Effect of intrauterine infusion of recombinant bovine interferon αI1 on luteal phase duration and oxytocin-induced release of 13,14-dihydro-15-keto-prostaglandin F2α in postpartum beef cows

ANIMAL

REPRODUCTION SCIENCE ELSEVIER

Animal Reproduction Science 40 (1995) 193-201

Effect of intrauterine infusion of recombinant bovine interferon a~l on luteal phase duration and oxytocin-induced release of 13,14-dihydro- 15-keto-prostaglandin F2~ in postpartum beef cows B.E. Salfen, D.H. Keisler, M.F. Smith, W.G. Zollers Jr., K.R. Keiborz-Loos, H.A. Garverick * Animal Science Department, 163 Animal Science Research Center, University of Missouri, Columbia, MO 65211, USA

Accepted 16 June 1995

Abstract The objective of this study was to determine if oxytocin-induced release of prostaglandin F 2 a (PGF2~; measured by the stable metabolite, 13,14-dihydro-15-keto-prostaglandin F 2 a (PGFM)) was inhibited following intrauterine infusion of bovine interferon-ai1 (rboIFNcql) into postpartum cows anticipated to have short estrous cycles following first ovulation postpartum. Cows expected to have short estrous cycles were assigned to receive twice daily intrauterine infusions of either placebo (SCP; n = 11) or 2 mg rboIFNai1 (SCIFN; n = 14) on Days 1-16 following hCG injection (2500 IU; day 0) on Days 30 or 31 postpartum. On Day 5 following hCG, each cow was injected with 100 IU oxytocin (i.v.) to induce the release of uterine PGFz,~ (as measured by PGFM). Other treatment groups consisted of cows expected to have normal estrous cycle lengths following pretreatment with a 9 day norgestomet implant on Days 21 or 22 postpartum followed by hCG injection to induce ovulation. Cows expected to have normal estrous cycle lengths received twice daily intrauterine infusions of either placebo from Days 1 to 16 of the cycle and i00 IU oxytocin (i.v.) on Day 5 (NCPE; n = 11) or twice daily infusions of placebo (NCPL; n = 7) or rboIFNai1 (NCIFN; n = 10), from Day 13 post-hCG injection until luteolysis. Oxytocin was injected (100 IU; i.v.) into cows in the NCPL and NCIFN groups on Day 16. The calculated areas under the curve (arbitrary PGFM units) were: 164 _ 18 units, 96 ___16 units, 93 _+ 18 units, 137 __+27 units and 53 _+ 20 units for SCP, SCIFN, NCPE, NCPL and NCIFN, respectively

* Corresponding author. 0378-4320/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI0378-4320(95)01419-5

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B.E. Salfen et al. / Animal Reproduction Science 40 (1995) 193 -201

(SCIFN < SCP; NCIFN < NCPL; P < 0.015). Mean luteal phase length was calculated as the number of days from injection of hCG until progesterone declined to below 0.5 ng ml- i and was: 6.7 + 1.0 days, 10.5 ___0.9 days, 12.0 _ 1.0 days, 18.0 ___1.3 days and 20.7 +__1.1 days for SCP, SCIFN, NCPE, NCPL and NCIFN, respectively (SCP < SCIFN = NCPE < NCPL = NCIFN; P < 0.01). In summary, luteal phase lengths were increased and oxytocin-induced release of PGFM was reduced by rbolFNall infusion in cows anticipated to have short luteal phases. Keywords: Corpus luteum; Eslxous cycle; Progesterone;Recombinantbovine interferon a~l; Prostaglandin

F2, 1. Introduction

In cattle, subnormal luteal function has been frequently observed following the first ovulatory estrus in prepuberal and postpartum cows (Corah et al., 1974; Gonzalez-Padilla et al., 1975; Lishman et al., 1979; Odde et al., 1980; LaVoie et al., 1981; Pratt et al., 1982). Subnormal luteal phases are characterized by estrous cycles of short duration (7-10 days) with decreased progesterone (P4) after Days 5 or 6 postovulation compared with animals having luteal phases of normal length (Kesler et al., 1980; Copelin et al., 1987; Garverick et al., 1992a). Work from our laboratory and others has provided evidence that subnormal luteal function in cows is due to a release of prostaglandin F2 (PGF2,~) from the uterus around Day 6 following estrus (for reviews see Garverick and Smith, 1986; Hunter, 1991; Lishman and Inskeep, 1991; Garverick et al., 1992a). Normal establishment and maintenance of pregnancy is dependent not only upon the embryo's ability to develop normally, but also upon the dam's ability to recognize and respond to the developing embryo (maternal recognition of pregnancy). The bovine conceptus releases a Type I interferon known as interferon-~- (IFN-~-; Roberts et al., 1992) which is believed to act locally on the endometrium to prevent the episodic release of the uterine luteolysin, prostaglandin F2~ (PGF2~; Roberts et al., 1985). Bovine IFN-~- is first produced at about Day 15 of pregnancy (Imakawa et al., 1989), just prior to the time when the corpus luteum (CL) would normally begin to regress during the estrous cycle (Roberts et al., 1985). In contrast, in cows with short luteal phases, luteal regression occurs prior to Day 10 (Garverick et al., 1992a). In previous studies, normal length estrous cycles in cows were extended following intrauterine infusion (Plante et al., 1988, 1989, 1991) or intramuscular injection (Plante et al., 1989, 1991) of recombinant bovine interferona~l (rbolFNai1). Short luteal phases were also extended following intrauterine infusion of rboIFN-a~l into postpartum cows anticipated to have short estrous cycles (Garverick et al., 1992b). The present study was designed to determine if intrauterine infusion of rbolFN-cql in cows anticipated to have short luteal phases inhibits oxytocin-induced release of PGF 2~, on Day 5 of the estrous cycle. 2. Materials and methods

On Days 21 or 22 post-parturition, 53 beef cows in good body condition were allotted into two pretreatment groups. Cows received either a norgestomet implant (Synchromate B; n = 28) from Day 21 or 22 postpartum (PP) for 9 days or no norgestomet implant

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B.E. Salfen et al./Animal Reproduction Science 40 (1995) 193-201

Table 1 Timing of norgestometimplantation, hCG and oxytocin injection, and intrauterine infusions for each treatment Treatment a Timingof injection and infusion

SCP SCIFN NCPE NCPL NCIFN

Norgestomet implant (Days 22/23 to Days 31/32) b

hCG 2500IU (Days 33/34)

Placebo rbolFNa~ 1 Oxytocin 2 mg (2 × per day) 2 mg (2 × per day) 100 IU

+ + +

+ + + + +

Days 1-16 c Days 1-16 Days 1-16 Days 13-L d Days 13-L

Day 5 Day 5 Day 5 Day 16 Day 16

a scP, short cycle placebo; SCIFN, short cycle rboIFNott1; NCPE, normal cycle placebo early; NCPL, normal cycle placebo late; NCIFN, normal cycle rbolFNa I1. b Days post-parturition. c Day 0 = hCG injection. L, luetolysis. (n = 25). Calves were removed from all cows for 48 h from Day 30 or Day 31 (day of implant removal for norgestomet pretreated cows) to Day 32 or Day 33 and then cows were injected (i.m.) with 2500 IU hCG (ICN Pharmaceuticals Inc; Costa Mesa, CA) to induce ovulation (Day 0; Table 1). Calves were returned to the dams following hCG injection. Cows were subsequently allotted into five treatment groups. The first two treatment groups (short cycle placebo (SCP), n = 11; short cycle interferon (SCIFN), n = 14) consisted of cows which were not pretreated with norgestomet and were expected to have short estrous cycles. Cows in the SCP and SCIFN groups received intrauterine infusions twice daily of either placebo (2 rag; CIBA Geigy) or r b o l F N a I l (2 mg; CIBA Geigy), respectively, from Days 1 to 16 following hCG-induced ovulation. On Day 5 following hCG, 100 IU oxytocin were injected i.v. The remainder of the treatment groups consisted of cows previously implanted with norgestomet and were expected to have normal length estrous cycles. Cows with normal cycles received intrauterine infusions twice daily with placebo from Days 1 to 16 of the normal cycle and injected with oxytocin on Day 5 (NCPE; n = 11) or were infused twice daily with placebo (NCPL; n = 7) or r b o l F N a l l (NCIFN; n = 10), respectively, from Day 13 following hCG until luteolysis, and oxytocin was injected on Day 16 (Table 1). The purpose of t h e oxytocin injection was to stimulate release of PGF2~ from the endometrium. Release of PGF 2 ~ was determined by assessing serum concentration of the stable metabolite of PGF2~, 13,14-dihydro-15-keto-prostaglandin F2~ (PGFM) (Homanics and Silvia, 1988). 2.1. Blood sampling

From 7 to 10 days post-calving, blood samples were collected by venipuncture thrice weekly from all cows and serum concentrations of progesterone (P4) were determined to verify that the cows were anestrus. Cows were considered anestrus if serum concentrations of P4 remained below 0.2 ng m l - ~. Blood samples were also taken by venipuncture

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B.E. Salfen et al./ Animal Reproduction Science 40 (1995) 193-201

daily following hCG injection and twice daily during all infusion periods until luteolysis. Serum P4 concentrations were measured in all samples by radioimmunoassay (Diagnostic Products Corporation; Los Angeles, CA). The inter- and intra-assay coefficients of variation for the P4 radioimmunoassays were 12.17% and 7.57%, respectively. Concurrent with injection of oxytocin (100 IU i.v.; Sanofi; Overland Park, KS) on Day 5 (SCP, SCIFN and NCPE groups) or Day 16 (NCPL and NCIFN groups) blood samples were collected via an indwelling jugular vein catheter at - 4 5 , - 3 0 , - 1 5 , 0, 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120, and 150 rain relative to injection of oxytocin, and concentrations of PGFM were measured by radioimmunoassay (Homanics and Silvia, 1988). The inter- and intra-assay coefficients of variation for the PGFM radioimmunoassays were 6.37% and 5.40%, respectively. 2.2. Infusions

Modified stainless steel artificial insemination catheters which were fitted with three-way stopcocks and sterile plastic sheaths were used for infusion of solutions. Infusions occurred at 07:00 and 18:00 h and consisted of 2 mg (0.8 ml) treatments of rbolFNcti1 or placebo followed by 3 ml phosphate buffered saline containing 1 mg ml -~ bovine serum albumin (Fraction V; Sigma; St. Louis, MO), penicillin (100 units m1-1 ) and streptomycin (100 /xg ml-~; Gibco; Grand Island, NY). 2.3. Statistical analysis

Serum concentrations of P4 among treatments were analyzed using the General Linear Model program of the Statistical Analysis Systems (SAS) Institute Inc. (1987) with cow within treatment as the error term (Gill and Hafs, 1971). Least Squares Mean analysis was used to estimate predetermined treatment differences. Area under the curve was used to describe the oxytocin-induced release of PGFM and results were expressed as arbitrary PGFM units. Area under the curve was defined as total area under the curve minus mean baseline (as determined from four samples collected prior to the oxytocin injection). All experimental protocols in this study met the approval of IACUC of the University of Missouri-Columbia.

3. Results 3.1. Effects on luteal lifespan

Intrauterine infusion of rbolNFa~l from Days 1 to 16 into cows expected to have short estrous cycles (SCIFN) resulted in longer luteal phase lengths ( = 4 days; P = 0.007) when compared with cows infused with placebo (SCP; Table 2). NCPL and NCIFN cows had longer (P < 0.01) luteal phase lengths when compared with SCP, SCIFN and NCPE groups. NCIFN and NCPL groups were not different in luteal phase lengths (18.0 _+ 1.3 days and 20.7 + 1.1 days, respectively (P = 0.12).

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Table 2 Luteal phase length, mean P4 concentration and PGFM response to oxytocin administration among treatment groups Treatment i

n

Luteal phase length (days) 2

Mean P4 concentration (ng ml- 1)

PGFM (area under under the curve) 3

SCP SCIFN NCPE NCPL NCIFN

11 14 11 7 10

6.7+1.0 a 10.5+0.9 b 12.0 + 1.0 b 18.0+ 1.3 c 20.7-t- 1.1 c

0.31+0.30 0.90+0.26 1.08 _ 0.30 2.38+0.46 2.72+0.39

164+18 a 96+ 16 bc 93 + 18 bc 137+27 ab 53+20 c

a a a b b

i SCP, short cycle placebo; SCIFN, short cycle rbolFNaj 1; NCPE, normal cycle placebo early; NCPL, normal cycle placebo late; NCIFN, normal cycle rbolFNoq 1. 2 Luteal phase length is expressed as days following ovulation until P,, concentration dropped below 0.5 ng ml- J. 3 Area under the curve expressed in arbitrary units. a.b.c Means (+SE) within the same column with different letters differ (P < 0.05).

3.2. S e r u m progesterone concentrations N o r g e s t o m e t p r e t r e a t e d c o w s h a d g r e a t e r m e a n c o n c e n t r a t i o n s o f P4 t h a n c o w s n o t p r e t r e a t e d w i t h n o r g e s t o m e t ( P < 0.01). M e a n c o n c e n t r a t i o n o f P4 in N C P L a n d N C I F N w e r e h i g h e r t h a n SCP, S C I F N a n d N C P E . T h e r e was also a n e f f e c t o f t r e a t m e n t w i t h r b o l F N a t l o n m e a n s e r u m P4 c o n c e n t r a t i o n s . D i f f e r e n c e s ( P < 0 . 0 1 ) w e r e s e e n w h e n c o m p a r i n g the SCP, S C I F N a n d N C P E g r o u p s w i t h the N C P L a n d N C I F N g r o u p s w i t h m e a n c o n c e n t r a t i o n s o f P4 in t h e N C P L a n d N C I F N g r o u p s h i g h e r t h a n the o t h e r t h r e e g r o u p s ( T a b l e 2; Fig. 1). H o w e v e r , P4 c o n c e n t r a t i o n s in the S C P g r o u p t e n d e d to b e l o w e r t h a n f o r the S C I F N ( P = 0 . 1 5 ) a n d N C P E ( P = 0 . 0 8 ) groups.

7 ' 6 A m

SCP

,.i.

"'*'"

5

SCIFN

E --e-- NCPE ql'

....~"' N C P L -*'-

0

5 DAY

10 OF

15

ESTROUS

20

NCIFN

25

CYCLE

Fig. 1. Concentrations of serum progesterone (P4) following induction of ovulation. Cows in SCP, SCIFN and NCPE groups were infused from Days 1 to 16. Cows in groups NCPL and NCIFN were infused from Day 13 until luteolysis.

198

B.E. Salfen et a l . / Anirnal Reproduction Science 40 (1995) 193-201 600 SCP 500

E :E

300

u.

a.

.....

SCIFN

-----

NCPE

400

200

.......... N C P L

100

....

0

i -45

i

i

-16 -$0

,

,

6 0

,

,

lO 10

TiME

,

,

48 SO

i

i

60

i

i

106

78

90

NCIFN

150 120

(rain)

Fig. 2. Mean concentration of 13,14-dihydro-15-keto-prostaglandin F2, (PGFM) in serum prior to and subsequent to injection of 100 IU oxytocin (i.v.) in cows receiving placebo or rboIFNall infusion.

3.3. Oxytocin-induced PGF2~ release The oxytocin-induced release of PGF2~ (area under the curve; Fig. 2) was greater in the SCP group compared with SCIFN, NCPE and NCIFN groups (all P < 0.01). Cows in the NCPL group had more PGFM release following oxytocin injection than NCIFN cows (P < 0.02) but did not differ from any other group (Table 2).

4. Discussion

The present study provides further evidence that the lengthening of luteal lifespan in cows anticipated to have short cycles by intrauterine rbolFNa~l infusion is through decreased uterine secretion of PGF2~. Extension of luteal lifespan following infusion of rboIFNaxl was greater in the short cycle groups (SCP vs. SCIFN; 3.8 days) compared with cows expected to have a normal length cycle (NCPL vs. NCIFN; 2.7 days; Table 2). There are relatively greater concentrations of endometrial ovine trophoblast protein-1 (oTP-1) receptors in the ewe at Days 4 and 16 of the estrous cycle (Knickerbocker and Niswender, 1989). The fact that short cycle cows showed a more pronounced effect of rboIFNcql infusion when compared with the normal cycle length cows may be due to a negative correlation between CL weights/luteal P4 concentrations and oTP-1 receptors (Knickerbocker and Niswender, 1989). One of the effects of whole conceptus secretory proteins or purified IFN-~" administration is a reduction of the number and amplitude of luteolytic pulses of PGF2~ (Bazer et al., 1986; Knickerbocker et al., 1986). Basal concentrations of PGF2~ are seemingly greater in pregnant ewes when compared with non-pregnant ewes; however, PGF2,~ is not secreted in a pulsatile manner in pregnant ewes (Bazer et al., 1991; Silvia et al.,

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1991). There may be a difference in regulation of PGF2~ secretion depending upon the species. Cattle treated with IFNa or IFN~- apparently secrete less PGF2~ than non-treated animals (Helmer et al., 1989; Barros et al., 1991; Plante et al., 1991). The antiluteolytic effects of IFNz in sheep may be via an inhibition of PGF2~ release rather than a disruption of the PGF 2 ~ biosynthetic mechanisms (Roberts et al., 1992). Release of PGF2~ can be assessed by measuring concentrations of prostaglandin following injection of oxytocin (Newcomb et al., 1977). A reflection of PGF2~ secretion can also be assessed by measuring the stable metabolite PGFM (Kindahl et al., 1976; Guilbault et al., 1984). Zollers, et al. (1989) reported an increase in serum concentrations of PGFM in cattle following oxytocin injection on Day 5 of a short cycle but not on Day 5 of a normal cycle. Additionally, cattle injected with oxytocin on Day 16 of normal length estrous cycles had increased levels of serum concentrations of PGFM similar to Day 5 of a short cycle (Zollers et al., 1989). This model has been used widely as an indication of PGF2, releasability (Garverick, 1992a; Plante et al., 1991). In the current study, the oxytocin-induced release of PGFM in cows infused with rbolFNoq 1 was suppressed, with the most dramatic suppression in serum concentrations of PGFM observed in the NCIFN group. The possible mechanism whereby rbolFNa I 1 decreases the release of PGF 2~ and therefore concentrations of PGFM may involve a reduction in the numbers of oxytocin receptors (Flint et al., 1991), or a direct inhibition on prostaglandin synthesis (Gross et al., 1988a). In cattle, bovine trophoblast protein-1 (bTP-1) may reduce the concentration of PGF2~ via an increase in prostaglandin synthetase inhibitor (Gross et al., 1988b). Both of these mechanisms may function to prevent luteolysis. An unexpected observation was the shorter luteal phase length in the NCPE group compared with the NCPL group. Perhaps the shorter luteal lifespan in the NCPE group was due to the timing of the oxytocin injection (Day 5 versus Day 16, respectively) or due to the timing of the uterine manipulation during infusions (Days 1 to 16 versus Days 13 to luteolysis, respectively).

Acknowledgments This research was supported by the Missouri Research Assistance Act and partially supported by NC-113. The authors thank Dr. R.M. Roberts and CIBA Geigy for the rbolFNai1 used in this study. Contribution from the Missouri Agric. Exp. Station Journal Series No. 12,331, and NC-113 Regional Research Project, Methods for Improvement of Fertility in Cows Postpartum.

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