o u l d be c o n s i d e r e d . ACKNOWLEDGMENTS
T h e a u t h o r s t h a n k M. Uskokovic o f Hoffman-La R o c h e Inc., Nutley, NJ for t h e crystalline 24,25-(OH)2D3 and 1,25-(OH)2D3. T h e lt~-OHD3 was g e n e r o u s l y s u p p l i e d b y Teva Ltd., Jerusalem, Israel. The t e c h n i c a l assistance o f Ms. N. Britzy is gratefully a c k n o w l e d g e d . REFERENCES
1 Bar, A., R. Perlman, and M. Sachs. 1985. Observation on the use of lcz-hydroxyvitamin D 3 in the prevention of bovine parturient paresis: the effect of a single injection on plasma l~-hydroxyvitamin D~, 1,25-dihydrovitamin D3, calcium, and hydroxyproline. J. Dairy Sci. 68:1952. 2 Bar, A., J. Rosenberg, and S. Hurwitz. 1984. The lack of relationships between vitamin D 3 metabolites and calcium binding protein in the eggshell gland of laying birds. Comp. Biochem. Physiol. 78B:75. 3 Bar, A., M. Sachs, and R. Perlman. 1986. Observation on the use of la-hydroxyvitamin D 3 in the prevention of bovine parturient paresis. 6. Lack of effect on the concentrations of vitamin D metabolites and on the vitamin Dz equivalence of the milk. J. Dairy Sci. 69:2810. 4 Barlet, J.-P., T. M. Nguyen, M.-J. Davicco, C. Dardillat, J. Lefaivre, and M. Garabedian. 1981. Plasma levels of vitamin D metabolites in the bovine species during the perinatal period. Reprod. Nutr. Dev. 21:127. 5 Bishop, J. E., A. W. Norman, J. W. Coburn, P. A. Roberts, and H. L. Henry. 1980. Studies on the metabolism of calciferol. XVI. Determination of the concentration of 25-hydroxyvitamin D, 24,25dihydroxyvitamin D and 1,25-dihydroxyvitamin D in a single two-milliliter of plasma sample. Miner. Electrolyte Metab. 3 : 181.
Journal of Dairy Science Vol. 71, No. 10, 1988
6 Braithwaite, G. D. 1980. The effect of dose rate of la-hydroxycholecalciferol on calcium and phosphorus metabolism in sheep. Br. J. Nutr. 44:183. 7 Dabev, D., and H. Struck. 1971. Microliter determination of free hydroxy proline in blood serum. Biochem. Med. 5:17. 8 Durand, D., G. D. Braithwaite, and J.-P. Baler. 1983. The effect of la-hydroxycholecalciferol on the placental transfer of calcium and phosphate in sheep. Br. J. Nutr. 49:475. 9 Edelstein, S., M. Charman, D.E.M. Lawson, and E. Kodicek. 1974. Competitive protein-binding assay for 25-hydroxycholecalciferol. Clin. Sci. Mol. Med. 46:231. 10 Fraser, D. R. 1980. Regulation of the metabolism of vitamin D. Physiol. Rev. 60:551. 11 Fukushima, M., Y. Nishii, M. Suzuki, and T. Suda. 1978. Comparative studies on the 25-hydroxylation of cholecalciferol and la-hydroxycholecalciferol in perfused rat liver. Biochem. J. 170:495. 12 Gascon-Barre, M., V. Plourdo, P. Haddad, and J. Martial. 1985. Fetal and neonatal uptake and microsomal C-25 hydroxylation of [aHlvitamin D~ by the rat liver. Page 654 in Vitamin D. Chemical, biochemical and clinical update. A. W. Norman, K. Schaefer, H.-G. Grigolt, and D. V. Herra, h, ed. de Gruyter, Berlin, 13 Goff, J. P., R. L. Horst, and E. T. Littledike. 1982. Effect of maternal vitamin D status at parturition on the vitamin D status of the neonatal calf. J. Nutr. 112:1387. 14 Golf, J. P., R. L. Horst, and E. T. Littledike. 1984. Effect of sow vitamin D status at parturition on the vitamin D status of the neonatal piglets. J. Nutr. 114:163. 15 Habener, J. F., M. Rosenblatt, and J. T. Potts, Jr. 1984. Parathyroid hormone: biochemical aspects of biosynthesis, secretion, action, and metabolism. Physiol. Rev. 64:985. 16 Holick, M. F., T. E. Tavela, S. A. Holick, H. K. Schnoes, H. F. DeLuca, and B. M. GaUagher. 1976. Synthesis of 1 hydroxy[6-aH]vitamin D3 and its metabolism to 1,25-dihydroxy[6-3H] vitamin Dz in the rat. J. Biol. Chem. 251:1020. 17 Hollis, B. W., H. H. Draper, J. H. Burton, and R. J. Etches. 1981. A hormonal assessment of bovine parturient paresis: evidence for a role of oestrogen. J. Endocrinol. 88:161. 18 Hollis, B. W., and W. B. Pittard, III. 1984. Evaluation of the total fetomaternal vitamin D relationships at term: evidence for racial differences. J. Clin. Endocrinol. Metab. 59:652. 19 Horst, R. L., N. A. Jorgensen, and H. F. DeLuca. 1978. Plasma 1,25-dihydroxyvitamin D and parathyroid hormone levels in paretic dairy cows. Am. J. Physiol. 235:E634. 20 Horst, R. L., and T. A. Reinhardt. 1983. Vitamin D metabolism in ruminants and its relevance to the periparturient cow. J. Dairy Sci. 66:661. 21 Hove, K. 1984. Effects of 1-hydroxylated metabolites of cholecalciferol on intestinal radiocalcium absorption in goats. Br. J. Nutr. 51:157. 22 lmmuno Nuclear Corp. 1986, Methods and reagents: C-terminal PTH by RIA.
CALVES OF lc~-HYDROXYVITAMIN D~-TREATED DAMS 23 Keaton, J. A., J. A. Barto, M. P. Moore, J. B. Gruel, and G. P. Mayer. 1978. Altered parathyroid response to calcium in hypercalcemic neonatal calves. Endocrinology 103:2161. 24 Kurdoba, E., T. Okano, N. Mizuno, T. Kobayashi, S. Kodama, M. Minomiya, Y. Morishita, and T. Matsuo. 1981. Plasma levels of 25-hydroxyvitamin Dz and 25-hydroxyvitamin D~ in maternal, cord and neonatal blood. J. Nutr. Sci. Vitaminol. 27:55. 25 Littledike, E. T., G. W. Engstrom, and M. Sachs. 1986. Methods for sequential sampling and analysis of renal 25-hydroxyvitamin D~ 1-, 24-, and 23hydroxylase activities of dairy cows and calves injected with la-hydroxyvitamin D~. J. Dairy Sci. 69:990. 26 Littledike, E. T., J. W. Young, and D. C. Beitz. 1981. Common metabolic diseases in cattle: ketosis, milk fever, grass tetany, and downer cow complex. J. Dairy Sci. 64:1465. 27 Marquardt, J. P., M. F. Holick, R. L. Horst, N. A.
28
29
30
31
2729
Jorgenson, and H. F. DeLuca. 1974. Efficacy of la-hydroxyvitamin D 3 on prevention of parturient paresis, J. Dairy Sci. 57:106. Sachs, M., A. Bar, R. Cohen, Y. Mazur, E. Mayer, and S. Hurwitz. 1977. Use of la-hydroxycholecalciferol in the prevention of bovine parturient paresis. Am. J. Vet. Res. 38:2039. Sachs, M., A. Bar, O. Nir, O. Ochovsky, B. Machani, E. Meir, B. Z. Weiner, and Z. Mazor. 1987. The efficacy of la-hydroxyvitamin D~ in the prevention of bovine parturient paresis. Vet. Rec. 10:39. Smith, P. N., and F. A. Kallfelz. 1985. Abnormalities in the regulation of vitamin D metabolism associated with bovine parturient paresis (milk fever), Page 630 m Vitamin D. Chemical, biochemical and clinical update. A. W. Norman, K. Schaefer, H.-G. Grigolt, and D. V. Herrath, ed. de Gruyter, Berlin. Snedecor, G. W., and W. G. Cochran. 1968. Statistical methods. 6th ed. Iowa State Univ. Press, Ames.
Journal of Dairy Science Vol. 71, No. 10, 1988