The effect of bovine interferon-alpha I1 on pregnancy rate in heifers.

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C M Barros, G R Newton, W W Thatcher, M Drost, C Plante and P J Hansen

The effect of bovine interferon-alpha I1 on pregnancy rate in heifers.

1992, 70:1471-1477.

J ANIM SCI

http://www.journalofanimalscience.org/content/70/5/1471

the World Wide Web at:

The online version of this article, along with updated information and services, is located on

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The

on

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C.

M.

M. Effect of

Bovine

Interferon-ar

1 Pregnancy Rate

in

Heifers1'2

**Barros*3,**

G.

R. Newtont.4, W. W. Thatchert,

Drost',

C. Plantet.5, and P. J. Hansent-6

zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

Departamento de Farmacologia, Universidade Estadual Paulista,

zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

Sao

Paulo,

Brazil and Departments of +Dairy Science and *Large Animal Clinical

Sciences, University

of

Florida, Gainesville

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326

1 1

ABSTRACT: Bovine interferon-a1 1 (bIFN-a) may be useful for enhancing fertility in sheep and cattle because it has extensive sequence homology with ovine and bovine trophoblast protein-1 and, like those proteins, extends corpus luteum lifespan. To test the effectiveness of bIFN-a to enhance fertility, several experiments were performed in which inseminated heifers were given i.m. injections of bIFN-a approximately at the time of embryo-mediated signals that result in mainte- nance of the corpus luteum. In Exp. 1, heifers

given 20 mg of bIFN-a daily from d 14 to 17 tended

zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

(P

< .071 to have lower pregnancy rates a t d 110 to

112 of gestation (36/75; 4 8 % vs 43/72; 6 0 % ) . Similar results were obtained in Exp. 2 when heifers

Key Words: Interferon, Fertility,

received a single injection of 40 mg of bIFN-a or placebo a t d 13 after estrus; pregnancy rates a t d

42 were 39/104 (38%) for bIFN-a and 47/98 (48%) for placebo. In Exp. 3, heifers were given gradually increasing doses of bIFN-a or placebo from d 11 to

19, because such a regimen had been shown to reduce the number of heifers experiencing hyperthermia after bIFN-a injection. Pregnancy rates were 42/95 (44%) for bIFN-a and 62/1ll (56%) for placebo. Across all three experiments, pregnancy rates were lower (P < .01) for heifers treated with bIFN-a (1 17/274; 43%) than for heifers treated with placebo (152/281; 54%). In conclusion, these results demonstrate that, under the administration systems used, bIFN-a does not increase pregnancy rate, but rather tends to reduce it.

Pregnancy, Hyperthermia, Cattle

'This paper is Journal Series No. R-01812 of the Florida Agric. Exp. Sta. Research was supported by a grant from CIBA- GEIGY, S.A., Basle, Switzerland and by USDA Grant

'The authors thank Larson Dairy Inc., Okeechobee, FL, for its generosity in allowing use of facilities a n d cattle to conduct Exp. 1, 2, and 3; Louis Larson, Jr., John Larson, Clint Gould, Taylor Holmes, and Gene Lowe for their excellent assistance in experimental procedures; Serge Martinod, CIBA-GEIGY, for valuable discussions; and Mary Ellen Hissem for typing the manuscript.

89-37240.

3 0 n sabbatical leave a t the Univ. of Florida.

4Current address: Coop. Agric. Res. Center, k a i r i e View A &

5Current address: Dept. of Pathol., Ontario Vet. College, 'To whom correspondence should be addressed: P.O. Box Received August 30, 1991.

Accepted December 9, 1991.

M Univ., Prairie View, TX 77446-2888.

Univ. of Guelph, Guelph, ON, Canada N1G 2W1. 110920, Univ. of Florida, Gainesville 3261 1-0920.

J. Anim. Sci. 1992. 70:1471-1477

Introduction

Ovine trophoblast protein-1 (oTP-1) and bovine trophoblast protein-1 (bTP-1) are antiluteolysins produced by the developing conceptus of sheep and cows (Bazer et al., 1991). Both oTP-1 and bTP-1 belong to a distinct class of type I interferons that shows sequence and functional homology with

interferons of the a11 (or

zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

w) class, and to a lesser

extent, a1 class (Imakawa et al., 1987, 1989; Newton et al., 1989; Roberts et al., 1989; Hansen et al., 1991;

Skopets et al., 1991). Interferon-a can also exert effects on the reproductive system that are charac- teristic of oTP-1 and bTP-1 (Plante et al., 1988, 1989,

1991; Salamonsen et al., 1988; Hansen et al., 1989;

Stewart et al., 1989; Barros et al., 1991). Collective- ly, these studies suggest that interferon-a may be used to reduce early embryonic mortality resulting from decreased or inappropriately timed produc-

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1472

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BARROS

zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

tion of oTP-1 or bTP-1 from the conceptus. The failure of the conceptus to prevent luteolysis seems to be a source of pregnancy loss in cattle because treatments that increased lifespan of the corpus luteum increased pregnancy rate in some

(though not all) studies (Macmillan et al.,

zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

1986;

McDermott et al., 1986; Heyman et ai., 1987;

Thatcher et al., 1987; Jubb et al., 1990). Moreover, administration of recombinant bovine interferon-

a11 (bIFN-a) increased the pregnancy rate of ewes (Nephew et al., 1990; Schalue-Francis et al., 1991;

Martinod et al., 19911.

We conducted experiments to test effects of bIFN-a on pregnancy rates in cattle. In the first

experiment, bIFN-a was given in a manner shown to extend luteal lifespan in cyclic cows (i.e., daily injections from d 14 to 17 after estrus; Newton et al., 1990). Next, we tested the effect of a single injection of a large dose of bIFN-a. We reasoned that a single injection of bIFN-a would result in supplementation of embryonic interferon production while avoiding potential deleterious effects associated with repeated administration of a

molecule (interferon-a) that has many side effects (Koot et al., 1989; van Miert et al., 1990; Barros et al., 1992). In the third fertility trial, a n injection regimen of increasing doses given twice daily was

used because twice-daily injection of bIFN-a was more effective in increasing fertility than once- daily injection in ewes (Martinod et al., 19911, and such a regimen reduces the hyperthermia that accompanies injection of bIFN-a (Newton et al.,

1990; Plante et al., 1991).

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ET AL.

Materials

and Methods

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Materials. The interferon used in these studies, recombinant bovine interferon-a1 1, was produced

in

zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

E. coli using recombinant DNA technology (Capon et al., 19851, purified to homogeneity as

determined by SDS-PAGE, and provided as a

lyophilized, dry

zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

substance. Before use, bIFN-a was

dissolved in a carrier solution. The amount of endotoxin in stock preparations was similar to that in placebo (carrier solution alone) and was always less than 4 units per milligram as determined by the Limulus test (Food and Drug Admin- istration, 1987). Both bIFN-a and carrier solution were donated by CIBA-GEIGY, Basle, Switzerland.

Experiment 1: Pregnancy Rates After Repeated

Administration

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of Bovine Interferon-ail

.

Holstein and Brown Swiss heifers (n = 187) were random-

ized to two groups and scheduled to receive either bIFN-a or placebo in a double-blind study. To induce synchronized estrus, all heifers received a n intravaginal implant containing 1.9 g of progesterone (Eazi-breed CIDR-B; CHH Agricultural Divi-

sion, Hamilton, New Zealand). Seven days later, each heifer received a n intramuscular injection of

25 mg of prostaglandin Fza (Lutalyse, Upjohn, Kalamazoo, MI). The CIDR devices were removed after 9 d and heifers were observed for estrus twice daily. Detection of estrus was facilitated using a paint-chalk scoring system (Macmillan et al., 1988). Of the 151 heifers detected in estrus after synchronization (8 1 147 (132 Holsteins and 15

Brown Swiss) were bred between 48 and 96 h after CIDR removal and entered the experiment. Heif- ers were bred by artificial insemination using thawed semen upon standing estrus or when paint-chalk scores were indicative of recent estrous activity. Some heifers in both treatment groups were rebred 12 to 24 h later if changes in paint scores indicated continued estrous activity. Heifers received i.m. either 20 mg of bIFN-a (n =

75) or a n equivalent volume (8 mL) of placebo (n =

72) daily on d 14 to 17 after estrus. Pregnancy diagnosis of each heifer was determined indepen- dently by two veterinarians using rectal palpation on d 42 to 44 after insemination and reconfirmed on d 110 to 112 of pregnancy.

Experiment 2: Pregnancy Rates After

a

Single Injection of Bovine Interferon-all. This experiment used Holstein and Brown Swiss heifers that were bred after synchronization of estrus by use of two i.m. injections of 25 mg of Lutalyse, 11 d apart. Detection of estrus was facilitated by chalk ap- plied to the tail head. Heifers were bred by artificial insemination using frozen and thawed semen a t estrus and, for heifers displaying continued estrous behavior, 12 h later. All heifers that came into estrus within 96 h after the second injection of Lutalyse and did not subsequently return to estrus for a t least 13 d were used in the project (180 Holstein and 22 Brown Swiss). These heifers were assigned randomly to receive a single i.m. injection of 40 mg of bIFN-a (n = 104) or equivalent volume (4 mL) of placebo (n = 98) on d

13 after estrus. Heifers were observed closely for return to estrus thereafter and pregnancy was diagnosed by rectal palpation a t 41 to 44 d after breeding.

Experiment 3a: Effects o f Bovine Interferon-a11

on

Rectal Temperature. Nonlactating Holstein cows were assigned randomly to receive twice-daily

(1000 and 20001 i.m. injections of bIFN-a according

to one of two schemes. The sequence of treatments lasted for 5 d. Cows in Treatment 1 received twice- daily injections of placebo (2 mL) on d 1 to 4 and one injection of 10 mg of bIFN-a on d 5. Cows in Treatment 2 were given bIFN-a in

a

manner designed to reduce the hyperthermia associated with bIFN-a injection. Cows received twice-daily injections of -01 mg (d 11, .1 mg (d 21, .50 mg (d 31,

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INTERFERON AND FERTILITY 1473 Table 1. Pregnancy rates of heifers as affected by treatment with recombinant bovine interferon-a11

Experiment Treatmenta

Pregnancy ratesb Probability values

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IFN Placebo ANOVA CATMOD

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~

1 20 mg, lx, d 14 to 17 36/75 (48%)

2 40 mg, lx, d 13 39/104 (38%)

3b Variable, 2x, d 1 1 to 19 42/95 [44/16<

Combined 117/274 (430/0)

43/72 (60%)

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.07

47/98 (48%) .OB 82/11] (56%) .35 1521281 (54%) c.01

.15 .07 .33 c.01

&Shown is amount of bIFN-a per injection, number of injections per day, and days after estrus when bIFN-a was injected. bData are number pregnantlnumber bred (percentage pregnant). Pregnancy diagnoses were made a t d 110 to 112 of pregnancy

[Exp. 11, d 41 to 44 (Exp. 2). and d 45 to 46 (Exp.

zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

3b).

been shown to cause hyperthermia (Newton et al.,

1990). Because previous results (Newton et al.,

1990; Plante et al., 1991) have demonstrated that repeated injection of bIFN-a makes cows resistant to hyperthermic effects of bIFN-a, it was hypothe- sized that injection of the low doses of bIFN-a would be too small to cause hyperthermia but would render animals refractory to the pyrogenic effects of larger amounts of bIFN-a. Rectal temperatures were measured immediately before and 6 h

after the morning injection.

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Experiment

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3b: Pregnancy Rates After Repeated

Twice-Daily Injections

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of Bovine Interferon-ail

. Heif-

ers were bred after synchronization of estrus using two i.m. injections of 25 mg of Lutalyse, 11 d apart. Detection of estrus was facilitated by chalk ap- plied to the tail head. All heifers that displayed estrus at 48 or 72 h after the second Lutalyse injection and subsequently did not return to estrus for a t least 11 d were used in the experiment (n =

154 Holstein, 42 Jersey, and 10 Brown Swiss). Heifers were bred artificially a t the estrus after the second Lutalyse injection with frozen and thawed semen. At breeding, tail paint was reap- plied. Those whose fresh paint had been removed by the day after breeding were rebred a t this time. At breeding, heifers were assigned randomly to one of two treatments. The group treated with bIFN-a (n = 95) received twice-daily injections, i.m., of bIFN-a from d 11 to 19 after estrus. The amount of bIFN-a was .01 mg on d 11, .10 mg on d

12, .50 mg on d 13, 1.25 mg on d

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14, and 10.0 mg on

d 15 to 19. All injections were in 2 mL and given a t about 0800 and 1600. The group receiving placebo (n = 1111 received twice-daily i.m. injections of 2 mL of placebo from d 11 to 19. Estrous behavior was monitored daily and pregnancy was diagnosed a t d 45 or 46 after breeding by two experienced diagnosticians.

Statistical Analysis. Data on pregnancy rate were analyzed by least squares analysis of variance and by the CATMOD@ procedure for categorical data (SAS, 1990). Data were first analyzed with all main effects and interactions. Main effects in- cluded factors such as treatment, breed, service

sire, barn where animal was born, inseminator, day bred after CIDR removal or Lutalyse, and number of inseminations per estrus (1 or 2). Data were subsequently reanalyzed after removing effects from the model that accounted for small and nonsignificant proportions of the total variance. Additionally, data from Exp. 1, 2, and 3b were combined and analyzed as one data set with treatment (bIFN-a vs placebo), experiment, and treatment x experiment as effects in the model. Data for interestrous intervals for nonpregnant cows were analyzed by least squares analysis of variance using models similar to those described above. Additionally, estrous cycles were classified

as being < 25 d, 25 to 30 d, or > 30 d in length and were analyzed by CATMOD.

Data on rectal temperatures in Exp. 3a were analyzed as follows. First, rectal temperatures of each cow were examined for hyperthermic epi- sodes. Hyperthermia was defined as any rectal temperature > 39.5OC. Effects of treatment on the proportion of cows experiencing hyperthermia in each treatment was evaluated by chi-square analysis, whereas effect of treatment on rectal temperature during hyperthermia was evaluated by least squares analysis of variance.

Results

Pregnancy Rates. Results are shown in Table 1.

In each experiment, pregnancy rates tended to be lower for heifers treated with bIFN-a than for heifers treated with placebo. The absolute decrease in pregnancy rate was 12, 10, and 12% for Exp. 1, 2, and 3, respectively. The effect of bIFN-a approached significance for Exp. 1

(P

= .07 by ANOVA and P = .15 by CATMOD) and Exp. 2

(P

=

.06 by ANOVA and P = .07 by CATMOD). Analysis of the combined data set indicated that bIFN-a reduced pregnancy rate (P < .01) and there was no interaction between treatment and experiment.

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BARROS

Exp. 2, in which heifers received a single injection of bIFN-a or placebo on d 13 after estrus, the

interestrous interval for heifers treated with bIFN-

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a was longer

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(P c .05)

than that for heifers

receiving placebo (26.7

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f .89 d vs 24.9 f .95 dl. For

heifers treated with bIFN-a, 42.6% of nonpregnant

heifers had interestrous intervals

zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

> 24 d, vs 32.6%

of nonpregnant heifers treated with placebo. The distribution of interestrous intervals was not affected by treatment.

For Exp. 3b, interestrous interval for nonpregnant heifers was greater ( P < .02) for those treated with bIFN-a (26.6 f .63 d) than for those treated with placebo (24.0 f .85 d). Similarly, CATMOD analysis indicated that the distribution of interes-

trous intervals was affected by treatment

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( P c

ET AL.

.001). For heifers treated with bIFN-a, 60.0% of the nonpregnant heifers had estrous cycles longer than 24 d, whereas only 19.1% of heifers treated with placebo had estrous cycles longer than 24 d. Recta2 Temperatures. Experiment 3a was conducted to determine whether injection of subpyro- genic doses of bIFN-a (such as was done in Exp. 3b) makes cows refractory to the hyperthermic effects of larger doses of bIFN-a. All eight control cows that received a single injection of 10 mg of bIFN-a developed hyperthermia (rectal temperature > 39.5" C) and the average rectal temperature

6 h after injection was 40.2 f .13"C. Of the cows receiving multiple doses of bIFN-a, one cow had a n elevated rectal temperature (40.0"C) 6 h after

the first injection of 1.25 mg of bIFN-a and 6 h after

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Exp. 3b/lnterferon

t

Exp. 2/1nterferon

I

5

E s t r o u s C y c l e L e n g t h ( D a y s )

Figure 1. Frequency distribution for estrous cycle lengths for nonpregnant heifers that returned to estrus. Note that heifers that returned to estrus before the first injection of interferon were excluded from the experiments and thus are not represented here. For Exp. 2, the average interestrous interval was 26.7 f .89 d and 24.9 2 .95 d for

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INTERFERON

zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

AND FERTILITY 1475

the first injection of 10 mg of bIFN-a (39.9"

C).

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Three

other cows experienced hyperthermia after the first injection of 10.0 mg of bIFN-a only, and a n additional three cows did not experience hyperthermia after any bIFN-a injection. Overall, four of seven cows treated with gradually increasing doses of bIFN-a experienced hyperthermia, and the mean rectal temperature during hyperthermia

was 40.0

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k .06" C. There was no significant effect of

treatment on the proportion of cows experiencing hyperthermia or on average rectal temperature during hyperthermia.

Discussion

These experiments failed to support the hypoth- esis that administration of bIFN-a increases pregnancy rates in heifers. Rather, administration of bIFN-a was associated with a reduction in pregnancy rate. The deleterious effect of bIFN-a is probably a consequence of the fact that bIFN-a has diverse effects on physiological function and some of these could compromise pregnancy. One such effect is the acute hyperthermia that follows the first injection of bIFN-a (Exp. 3a; Newton et al.,

1990; Plante et al., 1991; Barros et al., 1992). This increase in body temperature could affect pregnancy because heat stress of cows a t d 8 to 16 of pregnancy has been reported to lower conceptus size a t d 16 (Biggers et al., 19871. Furthermore, culture a t elevated temperature reduced bTP-1 secretion by conceptuses and increased prostaglandin Fza secretion by endometrial explants (Putney et al., 1988; Malayer et al., 1990). The injection regimen used for Exp. 3b was developed in Exp. 3a. Results of Exp. 3a indicated that gradually increasing the dose of bIFN-a to cows tended to reduce the number experiencing hyperthermia but not the magnitude of hyperthermia in responding animals. Nonetheless, pregnancy rates were lower for bIFN-a-treated heifers of Exp. 3b, possibly because the scheme used to prevent hyperthermia was effective only to a limited degree. Additionally, the heifers in Exp. 3b were smaller than the cows in Exp. 3a, and the effective dose of bIFN-a was probably greater in the former case.

It is likely that hyperthermia is not the only consequence of injection of bIFN-a that could be harmful to the conceptus. For example, bIFN-a, though extending luteal lifespan, also causes a n acute decrease in circulating concentrations of progesterone (Newton et al., 1990; Plante et al.,

1991; Barros et al., 1992) that is probably the result of acute alterations in LH secretion (Barros et al.,

1992). The effect of bIFN-a on progesterone concen-

trations, like the effect on body temperature, also dissipates upon repeated injection of bIFN-a. Administration of interferon-a has also been shown to cause leukopenia in cattle (Griebel et al.,

19891 and, in other species, altered hypothalamic neuronal activity (Nakashima et al., 19871,

hypoferremia and hypozincemia (Koot et al., 1989;

van Miert et al., 1990), and decreased ruminal contractility (Koot et al., 1989).

The reduction in fertility caused by bIFN-a administration in heifers is in contrast to the beneficial effects of bIFN-a on pregnancy rates in ewes (Nephew et al., 1990; Martinod et al., 1991;

Schalue-Francis et al., 19911. In sheep, twice-daily injection of bIFN-a caused a n improvement of pregnancy rates, whereas once-daily treatment had no beneficial effect and a slight, nonsignificant inhibitory effect. The reason for the difference between species in unclear. Administration of bIFN-a also causes hyperthermia and a n acute decline in serum concentrations of progesterone in

ewes

zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA

(S. Martinod, personal communication).

In Exp. 3b, heifers that received bIFN-a twice- daily from d 11 to 19 and that were subsequently nonpregnant had longer interestrous intervals than heifers treated with placebo. Such a n effect likely reflects the fact that injection of bIFN-a in this manner extends luteal lifespan (Plante et al.,

1989). In Exp. 2, a single injection of bIFN-a on d 13

had only a slight effect on interestrous intervals. Some of the extended cycles in both experiments may reflect missed estrus and embryonic mortality occurring after the conceptus acted to rescue the corpus luteum from luteolysis. Of interest was the large number of nonpregnant, bIFN-a treated heifers in Exp. 3b that experienced estrous cycles that were not extended. In previous studies, it was found that a fraction of heifers do not respond to bIFN-a treatment with extended estrous cycles (Plante et al., 1988, 1989). Such heifers may have been disproportionately present in the nonpregnant group if they were also unable to respond to

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AL.

Implications

Experiments were performed to determine whether administration of interferon would enhance pregnancy rate in heifers. In contrast to expected results, administration of interferon caused a slight reduction in pregnancy rate. Therefore, use of interferon to enhance fertility is

not warranted under currently available systems of delivery.

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1991. Regulation of bovine endometrial secretion of prostaglandins and synthesis of 2’,5’-oligoadenylate synthetase by

interferon-alpha molecules.

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Bazer, F. W., W. W. Thatcher, P. J. Hansen, M. A. Mirando, T. L. Ott, and C. Plante. 1991. Physiological mechanisms of pregnancy recognition in ruminants. J. Reprod. Fertil. Suppl. 43: 39.

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metrial receptors. J. Interferon Res.

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Heyman, Y., P. Chesne, S. Chupin, and Y. Menezo. 1987. Im- provement of survival rate of frozen cattle blastocysts after transfer with trophoblastic vesicles. Theriogenology 27.:477. Imakawa, K., R. V. Anthony, M. Kazemi, K. R. Marotti, H. G. Polites, and R. M. Roberts. 1987. Interferon-like sequence of ovine trophoblast protein secreted by embryonic trophecto- derm. Nature (Lond.) 330:377.

Imakawa, K., T. R. Hansen, P. V. Malathy, R. V. Anthony, H. G. Polites, K. R. Marotti, and R. M. Roberts. 1989. Molecular cloning and characterization of complementary deox- yribonucleic acids corresponding to bovine trophoblast protein-1. A comparison with ovine trophoblast protein-1 and bovine interferon-cq1. Mol. Endocrinol. 3: 127.

Jubb, T. F., D. Abhayaratne, J. Malmo, and G. A. Anderson.

1990. Failure of a n intramuscular injection of a n analogue of gonadotrophin-releasing hormone 11 to 13 days after insemination to increase pregnancy rates in dairy cattle. Aust. Vet. J. 67:359.

Klemann, S .

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W., J. Li, K. Imakawa, J. C. Cross, H. Francis, and R. M. Roberts. 1990. The production, purification, and bi-

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Citations

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