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Hepatic corticosteroid-binding globulin (CBG) messenger RNA expression and plasma CBG concentrations in young pigs in response to heat and social stress^1,2

J. Heo^*,3, H. G. Kattesh^*,4, M. P. Roberts^*, J. L. Morrow, J. W. Dailey and A. M. Saxton^*

^* Department of Animal Science, University of Tennessee, Knoxville 37996; and and ARS, USDA, Livestock Issues Research Unit, Texas Tech University, Lubbock 79409

	Abstract

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Plasma cortisol, porcine corticosteroid-binding globulin (pCBG), hepatic CBG expression, and other physiological and behavioral measures of stress were studied in pigs in response to elevated temperature in conjunction with establishing a social hierarchy. Twenty-four crossbred pigs were weaned at 25 d of age (three or six pigs from six sows) and housed in littermate groups at 23 ± 2°C. At 57 d of age (d 0), animals were weighed and placed under general anesthesia for collection of blood (10 mL) and liver (approximately 100 mg) samples. On d 1, three unacquainted pigs of similar BW (23 ± 1 kg) from different litters were allotted to each of eight nursery pens within two environmentally controlled rooms (12 pigs per room). From d 1 to 7, one room was maintained at 23 ± 2°C (CON) and the other at 33 ± 2°C (HEAT). Both rooms were kept at 23 ± 2°C from d 8 to 14. Animals were videotaped for 72 h beginning on d 1 and 8 to document behavioral changes in response to room temperature. The social hierarchy of pigs within each pen was based on fight activity recorded on d 1 to 3. Blood and liver tissue were collected again on d 7 and 14. The ADG for HEAT pigs increased (P < 0.05) over d 8 to 14 compared with d 1 to 7. In contrast to CON pigs, HEAT pigs displayed increased (P < 0.01) drinking but decreased feeding and lying in contact with other pigs from d 1 to 3, and similar drinking and feeding but increased (P < 0.01) lying with contact behaviors from d 8 to 10. With the exception of subordinate pigs exhibiting less (P < 0.05) frequent standing/walking behavior than the dominant or intermediate pigs on d 1 to 3, frequency of behaviors for both recorded time periods did not differ among pigs due to social status, regardless of treatment. The concentration of plasma haptoglobin in HEAT pigs on d 7 compared with d 0 increased (467 vs. 763 mg/L; P < 0.05), whereas cortisol and pCBG decreased (274 vs. 235 nmol/L and 11.4 vs. 9.9 mg/L, respectively; P < 0.05) as a result of treatment. The free cortisol index (total cortisol/pCBG) was greater (P < 0.05) in HEAT pigs on d 14 than on d 0 or 7. Hepatic CBG mRNA level was not affected by treatment. On d 14, HEAT pigs had plasma cortisol, pCBG, and haptoglobin concentrations similar to those of CON pigs. These results indicate that measured behavioral and physiological responses were not related to social status, and decreased circulating levels of cortisol and pCBG in pigs following a 7-d exposure to elevated temperature may not be determined by hepatic CBG mRNA expression.

Key Words: Behavior • Corticosteroid-binding Globulin • Cortisol • Heat Stress • Pig • Social Stress

	Introduction

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Swine are exposed to various stressful conditions including heat and humidity (Marple et al., 1972; Morrow-Tesch et al., 1994), feed and water deprivation (Parrott and Misson, 1989), social pressure (Mormede et al., 1990; Hicks et al., 1998), and mixing (Dalin et al., 1993; Ekkel et al., 1997). A stress response in an animal exhibits itself in both significant behavioral and physiological changes (Nagaraja and Jeganathan, 1999).

Social stress has significant effects on plasma cortisol, globulin, and acute-phase protein levels, as well as BW (Hicks et al., 1998). The exposure of pigs to elevated temperatures and humidity elicits significant changes in behavior, food intake, BW, endocrine, and immune status (Marple et al., 1972; Kelley, 1980; McGlone et al., 1987; Hicks et al., 1998; Matteri et al., 2000). It has been suggested that heat and social stress may interact in their effects on pigs (McGlone et al., 1987; Morrow-Tesch et al., 1994). Furthermore, behavioral and hormonal responses to stressors do not occur independently but are mutually related (Dantzer and Mormede, 1983).

Corticosteroid-binding globulin (CBG) is a circulating glycoprotein produced mainly by the liver that regulates plasma cortisol concentrations and its bioavailability (Schroeder and Henning, 1989; Rosner, 1990). Plasma CBG is determined by its biosynthesis, degradation, and/or transfer to extravascular spaces, and may be influenced by age, physiological conditions, or stressful situations (Heyns and Coolens, 1988; Heo et al., 2003b; Roberts et al., 2003). It is unclear as to how plasma CBG level is regulated during stressful situations and how changes in CBG affect cortisol levels within the circulation.

The objective of this study was to examine the relationships among plasma cortisol and porcine CBG (pCBG) levels, and hepatic CBG mRNA expression in pigs subjected to elevated environmental temperature in conjunction with establishing social hierarchy.

	Materials and Methods

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Animals
Twenty-four crossbred pigs (Landrace, Duroc, and Hampshire) were weaned at 25 d of age from six sows (three or six pigs per sow) and placed in raised nursery pens (1.22 m x 1.22 m) within littermate group (three pigs per pen) in two thermoneutral rooms (23 ± 2°C). All pigs were given ad libitum access to a commercial diet (3,315 kcal/kg of ME, 18% CP, 1.15% lysine; as-fed basis) and water. Pigs were maintained with constant light throughout the entire experimental period to facilitate behavioral data collection. Length of photoperiod has no effect on growth or development of pigs at this age (McGlone et al., 1988).

Experimental Design and Housing
At 57 d of age (d 0), all animals were weighed, and the first blood and liver tissue samples were collected as described below. On d 1, three unacquainted pigs of similar BW (23 ± 1 kg) from different litters were allotted to each of eight nursery pens within two environmentally controlled rooms (12 pigs per room). From d 1 to 7, one room was maintained at 23 ± 2°C (CON) and the other at 33 ± 2°C (HEAT). From d 8 to 14, both rooms were maintained at 23 ± 2°C. Body weight was recorded and additional blood and liver tissue samples were collected from each pig on d 7 and 14.

Behavioral Data Collection
All pigs were videotaped for a 72-h period beginning on d 1 and 8 to determine dominance hierarchy and to document behavioral changes. Pigs were individually marked with farm animal crayon markers (All Weather Paintstik; La-Co Industries, Elk Grove Village, IL). Video cameras (model WVCP412, Panasonic, Osaka, Japan) hung from the ceiling allowed for filming of the four pens with one camera. Behaviors were recorded continuously over the 72-h period (recording interval of 0.6 s per field) and subsequently viewed at real-time speed using a time-lapse recorder (Panasonic AG-6740P). When pigs were observed fighting, the videotape was slowed to record the duration of each fight. Length of fight, pigs involved, and winner were recorded for each observed fight. Pigs that pursued a second pig or caused the second pig to turn away from it were determined as the winner. Pigs were assigned to a rank using a dominance matrix, where the number of fights between each pair of pigs in a pen was listed along with the winner (McGlone, 1985). The dominance hierarchy was divided into three ranks: dominant (DOM), intermediate (INT), and subordinate (SUB). Because each pen had three animals, only one animal was assigned each social rank. For measurement of behavioral responses, each animal was viewed in one frame of videotape every 15 min to observe the frequency of the following behaviors: standing/walking, drinking, feeding, lying with contact, and lying without contact. The 15-min interval was based on the results of an unpublished study comparing continuous vs. 15-min scan data for group-housed weanling pigs. No differences were found between these two methods for the measurement of behaviors used in the present ethogram (J. W. Dailey, personal communication). A pig was considered to be standing/walking when it was up on all four feet and either standing or walking; drinking when its mouth/snout was touching the waterer; feeding when its head was in the feeder; lying with contact when it was lying down or sitting in physical contact with another animal; and lying without contact when it was lying down or sitting without physical contact with another animal.

Tissue Collection and Analysis
On d 0, 7, and 14, each pig was removed from its pen, weighed, and preanesthetized by i.m. injection of a solution of 30 parts ketamine (100 mg/mL) and one part acepromazine (10 mg/mL) at a dose of 0.2 mL/kg BW. The animal was placed under general anesthesia using closed-circuit halothane administration by a gas inhalation machine, and a single blood sample (10 mL) was immediately collected from the anesthetized pig via puncture of the external jugular vein and placed in evacuated glass tubes containing EDTA. Following centrifugation at 2,000 x g for 10 min, plasma was recovered and stored at –20°C until analyzed for total cortisol, haptoglobin, and pCBG concentrations.

For the collection of liver tissue, percutaneous ultrasound-guided liver biopsies were performed on each pig while under general anesthesia (Martino et al., 1984; Plecha et al., 1997). One-handed PGI EZ biopsy needles (14-gauge; Product Group Int., Lyons, CO) were used for all biopsies. Briefly, the animal was placed in dorsal recumbency, and a 10-cm² area caudal to the xiphoid cartilage was shaved and cleaned with 70% isopropanol. A small incision was made and the biopsy needle was guided into the liver under visualization using ultrasound (Aloka 900; Corometrics Medical Systems, Wallingford, CT) equipped with a 7.5-MHz convex transducer. Two or three biopsies, providing 30 to 50 mg of tissue per biopsy, were performed on each animal. The procedure was completed within 10 min after the onset of general anesthesia. The samples were quickly homogenized in 3 mL of Tri-Reagent (Sigma, St. Louis, MO) in order to isolate the total RNA. The animals were allowed to recover and then returned to their original pens.

Cortisol.
Plasma total cortisol concentration was determined by RIA as previously reported in our laboratory (Scroggs et al., 2002). Intra- and interassay CV was 3.6 and 9.1%, respectively.

Corticosteroid-Binding Globulin.
The concentration of porcine corticosteroid-binding globulin (pCBG) in plasma was measured by a direct ELISA as previously described (Roberts et al., 2003). Intra- and interassay CV was 11.7 and 13.4%, respectively.

Free Cortisol Index.
A surrogate measure of plasma free cortisol, the free cortisol index (FCI), was calculated using the ratio of plasma total cortisol to pCBG concentrations (le Roux et al., 2002).

Haptoglobin.
Plasma haptoglobin concentration was determined by a single radial immunodiffusion as previously described (Scroggs et al., 2002). Results were evaluated using a logarithmic regression equation (Y = –695.4 + 167.8lnX; r² = 0.98) to determine plasma concentration of haptoglobin in each sample using known standards. Intraassay CV of duplicate estimates was 4.8%.

Hepatic CBG mRNA.
The integrity of total RNA was determined by electrophoresis in a 1.3% agarose gel containing formaldehyde with ethidium bromide. The expression level of hepatic CBG mRNA was determined by slot blot (Sambrook et al., 1989) using a ³²P-labeled pCBG cDNA probe as described previously (Heo et al., 2003a). The expression level of hepatic CBG mRNA was determined relative to ß-actin mRNA level.

Statistical Analyses
The study was analyzed as a completely randomized, split-split plot design with repeated measures using the Mixed procedure of SAS (SAS Inst., Inc., Cary, NC). Fixed effects were treatment, social status, and treatment x social status interaction. Sex effects were examined as a possible source of variation, but were deleted in all cases due to non-significance. Variance among pens was used as the error term to test treatment (whole plot), whereas pig variation was used to test social status (sub-plot). Additional repeated measures (sub-sub-plot) factors of period and interactions of period with treatment and social status were included in the analysis. Residual error was used to test all sub-sub-plot effects. Behavioral data were log-transformed to normalize the data for statistical analysis. Data are presented as least squares means with standard errors, separated using Fisher’s least significant difference test.

	Results

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Pig Performace
There was no difference in BW between CON and HEAT pigs measured on d 7 or 14 (Tables 1 and 2). The ADG for HEAT pigs increased (P < 0.05) from 0.64 kg/d during d 1 to 7 to 0.84 kg/d during d 8 to 14. The ADG did not differ among CON pigs during the experiment. Neither BW nor ADG was different among DOM, INT, and SUB pigs on each of the days measured (Table 1).

Physiological Measures
In HEAT pigs, plasma haptoglobin concentration increased (P < 0.05) from 467 to 763 mg/L (d 0 vs. 7), which was greater (P < 0.05) than that measured on d 7 for CON pigs (355 mg/L; Table 5). Plasma haptoglobin concentration did not differ in CON pigs over days sampled. Plasma total cortisol concentration in HEAT pigs was lower (P < 0.05) on d 7 than on d 0 or 14 but similar to CON. Plasma pCBG concentration in HEAT pigs also was lower (P < 0.05) on d 7 than on d 0 (9.9 vs. 11.4 mg/L) but similar to d 14 (10.8 mg/L) or that measured in CON. Consequently, the FCI was similar for HEAT and CON pigs. Hepatic CBG mRNA expression from liver samples collected on d 0, 7, and 14 did not differ among pigs regardless of treatment or sampling day. None of the physiological variables measured was affected by social rank (Table 6).

	Discussion

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Although there was no difference in overall BW between CON and HEAT pigs, the ADG by HEAT pigs was significantly lower over the 7-d treatment period compared with that of the recovery period. Morrow-Tesch et al. (1994) found that BW between heat-stressed and nonheat-stressed pigs was not significantly different until 14 d after continuous exposure to 33°C. Decreased BW gains have been attributed to decreased feed intake (McGlone et al., 1987). Decreased feed intake and subsequently lower ADG in pigs subjected to high ambient temperatures is associated with a reduction in both the size and time spent consuming meals (Collin et al., 2001c). This, in addition to becoming more energy efficient and less active, results in decreased heat production by the animals (Collin et al., 2001b). During the first 3 d exposure to 33°C, our pigs similarly demonstrated decreased frequency of feeding as well as time spent in contact with other animals. This last activity may be a further attempt by the hyperthermic animal to maximize skin surface area, which along with an increase in blood flow of the skin (Collin et al., 2001a, 2002), may aid in dissipation of surface heat. In contrast to measures taken during heat exposure, HEAT pigs during the recovery period exhibited increased frequency of feeding and lying in contact with pen mates. Hicks et al. (1998) reported that pigs subjected to a 4-h acute cold stress spent more time feeding and huddling with pen mates. We suggest that increased animal contact observed in our study may represent an effort by the animal to decrease heat loss, while acclimating to the lower temperature.

The HEAT pigs were observed spending more time drinking than the CON pigs during their exposure to the elevated temperature. Higher temperatures will result in the animal consuming or at least have more contact with water (Scroggs et al., 2002). The increase in drinking behavior for the control pigs during the second week of the study may be a reflection of the animals adapting to the pen and drinker or simply an increase in water requirement of the pigs related to size.

Body weight and ADG did not differ among the pigs due to social status or the interaction between social status and environmental temperature. Morrow-Tesch et al. (1994) reported that the heaviest pig usually becomes the dominant pig, and that the differences in BW between dominant and subordinate pigs increased with increasing age. These researchers also noted, similar to our findings, that thermal treatment had no affect on the duration of aggressive or submissive behavior. It is well documented that social hierarchy is established among pigs through vigorous fighting within the first 24 h of mixing (McGlone, 1985, 1986). This would explain the greater frequency of standing/walking noted in our pigs during the first 3 d of the study, particularly for the DOM and INT animals in their quest to determine dominance. The SUB pigs, possibly in an attempt to avoid further confrontation with their pen mates, spent less time standing/walking and numerically more time lying without animal contact. Otten et al. (2002) noted that dominant pigs that lose most of their encounters during a 10-h social confrontation test with another dominant pig spend more time lying and less time moving or exploring the pen or other animals.

Haptoglobin is an acute-phase protein produced by the liver in response to injury, inflammation, or infection and has been proposed as an important marker for the health status of swine (Chen et al., 2003). We were concerned as to what effect tissue trauma associated with repeated biopsy of the liver would have on the pig’s well-being. Except for an increase in haptoglobin concentration for HEAT pigs on d 7 compared with d 0 or CON pigs on d 7, levels remained similar among the animals, suggesting that tissue trauma following the surgery was negligible. Interestingly, increased haptoglobin levels have been associated with decreased growth rate in pigs (Eurell et al., 1992), and in the present study, ADG was least by pigs immediately following 1 wk exposure to 33°C.

Plasma total cortisol concentrations were found to be abnormally high in all animals in the present study, regardless of time sampled. Anesthesia and restraint have been shown to increase circulating cortisol concentration in the pig (Dalin et al., 1993). Regardless, we still observed lower plasma cortisol levels in the pigs following a 7-d exposure to the high-temperature environment relative to their pre-treatment levels. Gilts exposed to 8-d of high temperature (32°C) exhibited a similar decrease in plasma cortisol, as well as an increase in plasma ACTH (Marple et al., 1972). The authors suggested that this may have resulted from a decrease in adrenal responsiveness to ACTH and/or increased turnover of plasma cortisol. Becker et al. (1985) found that gilts subjected to a 6-h heat stress for three consecutive days had increased plasma cortisol concentrations, but overall plasma cortisol levels decreased from d 1 to 3. It was suggested that the decrease in plasma cortisol concentration over the 3 d might have resulted from a possible alteration in the ability of the liver to metabolize cortisol.

Social status had no effect on plasma cortisol concentration in the present study. Parrott and Misson (1989) found that salivary cortisol levels in pigs significantly increased 3 h after mixing. A similar increase was reported by de Groot et al. (2001) independent of the pig’s social status or gender. Ekkel et al. (1997) reported finding no differences in salivary cortisol levels in young pigs 6 and 41 d after mixing compared with unmixed pigs. In that agonistic behavior associated with establishing social status among a group of pigs generally occurs within 24 h after mixing (McGlone, 1986), we would not have expected to detect changes in cortisol among pigs of differing social rank due to the small and infrequent sampling regime of our study.

Corticosteroid-binding globulin influences the bioavailability as well as metabolic clearance rate of cortisol within the circulation (Bright, 1995). In the present study, we found that plasma pCBG concentration was reduced in the HEAT pigs, but similar to our cortisol findings, returned to initial levels after the 7-d recovery period. Dalin et al. (1993) reported a similar decrease in plasma CBG-binding capacity in pigs 1 d following surgery. In the rat, starvation for 2 d and restriction for 2 h decreased plasma CBG levels, but acute stress by either treatment had no affect (Tinnikov, 1993). Hicks et al. (1998) reported that pCBG concentration was not altered following a 4-h exposure to heat, cold, or shipping stressors. It is evident that the duration and/or type of stressor that the animal encounters have a significant influence on CBG levels within the circulation.

The biological significance for the observed cortisol–CBG relationship reported here and in previous studies may reside in an examination of the unbound or free levels of circulating cortisol. The FCI, a ratio of circulating total cortisol to CBG, has been demonstrated to be a reliable and easy to use measure of plasma free cortisol (le Roux et al., 2002). In a recent study, postoperative patients exhibiting significant differences in total serum cortisol levels were found to have a similar FCI when CBG concentrations were considered (le Roux et al., 2003). Likewise in the present study, the FCI for HEAT pigs measured on d 7 did not differ from that measured on d 0 due to the simultaneous decrease in plasma total cortisol and pCBG concentrations. We proposed that a decrease in CBG synthesis, corresponding to increasing cortisol levels, would effectively increase the clearance rate and thereby lower circulating cortisol concentrations (Behrens et al., 1993). This may serve as a physiological means of adaptation to a stress for the animal. Interpretation of changes in plasma total cortisol levels in studies assessing stress in animals may be improved by taking into account the measure of its binding protein, CBG, and the calculation of FCI.

It has not been demonstrated directly whether stress-related changes in plasma CBG result from changes in CBG production, metabolic degradation, and/or transfer to target tissues. There is indirect evidence regarding the mechanism for the decrease in CBG following stress. Dalin et al. (1993) suggested that the decrease in plasma CBG-binding capacity seen in pigs following surgery may be due to increased cleavage of CBG by neutrophil elastase. Stefanski (2000) found a marked decrease in plasma CBG levels with increased number of granulocyte WBC in subordinate rats after chronic confrontation. However, there was no change in total corticosterone, which led the author to conclude that the reduction in plasma CBG more likely resulted from increased degradation of CBG rather then decreased CBG production. Inhibition of hepatic CBG biosynthesis has been suggested as a possible mechanism for the decrease in CBG following stress (Fleshner et al., 1995; Bernier et al., 1998). Earlier studies found that glucocorticoid administration inhibits the hepatic biosynthesis of CBG in the adult rat (Smith and Hammond, 1992) and fetal sheep (Berdusco et al., 1993). We recently reported that plasma pCBG concentrations in prenatal and early postnatal pigs were positively correlated with expression levels of hepatic CBG mRNA unrelated to plasma total cortisol concentrations (Heo et al., 2003b). In the present study, hepatic CBG mRNA expression was not different among the pigs, although both plasma cortisol and pCBG concentrations decreased in the HEAT pigs. Therefore, we conclude that the decrease in plasma pCBG levels after 7-d exposure to 33°C is more likely the result of other factors such as increased metabolism and/or transfer to extravascular spaces rather than a decrease in CBG biosynthesis by the liver.

Social status did not affect plasma pCBG levels or hepatic CBG expression levels in pigs in this study. Pigs exposed to stressors including cold, heat, or shipping after the establishment of social status, showed no difference in plasma pCBG levels among DOM, INT, and SUB pigs (Hicks et al., 1998). In the rat, chronic social stress resulted in reduced plasma CBG levels in both DOM and SUB animals (Spencer et al., 1996). In horses subjected to social stress situations, CBG binding capacity decreased slightly without a corresponding change in total cortisol concentration (Alexander and Irvine, 1998). In the present study, the lack of differences in plasma cortisol and pCBG among dominant, intermediate or subordinate pigs subjected to elevated temperatures may be related to the interactive effect of heat and social stress as reported by Morrow-Tesch et al. (1994).

In conclusion, growth rate, behavioral, and physiological measures were significantly affected by chronic heat stress but not by social stress in 8-wk-old pigs subjected to 7 d of elevated temperature in conjunction with establishing social hierarchy. Plasma total cortisol and pCBG concentrations were lower on d 7 of the treatment, but returned to pretreatment levels following a 7-d recovery period. The free cortisol index was higher in the treated pigs on d 14 compared with that measured immediately before or following treatment. The observed decrease in plasma pCBG concentration in pigs following mixing and 7-d exposure to elevated temperature does not seem to be a consequence of altered hepatic CBG mRNA expression.

	Footnotes

 
¹ This research is published with the approval of the Dean of the Tennessee Agric. Exp. Stn. and supported by state and Hatch funds allocated to the station.

² Animal use in this study was approved by the Univ. of Tennessee Animal Care and Use Committee.

³ Current address: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

⁴ Correspondence: 2640 Morgan Circle, Room 201B McCord Hall (phone: 865-974-7250; e-mail: hkattesh{at}utk.edu).

Received for publication May 16, 2004. Accepted for publication October 1, 2004.

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