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Domperidone can ameliorate deleterious reproductive effects and reduced weight gain associated with fescue toxicosis in heifers¹

K. L. Jones^*,2, S. S. King^*, K. E. Griswold^*, D. Cazac^* and D. L. Cross

^* Department of Animal Science, Food & Nutrition, Southern Illinois University Carbondale, Carbondale and and Department of Animal and Veterinary Science, Clemson University, Clemson, SC

	Abstract

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The aim of this study was to evaluate the effect of a dopamine antagonist, domperidone, in nonpregnant, reproductively cycling heifers consuming endophyte-infected (EI) fescue diets. Thirty crossbred heifers (Angus x Holstein or Hereford x Holstein) were assigned to one of three treatment groups (n = 10); endophyte-free (EF) fescue diet, EI fescue diet, or endophyte-infected diet and treated with domperidone (EID). Heifers fed EI diets had decreased weight gains compared with heifers fed EF or EID (P < 0.05) during a 21-d treatment period. Ovarian structures were monitored via transrectal ultrasound to determine follicle size and day of ovulation. Blood plasma samples were collected daily and analyzed for progesterone concentration to determine luteal function. Heifers ingesting EI diets had estrous cycles of shorter duration and lower mid-cycle progesterone concentrations than heifers in the EF or EID treatments (P < 0.05). Ovaries from a subset of heifers in each group (n = 3 per group) were harvested and in vitro secretion of progesterone from luteal tissue extracts was determined. No differences in progesterone concentrations were detected among luteal tissue incubates (P > 0.05). These results suggest that domperidone supplementation of heifers consuming EI fescue may ameliorate certain symptoms of fescue toxicosis.

Key Words: Antagonists • Body Weight • Bovidae • Festuca • Follicles • Progesterone

	Introduction

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Fescue toxicosis is a poorly defined, widespread phenomenon affecting ruminant and nonruminant grazing livestock species, including cattle, sheep, and horses. Cattle suffering from fescue toxicosis experience decreased feed intake and average daily gain, elevated respiration rates and body temperatures, rough hair coats and failure to shed winter coats, excessive salivation, and rarely, loss of circulation to and necrosis of the extremities (tail, feet, and ears) and of abdominal fat (Paterson et al., 1995). Endocrine and reproductive effects of fescue toxicosis in cattle include delayed puberty; decreased calving rates; reduced circulating concentrations of prolactin, cholesterol, progesterone, and melatonin; and altered function of the hypothalamus, pituitary, and pineal glands (Porter and Thompson, 1992). Fescue toxicosis results in estimated losses to the beef industry of $600 million annually due to lowered conception rates and depressed body weight gains (Hoveland, 1993; Paterson et al., 1995).

Deleterious reproductive effects of fescue endophyte ingestion in nonpregnant animals have been reported in mice (Zavos et al., 1988), rats (Varney et al., 1988), rabbits (Daniels et al., 1984), horses (Monroe et al., 1988), sheep (Bond et al., 1988), and cattle (Schmidt et al., 1986). Ultimately, failure of conception, prolonged gestation, agalactia, tough and thickened placentas, stillbirths, dystocia, elevated serum estrogens, and reduced serum progestogen levels have been reported in horses (Cross et al., 1997). The precise cellular mechanisms resulting in reproductive failure have not been well defined. The toxic endophyte produces ergopeptines that may be disrupting dopamine-signaling pathways, resulting in the symptoms of fescue toxicosis (Strickland et al., 1992, 1994). The most abundant of the ergopeptines is ergovaline, a known dopamine agonist. The aim of this study was to evaluate the effect of the dopamine antagonist domperidone on body weight gains and on luteal and follicular function using nonpregnant heifers consuming endophyte-infected fescue diets.

	Materials and Methods

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Animals and Facilities
Animal protocols were approved by the Southern Illinois University Carbondale Institutional Animal Care and Use Committee (#02-002). This study was conducted during May and June, 2002. Thirty Angus x Holstein or Hereford x Holstein heifers approximately 18 to 24 mo of age were sorted based on body weight for three treatment groups (mean body weight = 390 ± 3.5 kg). All heifers were fed a Canarygrass hay and a grain ration that did not contain tall fescue for 35 d before the beginning of the experimental period. Heifers were housed in sheltered drylot facility with ad libitum access to water. To synchronize estrous cycles, two i.m. injections of 25 mg of prostaglandin F₂ (Lutalyse, Pharmacia and Upjohn, Kalamazoo, MI) were given 12 d apart such that the heifers would ovulate on or about d 1 of the experimental period.

Treatments and Diets
Experimental treatments consisted of endophyte-free (EF) fescue, endophyte-infected (EI) fescue, and EI fescue with once daily injection of domperidone at a concentration of 0.44 mg/kg body weight (EID). Heifers were assigned to one of the three treatments and were penned by treatment group (n = 10 heifers per group). Treatment diets consisted of 7.7 kg of alfalfa hay and a pelleted grain mixture containing either EI or EF fescue seed (Table 1). Diets were fed to individual heifers within a treatment group using the Calan Broadbent Feeding System (American Calan, Northwood, NH). Diets were formulated to meet the nutrient requirements for 0.68 kg/d of gain (NRC, 1996) and to be isonitrogenous and isocaloric. Heifers were limit-fed to ensure complete daily intake of rations.

Dietary Analysis
Alfalfa hay and pelleted grain mixtures were analyzed (Table 2) for DM, CP, ash (AOAC, 1990), ADF, and NDF (Van Soest et al., 1991). Lipid content of the diets was determined by the procedures of Hara and Radin (1978). Dietary nonfibrous carbohydrate concentration was calculated using the following formula: Nonfibrous carbohydrate = 100 - (Ash + CP + NDF + Lipid). The ergovaline content of the fescue seed and the pelleted grain mixture was determined by the University of Missouri Veterinary Diagnostic Lab (Columbia, MO) using established methods (Rottinghaus et al., 1991).

Follicular development and the presence of a corpus luteum was monitored by transrectal ultrasonography (Aloka 500 V, Wallingford, CT) at every-other-day to daily intervals. The day of ovulation was recorded as well as the size of follicles 5 mm on each ovary. The presence and persistence of the corpus luteum was noted, as well as uterine edema and vaginal discharge.

RIA
Blood was collected daily by jugular venipuncture into heparinized syringes, immediately stored on ice, and processed within 3 h. After blood was centrifuged (1,850 x g, 15 min at 4°C), the plasma was aliquotted and stored frozen (-20°C) until assayed. Progesterone concentrations were determined by RIA (Coat-A-Count; Diagnostic Products, Los Angeles, CA) according to established methods (Srikandakumar et al., 1986). Detectability limits for the assay were between 0.01 and 40 ng/mL. The intraassay CV was 3.92%, and the interassay CV was 4.85%.

Luteal Cultures
Three heifers from each treatment group that were determined to be in the luteal phase of their estrous cycles (EI = 14 d, 14 d, 14 d; EF = 9 d, 11 d, 11 d; EID = 13 d, 14 d, 14 d postovulation) were humanely slaughtered at a local abattoir and their ovaries harvested. The ovaries were transported to the laboratory at approximately 30°C. Six luteal tissue samples from each corpus luteum were weighed and incubated. Approximately 0.002-g tissue samples were incubated individually in 96-well plates at 37°C in 5% CO₂ in air in 180 µL of Dulbecco’s modified eagles medium (DMEM; Life Technologies, Carlsbad, CA) supplemented with 20 µL charcoal-stripped calf serum (GeminiBio, Woodland, CA). Samples were incubated for at least 30 min, and the media removed, discarded, and replaced with fresh DMEM with 10% charcoal-stripped calf serum. After a timed 30-min incubation, the media was harvested and stored at -80°C until assayed. All media samples were thawed, vortexed, and diluted 1:20 in DMEM before being assayed for progesterone by RIA, as previously described. Results were adjusted for individual tissue weights and expressed as micrograms of progesterone produced per milligram of corpus luteum tissue.

Statistical Analysis
Data for circulating progesterone concentration were aligned retrospectively from the day of the second observed ovulation (ovulation = d 0) as determined by the disappearance of the preovulatory follicle. Follicular phase was determined to be the number of days from luteolysis to ovulation, where luteolysis was defined as the first day of circulating progesterone concentrations less than 1 ng/mL and ovulation was the day of disappearance of the Graafian follicle as determined by transrectal ultrasonography. Luteal phase length was determined to be the number of days from ovulation to luteolysis. Total estrous cycle length was measured from the day of ovulation to the day of the subsequent ovulation (interovulatory interval).

Body temperature data and plasma progesterone concentrations were analyzed using PROC MIXED of SAS (SAS Inst. Inc., Cary, NC) for a one-way treatment structure with repeated measures, where the error term used to test the main effect of treatment was heifer nested within treatment followed by LSD post hoc testing. Weight gain, follicle size on the day before ovulation, in vitro progesterone concentrations, length of follicular phase, length of luteal phase, and total estrous cycle length were analyzed by one-way ANOVA using Statistical Package for the Social Sciences (SPSS 10.0; SPSS Chicago, IL) with LSD post hoc testing. Probability differences were considered significant at P < 0.05.

	Results

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Urine ergot alkaloid analysis, normalized to creatinine, confirmed that the correct diets were consumed by the appropriate group of heifers (Table 3). Body temperatures (Figure 1) were higher (P < 0.05) in heifers consuming EF diets than in those fed EI diets. Body temperatures were not different in heifers in the EID treatment group than those fed EI or EF diets. Daily ambient high temperatures were between 25.0°C and 33.3°C with daily high humidities ranging from 90 to 100% during this study.

View larger version (17K): [in this window] [in a new window]   Figure 1. Body temperatures of heifers fed endophyte-free (EF) fescue, endophyte-infected fescue (EI), or endophyte-infected fescue supplemented with domperidone (EID). Pooled standard errors were EF = 0.0303, EI = 0.0298, and EID = 0.0298. Differences in body temperature were different (P < 0.05) between the EF and IE treatment groups.

One heifer in the EF group never developed a follicle >5 mm in diameter nor achieved plasma progesterone concentrations >1.5 ng/mL. Data from this heifer were eliminated from further analysis. Two animals in the EID group did not respond to the prostaglandin injections to synchronize their estrous cycles, and their data were removed subsequently from analyses of reproductive variables.

Plasma progesterone concentrations (Figure 2) were greater in EF-treated heifers in the mid-to-late luteal phase, on d 14, 13, 12, 10, 9, and 7 before ovulation compared with EI-treated heifers (P < 0.05). No differences in progesterone concentrations were detected between EF and EID treatments on any day of the trial. Progesterone concentrations were elevated in EID as compared with EI on d 10, 9, and 6 before ovulation (P < 0.05). No differences were detected in diameter of follicle on the day before ovulation (Table 3).

View larger version (15K): [in this window] [in a new window]   Figure 2. Daily plasma progesterone concentrations of heifers fed endophyte-free (EF), endophyte infected (EI), or EI injected with domperidone (EID) reported as day before observed ovulation. Pooled standard errors were EF = 0.3993, EI = 0.3451, and EID = 0.4007. Significant differences (P <0.05) were detected between EF and EI on d 6, 7, 9, 10, 11, 12, 13, 14, and 16; between EI and EID on d 5, and 10; and between EF and EID on d 4.

Corpora lutea tissue incubates from EI-, EF-, and EID-treated heifers did not secrete different concentrations of progesterone (P > 0.05; Table 3).

	Discussion

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The results of this study showed that treatment with domperidone completely prevented the decrease in weight gain in heifers consuming EI fescue. Heifers that ingested EI fescue in this study had a decreased weight gain, an observation consistent with previous reports (Gay et al., 1988; Strickland et al., 1993). Reduced weight gains associated with fescue consumption are generally attributed to reduced feed intake and decreased digestibility of feed (Strickland et al., 1993). Decreased dry matter intakes have been observed in ruminants fed an EI diet compared with those fed an EF diet (Strahan et al., 1987; Jackson et al., 1988; Aldrich et al., 1993b). Decreased feed intake is usually attributed to the reduced palatability of infected fescue. In this study, heifers were limit-fed a pelleted ration on an individual-BW basis, thus eliminating reduced feed intake as a cause of reduced gains.

Negating feed intake differences suggests that decreased digestibility may be the cause of reduced weight gains in this study. Consumption of EI fescue hay was shown to reduce total-tract digestibility (Humphry et al., 2002) even though differences in the in vitro digestibility of EF and EI were minimal (Arachevleta et al., 1989; Fritz and Collins, 1991). An alternate hypothesis is that lowered body weight gains in EI-fed heifers may be attributable to reduced gut motility caused by the dopamine-mimicking compounds, such as ergovaline, found in EI fescue. Dopamine has been shown to decrease the frequency and amplitude of contractions in the forestomach of sheep (Sorraing et al., 1984), and to inhibit the motility of the ileum (Cebrat et al., 1989). Administration of the dopamine receptor agonist bromocryptine reduced feed intake and inhibited forestomach contractions in goats (Kaya et al., 1994). Frequency of contraction, duration of contraction, and the associated pressure changes in the reticulorumen are all involved in particulate flow (Mathison, 1995). Reduced particulate flow results in lower production performance. It is therefore conceivable that dopamine-mimicking ergot alkaloids may be acting in the ruminant digestive system to retard gut motility. Although EI fescue is known to have reduced palatability, it is also possible that reduced feed intakes reported in previous ad libitum experiments could have been attributed to decreased passage of forestomach contents.

In support of this theory is the present observation whereby treatment of EI-fed heifers with the dopamine receptor antagonist domperidone resulted in weight gains similar to EF-fed heifers. Utilization of dopamine antagonists to treat reduced feed intake and decreased digestibility associated with fescue toxicosis has been investigated. Aldrich et al. (1993b) reported that lambs fed EI fescue supplemented with a dopamine antagonist, metoclopramide, consumed more DM than did lambs fed EI alone but digestibility was not altered. Domperidone is similar to metoclopramide in that they are both dopamine D2-receptor antagonists. Domperidone differs from metoclopramide in that it does not cross the blood-brain barrier (Barone, 1999) and, therefore, does not elicit neuroleptic side effects. Domperidone acts on dopamine D2-receptors in the digestive tract through inhibiting the effects of dopamine on smooth muscle (Barone, 1999). In previous studies, domperidone antagonized a dopaminergic-induced reduction of rumen contractions in goats (Kaya et al., 1994) and metoclopramide decreased intraruminal pressure peaks associated with cyclical contractions without changing contraction rate in calves (Guard et al., 1988). Domperidone administration in the present study restored weight gains to control values, presumably by blocking the motility-reducing dopaminergic effects produced by EI fescue and returning gut motility characteristics to near normal values.

The consumption of the EI diet did not significantly alter luteal or follicular phase duration when compared with the EF diet but did decrease total estrous cycle duration. The fescue endophyte effects on progesterone concentrations observed in the current study were similar to other reports. A decline in circulating progesterone associated with fescue toxicosis has been reported in horses (Monroe et al., 1988) and heifers (Estienne et al., 1990; Mahmood et al., 1994; Burke et al., 2001). Campbell et al. (1999) reported an increase in serum progesterone levels in domperidone-treated beef cows grazing EI pastures. This decrease in progesterone concentrations associated with fescue toxicosis may be due to stimulation of subluteolytic concentrations of the luteolysin prostaglandin F₂ by ergopeptides (Browning et al., 1998). Burke et al. (2001) noted a higher frequency of EI heifers experiencing an early rise in serum progesterone following ovulation, but this observation could have been confounded by the inclusion of heifers that did not respond to an estrous synchronization protocol. Normally, progesterone concentrations in the cyclic cow begin to increase from about d 4 postovulation to reach a plateau around d 10 and subsequently decline to basal levels by d 17 or 18 (Schams et al., 1977). In this study, heifers consuming EI diets had plasma progesterone concentrations significantly lower than EF heifers during the mid-to-late portions of the luteal phase. Reduced progesterone after pregnancy recognition at d 12 may cause a failure to maintain a pregnancy and could explain pregnancy failure in EI fed cows. In general, the circulating progesterone profile for the EID group was intermediate between the EF and EI groups. In the event of a pregnancy, the increased progesterone concentrations in the EID-treated heifer compared with the EI-treated heifers may serve to improve pregnancy retention rates.

Various ergopeptines could cause vasoconstriction of bovine blood vessels (Rhodes et al., 1991) through their stimulatory effect on ₂-adrenergic receptors (Strange, 1996), which could explain the vasoconstriction of the extremities and resulting reduction in peripheral temperatures. Similarly, this mechanism or a dopamine-controlled mechanism may be responsible for vasoconstriction in the ovary or corpus luteum, resulting in the reduction of progesterone released into the peripheral circulation. This theory is supported by the present results of in vitro luteal secretion of progesterone, where no differences were detected between EI, EF, and EID incubates. This result would suggest that corpora lutea from EI heifers likely are secreting progesterone in vivo but that the progesterone is not entering the peripheral blood supply possibly due to local vasoconstriction.

Humans and rats offer examples for possible ovarian dopaminergic mechanisms that may be operating in the cow. Dopamine and/or norepinephrine-secreting neurons appear to control folliculogenesis in the rat by stimulating the production of follicle-stimulating hormone receptors on the follicle (Mayerhofer et al., 1997). Ovarian function may be controlled in part by dopamine that binds to ovarian D1- or D2-receptors. High levels of dopamine have been discovered in the antral fluid of preovulatory human follicles (Bodis et al., 1993), and human luteinized granulosa cells possess functional dopamine D1-receptors (Mayerhofer et al., 1999), through which dopamine can exert possible effects on follicular development, ovulation and/or the regulation of the corpus luteum.

In this study, sizes of preovulatory follicles were similar among treatment groups. The number of mid-sized and large-sized follicles did not differ among treatment groups (data not presented). This observation is consistent with Seals et al. (1996), who observed no change in the numbers of follicles in heifers administered ergotamine. However, McKenzie and Erickson (1991) reported decreased numbers of primary through tertiary follicles in heifers consuming EI fescue. Burke and Rorie (2002) observed a decrease in number of mid-sized follicles on d 10 through 20 of the estrous cycle but no differences in small or large follicle numbers. Heat stress, in combination with EI fescue consumption (Burke and Rorie, 2002), resulted in the reduction of preovulatory follicle size. Heat stress did not appear to be a factor in this study and may explain why no differences in follicle sizes were observed.

Results of consuming EI fescue on rectal body temperature in cattle are contradictory. Jacobson et al. (1970) and Osborn et al. (1992) reported that rectal temperatures increased in steers consuming EI fescue or EF fescue with ergotamine added. Dopamine can cause vasoconstriction, particularly through its interaction with D1-receptors on vascular smooth muscle. Diets containing EI fescue caused cattle to have a reduction in blood flow to the skin (Rhodes et al., 1991). Steers with reduced blood flow to the periphery showed an increase in rectal temperature. A reduction of blood flow to the periphery can reduce an animal’s ability to move heat from core tissues to the surface for cooling, consequently explaining the increase in rectal temperature. In contrast, several authors have not detected changes in rectal temperature as a result of feeding EI fescue or exposing animals to ergot alkaloids (Stamm et al., 1994; Jackson et al., 1997). Rhodes et al. (1991) reported inconsistent increases in rectal temperature due to the EI diet, and Aldrich et al. (1993a) indicated that rectal temperature was actually reduced in cattle consuming EI tall fescue in one experiment but elevated in a second experiment when environmental temperatures were controlled. These differing results may be attributed to the influence of ambient temperatures during the experimental trial and possibly to other unexplained effects.

	Implications

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Domperidone ameliorated certain symptoms of fescue toxicosis in heifers, including reversal of decreased weight gains and increased circulating concentrations of progesterone. These results suggest that treatment of cattle grazing endophyte-infected fescue with domperidone may decrease the economic losses associated with fescue toxicosis in cattle. Further research investigating dopaminergic mechanisms and the specific effects of individual ergot alkaloids will help to define the factors by which fescue toxicosis influences weight gains and reproductive potential.

	Footnotes

 
¹ The authors thank N. Hill for urine analysis, G. Rottinghaus for ergovaline analysis, and D. Weakley (Purina Mills LLC, Gray Summit, MO) for ration components and preparation. Thanks to J. Wyatt and G. Weidlocher for animal handling, as well as student aid from the research groups of K. Griswold and K. Jones. Thanks to E. Dille for RIA analysis. This technology is protected by the following U.S. patents assigned to Clemson University: 5,372,818; 6,224,895; 6,455,546; 6,534,526 and licensed to Equi-Tox, Inc. 112 Central Rd. Central, SC. 29630. This research was supported by Illinois Council for Food and Agricultural Research (grant #02-I17).

² Correspondence: #129 Agriculture Building, 1205 Lincoln Drive (phone: 618-453-1774; fax: 618-453-5231; E-mail: kljones{at}siu.edu).

Received for publication February 7, 2003. Accepted for publication May 27, 2003.

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