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Exogenous prolactin stimulates mammary development and alters expression of prolactin-related genes in prepubertal gilts^1,2

Agriculture and Agri-Food Canada, Dairy and Swine Research and Development Centre, Lennoxville, Quebec J1M 1Z3, Canada

	Abstract

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The goal of this project was to determine whether recombinant porcine (rp) prolactin (PRL) can enhance mammary development when given to pre-pubertal gilts and/or modify the expression of PRL-related genes. Crossbred gilts were injected s.c. twice daily with saline (CTRL; n = 13), 2 mg of rpPRL (4PRL; n = 13), or 4 mg of rpPRL (8PRL; n = 13) in a 2.0-mL volume for a period of 29 d, starting at 75.1 ± 0.5 kg BW. Jugular blood samples were collected before the first injection, as well as 14 and 28 d later, and were assayed for PRL, IGF-I, and leptin. Gilts were slaughtered on d 29 of treatment, and mammary glands were collected for dissection of parenchymal and extraparenchymal tissues, and for determination of parenchymal DNA, DM, protein, and fat contents. Levels of mRNA for PRL, PRL receptor (PRL-R), and signal transducers and activators of transcription (STAT5A and STAT5B) were determined via real-time PCR in the mammary parenchyma, as well as levels for PRL and PRL-R in the pituitaries. Treatments did not alter plasma (P = 0.48) IGF-I. Serum concentrations of PRL at slaughter were greater (P < 0.01) in both 4PRL and 8PRL compared with CTRL, whereas at mid-treatment, they were greater (P < 0.05) only in 8PRL gilts. Parenchymal tissue weight and parenchymal DNA concentrations increased with exogenous rpPRL (P < 0.001). The percentage of protein in parenchyma increased (P < 0.001), whereas that of DM (P < 0.001), fat (P < 0.001), and the protein:DNA ratio (P < 0.05) decreased with exogenous rpPRL. Treatment differences were always observed between the 4 mg dose and CTRL, and no further differences were noted when the dose was increased to 8 mg daily. Expression levels of PRL, but not PRL-R, were decreased (P < 0.05) in anterior pituitary glands and mammary glands of treated gilts. The mRNA levels of STAT5A and STAT5B increased (P < 0.05) with exogenous rpPRL. It is evident from these data that rpPRL can stimulate mammogenesis in prepubertal gilts through hyperplasia and increased expression of PRL-related genes.

Key Words: Gilt • Mammary Development • Mammary Glands • Prepuberty • Prolactin • Swine

	Introduction

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Prolactin (PRL) is one of the most versatile hormones of the anterior pituitary gland in terms of biological actions. It is a known lactogenic hormone in various species (Tucker, 1985) and also regulates the development of the mammary gland at three physiological stages (i.e., during organogenesis, during pregnancy, and after parturition; Horseman, 1999). Indeed, PRL was shown to affect mammary morphogenesis via ductal development and terminal end bud regression in virgin mice (Brisken et al., 1999). In swine, there are two phases of rapid accretion of mammary cells: namely, from 90 d of age until puberty and during the last third of gestation (Sorensen et al., 2002). The essential role of PRL for mammary development in gestation was demonstrated through inhibition studies (Farmer et al., 2000; Farmer and Petitclerc, 2003). Furthermore, McLaughlin et al. (1997) noticed a stimulatory effect of exogenous recombinant porcine PRL (rpPRL) on mammary development of gilts when injected for a 28-d period, starting at 75 kg BW. However, this was demonstrated on a small number of animals and mammary gland composition was not determined. Biological actions of PRL at the level of the mammary gland are likely exerted via activation of the janus kinase/signal transducers and activators of transcription (STAT) pathway, whereby binding of PRL to its receptor activates STAT-5 proteins (Rui et al., 1994), which, once phosphorylated, bind to target gene promoters (Liu et al., 1995), but this was never demonstrated in swine. The current project was therefore undertaken to establish whether exogenous rpPRL can stimulate mammogenesis in prepubertal gilts and if so, whether this effect could be via differential expression of PRL-related genes.

	Materials and Methods

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Animals and Treatments
Thirty-nine crossbred (F₂) prepubertal gilts from a cross between Large White x Landrace sows and HC2000 boars (containing 50% Large White and 50% Hamline genetics) were fed a commercial diet (14.0% CP, 3,250 kcal/kg DE, and 0.53% lysine; as-fed basis) throughout the trial. At 75 ± 2 kg BW (141 ± 5.1 d of age), gilts were equally divided among three treatment groups: 1) two daily s.c. injections of sterile water (CTRL, 2 mL each); 2) two daily s.c. injections of 2 mg of rpPRL (4PRL) diluted in 2 mL of sterile water; and 3) two daily s.c. injections of 4 mg of rpPRL (8PRL) diluted in 2 mL of sterile water. The rpPRL was provided by Monsanto (St. Louis, MO), and injections were given at 0800 and 1600 for 29 consecutive days. Animals were slaughtered on the morning of the last day of injections. They were fed ad libitum with fresh feed given once daily at 1000, and individual feed consumption was recorded daily starting at the onset of treatments. Gilts were weighed, and their backfat thickness was measured ultrasonically at the last rib and at the ileum (Ultra-scan 50, Alliance Médicale Inc., St-Laurent, Canada) the day before the onset of treatments and the day before slaughter. Gilts were housed in groups of four to five until reaching 75.1 ± 0.5 kg BW, at which time they were transferred to individual stalls (0.6 m x 2.1 m) the day before the onset of treatments. The experiment took place between November and March. Animals were cared for according to a recommended code of practice (AAFC, 1993).

Jugular blood samples were obtained at 0730 on the first day of treatment, before giving the first injection, on d 14 of treatment, and on the day of slaughter to determine concentrations of PRL and IGF-I. Concentrations of leptin were also determined on blood samples taken at slaughter. Samples collected for PRL assays were left at room temperature for 4 h, stored overnight at 4°C, centrifuged for 12 min at 2,000 x g the following day, and serum was then harvested. Samples for IGF-I and leptin measurements were put on ice, centrifuged (12 min at 2,000 x g) within 20 min and plasma was immediately pipetted. Tubes for IGF-I and leptin assays were EDTA-coated and serum and plasma samples were frozen at –20°C until they were assayed.

Bioactivity of rpPRL
The activity of rpPRL was compared with that of recombinant and pituitary-derived bovine PRL, as well as with that of the rpPRL used in the study from McLaughlin et al. (1997), using the Nb2 lymphoma proliferation assay. This bioassay was performed as described by Gertler et al. (1985), with the exception that assays were carried out in 96-well culture plates (Falcon, Becton Dickinson Labware, Lincoln Park, NJ) with flat-bottom wells. Cells were seeded at an initial density of 50,000 cells per well, and the assay was terminated after a 72-h incubation. Cell number was estimated by a dye binding assay kit (CellTiter, Promega, Madison, WI) that was carried out according to manufacturer’s recommendations. The absorbance of each well (492 nm) was measured with a plate reader (Bio-Tek Instruments, Winooski, VT) after a 3-h incubation with the dye-binding reagent.

Anterior Pituitary and Mammary Glands Collection
The pituitary glands were removed within 5 min of death. The anterior lobe was dissected from the posterior lobe and placed in liquid N and then stored at –80°C until determination of endogenous PRL and PRL receptor (PRL-R) mRNA levels by real-time PCR. The mammary glands were excised from the abdominal wall and stored at –20°C until dissection and analyses for tissue composition. Parenchymal tissue samples were also collected, frozen immediately in liquid N, and stored at –80°C. The mammary parenchyma was collected right under the teats and tissue from at least five teats was pooled to ensure that samples were representative. Levels of PRL, PRL-R, STAT5A, and STAT5B mRNA were measured. Frozen whole mammary glands were sawed into 2-cm slices and trimmed of skin and teats according to the procedure of Petitclerc et al. (1984). All glands were homogenized and a representative sample was used for determination of composition by biochemical analysis. Mammary parenchymal tissue from each slice was dissected from surrounding adipose (i.e., extraparenchymal tissue) at 4°C, and both parenchymal and extraparenchymal tissue weights were recorded. Mammary parenchyma was defined as containing duct and alveolar tissue; however, it also contained a large amount of adipose tissue to ensure that all duct and alveolar tissues were collected. The DNA content of parenchymal tissue was evaluated using a method based on fluorescence (Labarca and Paigen, 1980). Protein, lipid, and DM contents were also measured (AOAC, 1998). Extraparenchymal tissue composition was not determined because it is largely comprised of fat, and it does not contain the milk secretory cells. Ovaries were collected at slaughter to verify whether the gilts had achieved cyclicity; only prepubertal gilts were used in the study.

RNA Isolation and Reverse Transcription
Total RNA was extracted from parenchymal tissue and from anterior pituitary glands. Briefly, 200 mg of tissue was extracted with 2 mL of Trizol reagent (Gibco-BRL, Bethesda, MD) according to the manufacturer’s instructions. The extracted RNA was dissolved in 50 µL of water and quantified spectrophotometrically at 260 nm. An RNA aliquot was electrophoresed in a 1% agarose gel to verify its integrity. For all samples, 5 µg of total RNA was treated with 3 U of DNAse I (Amplification grade No. 8068-015; Gibco-BRL) to remove contaminating genomic DNA. First-strand cDNA was synthesized from 5 µg of total RNA using a SuperScript II pre-amplification system for first-strand cDNA synthesis (Gibco BRL) and 500 ng of oligo(dT)12-18 primer in a total reaction volume of 50 µL.

Real-Time PCR Amplifications of Studied Genes
The mRNA levels of PRL, PRL-R, STAT5A, and STAT5B were measured using real-time PCR amplifications. Primers were designed with the Primer Express software (PE Applied Biosystems, Foster City, CA) and are listed in Table 1. Real-time PCR amplifications were performed in a 25-µL reaction volume containing 5 µL of 5x-diluted cDNA, 0.25 µL of AmpErase (PE Applied Biosystems), 1x final concentration of SYBR Green Master MIX (PE Applied Biosystems), and the corresponding concentration of each primer (Table 1). Cycling conditions were 2 min at 50°C followed by 10 min at 95°C, and by 40 cycles at 95°C for 15 s and 60°C for 60 s. Amplification, detection, and data analysis were performed with an ABI 7700 prism sequence detector (PE Applied Biosystems). Samples were normalized using the housekeeping genes, cyclophilin, and glyceraldehyde-3-phosphate dehydrogenase (Table 1), and PCR amplifications were performed in triplicate. The mRNA levels data for glyceraldehyde-3-phosphate dehydrogenase and cyclophilin genes showed no significant variations compared across treatment groups. Standard curves were prepared in duplicate for all studied and housekeeping genes. For each experimental sample, mRNA levels of each studied gene and of housekeeping genes were determined by interpolating the threshold cycle values to their respective standard curves. Amplification specificity was checked by running amplification products on 3% agarose gel and with the melting curve analysis of these products (Dissociation Curves software, PE Applied Biosystems).

Statistical Analyses
The Mixed procedure of SAS (SAS Inst., Inc., Cary, NC) was used for statistical analyses. The univariate model used for mammary gland and leptin data included the effect of treatments with the residual error being the error term used to test main effects of treatment. Repeated measures ANOVA with the factors treatment (the error term being gilt within treatment) and day of age (the residual error being the error term), as well as the treatment x day of age interaction, were conducted on backfat thickness, BW, ADFI, IGF-I, and PRL data. Multiple mean comparisons between treatments were performed with Tukey’s test. Data were corrected with a logarithmic transformation (using natural logarithms) when variances were not homogeneous. All real-time mRNA data were analyzed according to the relative standard curve method (PE Applied Biosystems, 1997). Data in tables and figures are presented as least squares means ± pooled SEM (or ± confidence intervals when a transformation was needed).

	Results

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Performance and Hormonal Data
Weight and backfat thickness of gilts are presented in Table 2. There was a tendency (P = 0.08) for a treatment x day interaction on weight, and weight gain tended (P = 0.07) to be less in 8PRL than in CTRL or 4PRL gilts. Backfat thickness was not altered by treatments (P = 0.81) and increased during the 4 wk of the experiment (P < 0.001). The ADFI by gilts was not affected by treatments (P = 0.84) and increased with time (P < 0.001; data not shown). There were no time x treatment interactions on either of these variables (P = 0.79 and 0.41 for backfat thickness and ADFI, respectively). The ADFI (as-fed basis) values over the three treatment groups for wk 1, 2, 3, and 4 of the experiment were 2.57, 2.90, 2.94, and 3.01 ± 0.08 kg/ d, respectively.

View larger version (19K): [in this window] [in a new window]   Figure 1. Levels of mRNA for prolactin (PRL), PRL receptor (PRL-R), and signal transducer and activator of transduction 5A and 5B (STAT5A and STAT5B) in mammary tissue of crossbred gilts injected twice daily with sterile water (CTRL, n = 13), 2 mg of recombinant porcine (rp) PRL (4PRL, n = 13), or 4 mg of rpPRL (8PRL, n = 13) for 29 consecutive days, starting at 75 kg BW. A value of 1 was set as reference standard for CTRL. Bars for a specific gene without common letters differ, P < 0.05.

View larger version (13K): [in this window] [in a new window]   Figure 2. Levels of mRNA for prolactin (PRL) and PRL receptor (PRL-R) in anterior pituitary tissue of crossbred gilts injected twice daily with sterile water (CTRL, n = 13), 2 mg of recombinant porcine (rp) PRL (4PRL, n = 13), or 4 mg of rpPRL (8PRL, n = 13) for 29 consecutive days, starting at 75 kg BW. A value of 1 was set as reference standard for CTRL. Bars for a specific gene without common letters differ, P < 0.05.

	Discussion

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The fact that significant biological effects of PRL were seen without a concurrent increase in mRNA levels of mammary PRL receptors at the 4 mg daily dose is intriguing and could be a false negative result. Conversely, it could also suggest that PRL receptors were not saturated in 4PRL gilts or that PRL may bind to other receptors to then undergo signal transduction. Indeed, significant increases in the expression of STAT5B and STAT5A genes were observed both at the 4 and 8 mg daily doses. These increases were expected because it is known that in other species, the biological actions of PRL at the level of the mammary gland are mediated by activation of the JAK/STAT pathway (Rui et al., 1994; Gallego et al., 2001). In fact, STAT5A enhances proliferation of mammary epithelial cells in pregnant cows (Jeon et al., 2002) and is essential for differentiation and development of the mammary glands in mice. However, the role of STAT5B is less clear (Liu et al., 1997; Watson, 2001). Unlike other mammals, STAT5B expression in mammary parenchyma of pregnant swine is predominant compared with that of STAT5A (Palin et al., 2002). To the best of our knowledge, current findings are the first report of the involvement of STAT5A and STAT5B in mammogenesis of nonpregnant swine.

The decreased levels of PRL mRNA in the anterior pituitary gland of treated gilts indicate the presence of a negative feedback of exogenous rpPRL on PRL synthesis, concurring with known endocrine controls (Grattan et al., 2001). Present results demonstrate that such a negative control also occurred at the level of the mammary gland, which agrees with the finding that mammary-derived PRL acts via autocrine/paracrine mechanisms to affect mammogenesis (Naylor et al., 2003). In mice, the feedback regulation of PRL secretion was recently shown to be mediated by STAT5B (Grattan et al., 2001), which concurs with present findings. However, current data further suggest that STAT5A might be equally involved in this negative feedback of PRL synthesis in swine. Whether species differences may be present is unknown.

Prolactin receptors are widely expressed in the brain of mammals (Bole-Feysot et al., 1998), and during states of hyperprolactinemia, such as pregnancy and lactation, increases in PRL-R mRNA levels were observed (Sugiyama et al., 1994). Current findings suggest that this is not the case at the level of the anterior pituitary gland when supraphysiological levels of PRL are induced via injections; however, there was an increase in mammary mRNA levels for PRL receptors in 8PRL gilts. Conversely, Schuff et al. (2002) suggested a downregulation or desensitization of pituitary PRL receptors in response to chronic hyperprolactinemia in mice. However, this was seen in knockout mice exhibiting increased PRL concentrations throughout their entire development and not during a specific period. Discrepancies between these and present findings are therefore likely due to duration of hyperprolactinemia. The involvement of PRL receptors in mammary development was demonstrated in virgin transgenic mice, whereby the magnitude of ducts and lobuloalveolar development was stimulated by the expression of an active mutant form of the PRL-R (Gourdou et al., 2004). Once more, the duration of increased sensitivity to PRL seemed to be crucial because milk yield was decreased in these animals, likely due to premature development of mammary glands (Gourdou et al., 2004). When PRL activity was inhibited, such as in knockout mice lacking the PRL-R, abnormal mammary development was observed after puberty (Brisken et al., 1999). It therefore seems that inhibition of PRL action in virgin animals has a negative effect on mammogenesis, but that increasing PRL concentrations and/or sensitivity is not beneficial if it occurs over too long a period of time. It would therefore be important to follow the present findings with a study aimed at determining the effect of exogenous PRL in prepubertal gilts on their future lactation performance.

	Implications

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Stimulation of mammogenesis in gilts could be an interesting tool to increase lactation performance. Present findings demonstrated that injections of recombinant porcine prolactin for only 28 d in prepubertal gilts enhanced mammary development via an increase in the number of mammary cells. Effects of exogenous prolactin were most likely a result of differential expression of prolactin-related genes. Present results are encouraging, but a study must be undertaken to determine the effect of such a treatment on future lactation performance of sows before making recommendations to producers.

	Footnotes

 
¹ Lennoxville Dairy and Swine R & D Centre Contribution No. 846.

² The authors thank L. Thibault, L. Marier, S. Horth, K. Fisette, and D. Beaudry for their invaluable technical assistance, the staff of the Swine Complex, especially J. Boudreau and M. Turcotte, for care of the animals, and S. Méthot for statistical analyses.

³ Correspondence—phone: 819-565-9174, ext. 222; fax: 819-564-5507; e-mail: farmerc{at}agr.gc.ca.

Received for publication November 9, 2004. Accepted for publication December 23, 2004.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Farmer, C. Articles by Palin, M.-F. Search for Related Content PubMed PubMed Citation Articles by Farmer, C. Articles by Palin, M.-F.