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Plasma reduced folates, reproductive performance, and conceptus development in sows in response to supplementation with oxidizedand reduced sources of folic acid¹

A. F. Harper^*,2, J. W. Knight^*, E. Kokue and J. L. Usry

^* Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg 24061; and Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Japan; and and Ajinomoto Heartland Incorporated, Chicago, IL 60631

² Correspondence:
Virginia Tech Tidewater AREC, 6321 Holland Rd., Suffolk 23437 (phone:757-657-6450, ext. 106; fax:757-657-9333; E-mail:
alharper{at}vt.edu).

	Abstract

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The study was conducted to determine the response of sows to oxidized and reduced forms of supplemental folic acid in the diet. Gilts were mated and fed a standard corn–soybean meal diet with no supplemental folic acid. On d 105 of gestation, gilts were randomly assigned to one of four dietary treatments for the remainder of the study. Treatments were: 1) diet with no supplemental folate (control), 2) diet with 2.1 ppm (calculated) of added folate supplied by a synthetic pteroylmonoglutamate form (MG), 3) diet with 2.1 ppm (calculated) of added folate supplied by N5-formyl-5,6,7,8,-tetrahydrofolic acid (THFA), or 4) a commercial bacterial cell powder source (Aj-PG) rich in reduced folates. Blood samples for high-performance liquid chromotography determination of reduced plasma folates were collected from gilts on d 105 of gestation, at weaning, at mating, and when the females were slaughtered on d 45 after mating for the second parity. There were 19, 18, 18, and 22 sows for the control, MG, THFA, and Aj-PG treatments, respectively. Supplementing folacin just before farrowing and during lactation had no effect on sow and litter performance during parity 1 (P > 0.10). Live fetuses at d 45 of gestation in Parity 2 were 10.06, 12.23, 10.87, and 11.07 for the control, MG, THFA, and Aj-PG treatments, respectively, and did not differ (P > 0.10). Fetal survival and placental size and protein content were generally unaffected by folate treatment. Concentration of reduced folates in sow plasma was 13.50, 13.58, 22.50, and 17.79 nM at weaning and 12.55, 19.29, 18.96, and 21.88 nM at mating for the control, MG, THFA, and Aj-PG treatments, respectively, with the THFA treatment elevated above the controls at weaning (P < 0.05) and the Aj-PG treatment greater than controls at mating (P < 0.05). At weaning, the reduced sources of supplemental folate (THFA and Aj-PG) were more effective in elevating plasma reduced folates than the oxidized folate supplement (MG; P < 0.05). Nonetheless, folate supplementation did not significantly improve sow reproductive performance in the subsequent parity, and there was no indication that reduced folate sources were superior to the oxidized pteroylmonoglutamate form as folate supplements for sows.

Key Words: Folic Acid • Reproduction • Sows

	Introduction

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Folic acid is essential for reproduction and embryo development in litter-bearing species, such as rats (Tagbo and Hill, 1977) and guinea pigs (Habibzadeh et al., 1986). This is due to the role of folic acid as an essential cofactor for nucleic acid synthesis and amino acid metabolism in rapidly developing products of conception (Herbert and Das, 1976). In reproducing sows, Matte et al. (1984a) demonstrated a decrease in total serum folate concentration during early gestation, suggesting a greater metabolic demand for the vitamin during this time. Subsequent studies demonstrated that folate supplementation during mating and gestation by injection (Matte et al., 1984b; Friendship and Wilson, 1991) or inclusion in grain–soybean meal diets at levels of 1 to 1.65 ppm (Lindemann and Kornegay, 1989; Thaler et. al., 1989) resulted in improved litter size in sows.

However, a litter size response to dietary supplementation of gilts and sows with folic acid has not been observed in all studies (Easter et al., 1983; Gannon, 1991; Harper et. al., 1994). In previous studies, the oxidized or pteroylmonoglutamate form of the vitamin has been used, but in vivo, the reduced forms dihydrofolate and tetrahydrofolate function in single-carbon transfer reactions for nucleic acid synthesis and amino acid metabolism (Krumdieck, 1990). Mizuno et al. (1997) reported that oral supplementation of pigs with tetrahydrofolic acid or a bacterial cell powder rich in reduced folates was more effective than an oxidized source in elevating plasma reduced folates. Considering these factors, reduced sources of supplemental folate may produce greater litter size responses in sows than the pteroylmonoglutamate traditionally supplemented. The objective of this experiment was to assess the effects of a pteroylmonoglutamate source of dietary folate supplement and two reduced folate supplements on plasma reduced folates, reproductive performance, and conceptus development in sows.

	Materials and Methods

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General Management and Experimental Diets
Before initiation of the study, the protocol and animal management procedures were reviewed and approved by the Virginia Tech Animal Care Committee. Contemporary groups of Yorkshire and Yorkshire x Landrace gilts reared in confinement conditions at the Virginia Tech Tidewater Agricultural Research and Extension Center swine unit in Suffolk served as the experimental population. The gilts were fed ad libitum a standard corn–soybean meal-based diet (2.2 ppm added folate) throughout growth and development. Beginning at a minimum age of 200 d, gilts were evaluated once daily for estrus using mature boars. Females were naturally mated to mature boars on the day estrus was first detected and again 24 h later. At the time breeding periods were initiated, all gilts began receiving the control breeding/gestation diet at a feeding rate of 1.8 kg/d (Table 1). This diet was formulated to contain no supplemental folates beyond that found intrinsically in the corn and soybean meal used to prepare the diets (as-fed assayed total folates = 0.62 ppm). The purpose of feeding this diet during gestation of Parity 1 was to have all gilts consuming a reduced level of folates throughout the initial pregnancy and before initiation of feeding the experimental diets. Pregnant gilts continued to receive this diet until d 105 of gestation, at which time they were moved to individual farrowing crates in an environmentally controlled farrowing room. A total of 111 gilts were bred for this preliminary phase of the experiment and were available for allotment to dietary treatments at d 105.

A premix unique for each experimental diet was prepared by manual mixing followed by continuous mixing in a laboratory mixer for 15 min (Table 2). The premix was formulated for addition to the remaining dietary ingredients in a vertical feed mixer at a level of 1.18% of the diet. Samples of diets formulated by this method were assayed by methods described by Tamura et al. (1990) for folate concentration using the Lactobacillus casei (total folates) and Pediococcuss acidilactici microbiological methods (tetrahydrofolates excluding 5-methyl tetrahydrofolate). Assayed values were in general agreement with expected folate values (Table 1). However, considering the intrinsic concentrations of 0.62 and 1.20 ppm of folate detected in the control gestation and lactation diets, respectively, assayed folates concentration in the MG and THFA diets were slightly less than expected values. After preparation, the experimental diets were stored in labeled burlap bags out of direct sunlight. Storage time before feeding did not exceed 2 wk.

After weaning, the sows were returned to the breeding/gestation facility, where they received their assigned experimental breeding/gestation diets at a rate of 1.8 kg/d. Therefore, the dietary concentration and source of supplemental folate was continuous from farrowing through lactation and weaning of the first parity and during breeding and through d 45 of gestation of the second parity. Beginning on the second day after weaning, the sows were checked once daily for estrus using mature boars. Those identified to be in estrus were mated naturally that morning, mated by artificial insemination with pooled semen from a commercial boar stud that afternoon, and mated again by natural service the following morning. Sows that failed to express estrus within 10 d after weaning were eliminated from the study. After mating for the second parity, sows were moved to individual pens in a separate facility and continued to be fed the experimental gestation diets (1.8 kg/d) until completion of the experiment at d 45 ± 1 of gestation. Of the 111 pregnant gilts that were available for dietary treatment allotment on d 105 of the first parity, 77 completed the experiment and were included in the data analysis. These included a total of 19, 18, 18, and 22 sows for the control, MG, THFA, and Aj-PG treatments, respectively. Reasons for failure of gilts to complete the experiment or to be excluded from analysis included gilt deaths associated with difficult farrowing (n = 5), exceptionally small litters (less than five live piglets) in Parity 1 (n = 7), failure to express estrus within 10 d after weaning (n = 12), and sows that were mated but failed to conceive for Parity 2 (n = 10). All treatment groups were represented throughout the sows that were removed from the study, and no relationship between experimental treatment and removal from the study was observed.

Plasma Reduced Folates Determination
Blood samples were collected from each sow by vena cava puncture immediately before initiation of feeding the experimental diets on d 105 of the first parity, at weaning, at mating, and on d 45 ± 1 of gestation of the second parity. In addition, a blood sample was collected from a randomly selected male and female piglet from each litter at weaning time of the first parity. Blood was collected into sterile syringes and transferred to tubes containing a 15% EDTA solution as an anticoagulant. Samples were transported directly to the laboratory, and within 1 h after collection, the blood was centrifuged (1,500 x g) and plasma was harvested and transferred into cryogenic vials. Ascorbic acid (0.3%) was added to each plasma sample as an antioxidant, and the samples were immediately placed in frozen storage at -20°C until analysis for plasma folates within 10 mo of collection. Assayed plasma folates included the reduced forms of the vitamin, tetrahydrofolate (THF) and 5-methyltetrahydrofolate (5-MF). These metabolites of folic acid were determined using HPLC with electrochemical detection as described previously (Shimoda, 1992).

Evaluation of Reproductive Performance and Conceptus Development
On d 45 ± 1 of gestation in the second parity, sows were killed by electrocution immediately followed by exsanguination. This stage of gestation was chosen as a strategic time to assess litter size and fetal–placental development during early gestation (Knight et al., 1977). The reproductive tracts were removed and separated from the mesometrium and cut free at the cervix. Each individual fetus and placenta was carefully separated, and the following measurements were recorded for each conceptus unit: placental length and weight, fetal crown-rump length and weight, allantoic and amniotic fluid volumes, weight of the empty uterus, number of corpora lutea, and the number of presumably live and dead fetuses. A fetus was considered to be alive at slaughter if there were no visible signs of tissue degeneration. The number of corpora lutea was considered to be an accurate measure of ovulation rate and the percent fetal survival was calculated using the number of live fetuses as a percentage of the number of corpora lutea.

Dry matter was determined for all fetal pigs for each sow using a drying oven (95°C) for a minimum of 7 d. Dry matter was also determined for a subsample of placentae from each sow. The subsample represented the even-numbered placentae in each sow when numbering each conceptus from the tip of the right uterine horn to the tip of the left uterine horn. The remaining odd numbered placentae were placed in physiological saline solution in labeled plastic bags and stored frozen (-20°C) until subsequent analysis for protein and DNA concentration. Placental tissue protein and DNA concentrations were determined by previously described methods (Knight et al., 1977). Progesterone and total estrones concentrations in composite samples of amniotic and allantoic fluids from each litter were also determined by methods described previously by Knight et al. (1977).

Statistical Analyses
Each sow and her litter was considered an experimental unit. The data were analyzed using the GLM procedures of SAS (SAS Inst., Inc., Cary, NC). Day of gestation at the time of slaughter was used as a covariate in the analysis to correct for minor differences in stage of gestation (d 44, 45, or 46). The Tukey-Kramer mean separation procedure was used within SAS to detect differences between individual treatment means. Preplanned orthogonal contrasts were also performed to test differences between folate supplementation from all sources (MG, THFA, and Aj-PG) vs the control. Contrasts were also used to test reduced sources (THFA and Aj-PG) vs the oxidized source (MG).

	Results and Discussion

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First-Parity Sow and Litter Performance
The experimental protocol was such that all females in each breeding group were fed the control diet containing no supplemental folate (Table 1) until d 105 of their first-parity pregnancy. The purpose of this protocol was to have a similar folate nutritional status for all females until d 105, at which time the pregnant gilts were assigned to the four dietary treatments. Using this protocol, it would be expected that first-parity sow breeding and prefarrowing weights, gestation weight gain, and litter size at birth would be balanced and similar across dietary treatments. These data were indeed similar and not different (P > 0.50) across treatments (Table 3). Therefore, the pregnant females used in the experiment seem to have been reasonably homogeneous across dietary treatments for the measurements obtained.

Plasma Reduced Folates—Piglets
Plasma 5-MF concentrations were higher in piglets from sows fed the Aj-PG supplement (Figure 1, P < 0.05) and tended to be higher (P < 0.08) from sows fed the MG folate supplement. Furthermore, use of supplemental folate of any form in the sow diet increased plasma 5-MF concentration in piglets at weaning (Figure 1, P < 0.05). Total reduced folates concentration in piglet plasma also tended to be higher (P < 0.08) in piglets from sows fed supplemental folates, with no apparent difference in response among the sources (Figure 1). Access to creep feed was not allowed in this study, but it is possible that some dietary folates were consumed by piglets via the sow feed. However, the relative contribution of this to plasma folate status of the piglets was likely small because the sow feeders were elevated and not easily accessible to the nursing piglets. These results are in general agreement with Matte and Girard (1989), who reported that weekly folate injections in lactating sows elevated total folate concentration in sow milk and in the serum of nursing piglets throughout a 28-d lactation. As in the current study and that of Pharazyn and Aherne (1987), dietary folate supplementation for the sow did not affect piglet survival or growth performance during lactation.

View larger version (35K): [in this window] [in a new window]   Figure 1. Plasma tetrahydrofolate (THF), N-methyltetrahydrofolate (5-MF), and total reduced folates (THF + 5-MF) concentration in nursing piglets after dietary supplementation (2.1 ppm) of lactating sows. Values are for two randomly selected pigs per litter (1 male, 1 female) with 19, 18, 18, and 22 litters per LS mean (± SEM) for the control, pteroylmonoglutamate (MG), N5-formyl-5,6,7,8-tetrahydrofolic acid (THFA), and dried bacterial cell powder (Aj-PG) dietary folate treatments, respectively. For each plasma metabolite, bars without a common letter differ, P < 0.05. *For plasma 5-MF concentration, all dietary folate sources combined differ from the control, P < 0.05. **For THF + 5-MF plasma concentration, all dietary folate sources combined tended to be greater than the control, P < 0.08.

Previous studies with sows had measured total serum or plasma folates concentration rather than specific metabolites of folic acid. Matte et al. (1984a) determined that total serum folate concentration declines during early to mid-gestation in sows, a finding that has been confirmed by others (Tremblay et al., 1986; O’Conner et al., 1989; Harper et al., 1994). The decrease in plasma folates concentration during early gestation does not seem to be related to plasma volume expansion because significant plasma volume expansion in sows does not occur until late pregnancy (Anderson et al., 1970). Furthermore, it has been determined that this decrease in serum folates can be attenuated by dietary supplementation of the pteroylmonoglutamate (oxidized) form of folic acid. In the current study, plasma concentrations of the principal reduced forms of folacin, THF, and 5-MF were determined.

Only at weaning did the form of folate supplemented have an effect on concentration of reduced plasma folates. In this case, the reduced sources (THFA and Aj-PG) increased plasma reduced folates more effectively than did the oxidized source (MG). However, at mating and at d 45 after mating, all three folate supplements resulted in a similar plasma reduced folate concentrations. When oxidized folates are absorbed into the intestinal cell, reductase enzyme systems transform the vitamin into the reduced form. At high dietary folate concentrations, a greater proportion of folates will enter circulation in the unreduced form (Selhub et al., 1973). Natsuhori et al. (1991) determined that THF and 5-MF are the principal folate metabolites in pig plasma. Furthermore, these metabolites are considered to be the primary bioactive forms for single-carbon transfer reactions involving folate (Stokstad and Koch, 1967).

One potential explanation for reduced folate sources having a greater effect at weaning than MG may be the fact the samples were collected on the day of weaning from lactating sows fed ad libitum, whereas at other times sows were limit fed 1.8 kg daily. Throughout lactation, the average daily feed consumption of sows was 5.45, 5.30, 5.26, and 5.01 kg for the control sows and those fed diets supplemented MG, THFA, and Aj-PG, respectively, with no differences among treatments (P > 0.30). It is possible that intestinal reduction of folates is more efficient under limit-feeding conditions, but this point cannot be determined from these data. Using mature, nonpregnant miniature pigs, Mizuno et al. (1997) have presented data indicating that oral supplements of THFA and a bacterial cell powder rich in reduced folates were more effective than pteroylmonoglutamate (oxidized) folate in elevating plasma THF. Furthermore, it has been demonstrated in rats that intestinal absorption of 5-MF is inhibited by the pteroylmonoglutamate form of the vitamin (Kudo et al., 1995). This negative relationship could have an impact on intestinal absorption of reduced folates from dietary sources, as well as reduced folates excreted into the intestine in bile fluid. Recirculation of folates from bile fluid as a component of the "folate enterohepatic cycle" is important to maintenance of folate homeostasis in the animal (Steinberg et al., 1979). This negative relationship between supplementation of oxidized forms of folate and intestinal absorption of reduced folates also seems to exist in pigs (Kokue et al., 1998). Although the relationship and circumstances are not fully clear, the form of folate supplemented seems to influence concentration of reduced plasma folates in swine.

Reproductive Performance and Conceptus Development in Parity Two
Sow and unborn litter data at d 45 of gestation in the second parity are summarized in Table 5. Mean days to estrus and sow weight at breeding and at slaughter on d 45 were similar and not different across dietary treatments (P > 0.50). Ovulation rate, as estimated by the mean number of corpora lutea on the ovaries, was 16.06 for the control sows and 17.58, 16.80, and 18.08 for sows fed the MG, THFA, and Aj-PG supplemented diets, respectively. Mean live litter size present at d 45 ± 1 was 10.06 for the control sows and 12.23, 10.87, and 11.07 for sows fed the MG, THFA, and Aj-PG supplemented diets, respectively. Although ovulation rate and live litter size tended to favor sows fed supplemental folate relative to the controls (P < 0.15; contrast test of all folate sources combined vs control), the differences were not significant. The number of dead fetuses present at d 45 was also similar across dietary treatments (Table 5). Furthermore, the concentration of steroid hormones (progesterone and total estrones) in amniotic and allantoic fluids of the developing litters was not affected by dietary treatment (data not shown).

However, in studies using gilts and 0.2 ppm of dietary folate supplementation (Easter et al., 1983) or gilts and sows on a 3,200-sow commercial farm and dietary supplementation of 1 ppm (Gannon, 1991), no significant effects of dietary folate supplementation on litter size were observed. Furthermore, in a multiparity study involving 993 litters, continuous supplementation of corn–soy diets with 1, 2, or 4 ppm of folic acid had no effect on litter size at birth or weaning (Harper et al., 1994).

In general, average fetal and placental length and weight measures were not different across dietary treatments (Table 5). One exception was fetal and placental dry weight for sows fed THFA- and Aj-PG-supplemented diets. Mean fetal pig dry weight was slightly greater (P < 0.05) in sows fed supplemental THFA as the folacin source compared with sows fed Aj-PG as the folate source (2.11 vs 1.94 g). Likewise, mean placental dry weight for sows fed THFA-supplemented diets was greater (P < 0.05) than for those fed Aj-PG supplemented diets. (4.94 vs 4.12 g). No explanation for these differences in the two reduced folate dietary supplements is apparent. Fetal and placental dry weights for sows fed the control and MG-supplemented diets were intermediate and not different from the THFA- or Aj-PG-supplemented treatments. Furthermore, there was no effect of folate supplementation on placental protein or DNA concentrations, average allantoic and amniotic fluid volume, or intact uterine length and uterine weight measures (Table 5).

There is evidence that dietary folate supplementation can influence growth and development of embryonic or fetal pigs. Tremblay et al. (1989) reported increased protein concentration in fetal pigs assessed after d 30 of gestation in sows supplemented with 5 ppm of folic acid, but there was no difference in fetal DNA or RNA concentration. Data have also been presented indicating greater fetal wet and dry mass and greater fetal protein content after d 42 of gestation in sows fed 2 ppm of supplemental folate (Harper et al., 1996) and greater embryonic protein content at d 12 in sows fed diets supplemented with 15 ppm of folate (Matte et al., 1996). However, Guay et al. (2002) reported no effect of dietary supplementation with 15 ppm folate on fetal pig weight, embryo survival, or litter size at d 25 of gestation in multiparous and nulliparous sows.

Lindemann (1993) reviewed sow reproduction studies reported between 1972 and 1990 involving injections of folic acid and dietary supplementation and concluded that, although responses were not significant in all cases, the preponderance of the data indicated that dietary folate supplementation was warranted. Nevertheless, reasons for inconsistent litter size responses to folate supplementation are not clear. Presence of folate in the diet is essential for normal reproduction and embryonic development in litter-bearing species such as rats (Tagbo and Hill, 1977) and guinea pigs (Habibzadeh et al., 1986). As an essential cofactor in nucleic acid synthesis and the metabolism of methionine and homocysteine (Herbert and Das, 1976), the vitamin plays an important role in the rapid cellular development of the products of conception. Human and laboratory animal studies reviewed bv Rosenquist and Finnel (2001) suggest that folate insufficiency during early pregnancy can affect developing embryos directly through limits of folate for proliferation of embryonic cells or by reduced conversion of homocysteine to methionine. Indeed, serum folates decrease during early to mid-gestation in sows (Matte et al., 1984a; Harper et al., 1994), suggesting greater metabolic demand for the vitamin during this time. It is also possible that folate homeostasis from mating through early pregnancy could be maintained in the sow and developing litter by the presence of folate body stores, potential absorption of microbial folates in the hindgut (Blair and Newsome, 1987), and because folates are found naturally in corn, soybean meal, or other feed ingredients. Using NRC (1998) estimates for folate content of corn grain (0.15 ppm) and dehulled soybean meal (1.37 ppm), it was predicted that that the control breeding–gestation diet used in this experiment would contain a total folate level of approximately 0.33 ppm, and the lactation diet approximately 0.46 ppm. However, microbiological assay indicated a total folate concentration of 0.62 ppm in the breeding–gestation diet, and 1.20 ppm in the lactation diet, much of which existed in the form of THFA (Table 1). These concentrations are still below the current folate requirement for sows indicated by NRC (1998) , which was increased from 0.3 ppm (NRC (1988) ) to the current recommendation of 1.30 ppm of the diet.

In summary, supplementation of sow diets with reduced or oxidized forms of folate at 2.1 ppm increased plasma concentration of reduced folates in sows and nursing piglets. Only at weaning were the reduced sources of supplemental folate (THFA and Aj-PG) measurably more effective in elevating sow plasma reduced folates than the oxidized (MG) source. The biological significance and relationship of oxidized and reduced supplemental folate sources and circulating folates is not clear. Although sows fed diets supplemented with folate showed a tendency for larger litter size at d 45 of gestation, these results are further evidence that the requirement for additional folate in corn–soy sow diets is small, and a response in sow reproductive performance will not be observed in all cases. There was no evidence that reduced folate sources were superior to the oxidized pteroylmonoglutamate form as folate supplements for sows.

	Implications

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Previous studies have demonstrated improved reproductive performance in sows with dietary supplements of folic acid. However, using diets based on corn and soybean meal an improved reproductive performance response to supplemental folate will not be realized in all circumstances.

	Footnotes

 
¹ This work is supported in part as a component of Project VA-135586, Virginia Agric. Exp. Stn., with the USDA cooperating. Additional financial support of the Ajinomoto Co. Inc., Tokyo, Japan, is gratefully acknowledged. The laboratory and technical assistance of C. Babb, L. Byrd-Masters, L. Johnson, T. Lee, P. Taylor, T. Vaughan, and the editorial advice of M. Estienne is gratefully acknowledged.

Received for publication April 9, 2002. Accepted for publication October 21, 2002.

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