J. Anim. Sci. 2004. 82:2930-2936
© 2004 American Society of Animal Science
ANIMAL GROWTH, PHYSIOLOGY, AND REPRODUCTION |
Chronic administration of recombinant ovine leptin in growing beef heifers: Effects on secretion of LH, metabolic hormones, and timing of puberty1
M. N. Maciel*,
,
,
D. A. Zieba*,,
M. Amstalden*,,
D. H. Keisler
,
J. P. Neves and
G. L. Williams*,,2
* Animal Reproduction Laboratory, Texas A&M University Agricultural Research Station, Beeville 78102;
and
Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil;
and
Department of Animal Science, Center for Animal Biotechnology and Genomics, Texas A&M University, College Station 77843; and
and
Department of Animal Science, University of Missouri, Columbia 65211
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Abstract
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Serum concentrations of leptin increase linearly from approximately 16 wk before until the week of pubertal ovulation in beef heifers. To test the hypothesis that exogenous leptin can hasten the onset of puberty in heifers, we examined the effects of chronic administration of recombinant ovine leptin (oleptin) on timing of puberty, pulsatile and GnRH-mediated release of LH, and plasma concentrations of GH, IGF-I, and insulin. Fourteen fall-born, prepubertal heifers (Brahman x Hereford, 12 to13 mo; 304.7 ± 4.12 kg) were used. Heifers were stratified by age and BW and assigned randomly to one of two groups (seven animals per group): 1) Control; heifers received s.c. injections of saline twice daily (0700 and 1900) for 40 d; and 2) Leptin; heifers received s.c. injections of oleptin (19.2 µg/kg) twice daily at 0700 and 1900 for 40 d. Blood samples were collected at 10-min intervals for 5 h on d 0, 5, 10, 20, 30, and 40, and twice daily, just before each treatment injection, throughout the study. On d 41, heifers received i.v. injections of GnRH at 0 (0.0011 µg/kg) and 90 min (0.22 µg/kg), with additional sampling for 5.5 h to examine releasable pools of LH. Diets promoted a gain of 0.32 ± 0.09 kg/d, which did not differ between groups. Plasma concentrations of leptin increased markedly in leptin-treated heifers and were greater (P < 0.001) than controls throughout (27.8 ± 0.8 vs. 4.9 ± 0.12 ng/mL). None of the heifers reached puberty during the experiment, but did so within 45 d of its termination. Mean concentrations of plasma LH, GH, IGF-I, and insulin were not affected by treatment, nor was there an overall effect on the frequency of LH pulses. However, a treatment x day interaction (P = 0.02) revealed that the frequency of LH pulses (pulses/ 5 h) was greater (P = 0.03) in controls (3.6 ± 0.36) than in leptin-treated heifers (1.7 ± 0.28) on d 10. Characteristics of GnRH-induced release of LH were not affected by treatment. In summary, chronically administered leptin failed to induce puberty or alter endocrine characteristics in beef heifers nearing the time of expected puberty.
Key Words: Heifer • Leptin • Luteinizing Hormone • Metabolic Hormones • Puberty
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Introduction
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Both BW and adipose tissue mass are considered to play critical roles in regulating the onset of puberty (Kennedy and Mitra, 1963
; Frisch et al., 1973). Moreover, the retarded growth caused by chronic diet restriction results in delayed puberty in rodents (Cheung et al., 1997), sheep (Foster and Olster, 1985), and cattle (Day et al., 1986). However, the hormones and metabolites linking nutrition and puberty, as well as the neuroendocrine mechanisms by which GnRH neurons are stimulated to increase their secretory activity, resulting in the first pubertal ovulation, have not been elucidated.
Leptin, an adipose-derived peptide first characterized in 1994 (Zhang et al. 1994), not only decreases food intake and BW in mutant, leptin-deficient (ob/ob) obese mice, but also restores their fertility (Barash et al., 1996; Chehab et al., 1996). As a result of these and other observations, leptin is considered to be a major link between nutrition, metabolism, and reproduction. In humans (Kiess et al., 1999), rats (Ahima et al., 1997; Quinton et al., 1999), and heifers (Garcia et al., 2002), increasing circulating concentrations of leptin precede the onset of puberty, and leptin has been shown to regulate either acutely (Ahima et al., 1997) or permissively (Cheung et al., 2001) the onset of puberty in rodents. Furthermore, studies in our laboratory have confirmed the ability of leptin to modulate acutely the hypothalamic-hypophyseal axis of nutritionally stressed cattle (Amstalden et al., 2002, 2003; Maciel et al., 2004). To test the hypothesis that leptin regulates pubertal onset in heifers, we examined the effects of chronic treatment with recombinant ovine leptin (oleptin; Gertler et al., 1998) on patterns of LH secretion, adenohypophyseal responsiveness to GnRH, circulating metabolic hormones, and timing of the onset of puberty.
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Materials and Methods
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The Institutional Agricultural Animal Care and Use Committee of the Texas A&M University System approved in advance all procedures used in these studies.
Establishment of Dose of Oleptin
In a preliminary experiment, we compared three doses of oleptin, administered s.c., to establish a dose appropriate for the current study. The criterion used to choose the appropriate dose was the amount of oleptin that would result in mean plasma concentrations between 5 and 10 ng/mL, which would then remain above baseline for approximately 8 to 12 h after a single injection. Eleven heifers (Brahman x Hereford-F1, 15 to 16 mo of age) were assigned randomly to one of four groups: 1) Control (n = 3); s.c. injection of saline; 2) Low dose (n = 3); single s.c. injection of recombinant oleptin (4.8 µg/kg BW); 3) Mid dose (n = 3); single s.c. injection of oleptin (9.6 µg/kg BW); and 4) High dose (n = 2); single s.c. injection of oleptin (19.2 µg/kg BW). Heifers averaged 318 ± 5.11 kg, with an average BCS of 5 (1 to 9 scale). Blood samples were collected by coccygeal venipuncture at –15 min, just before each injection, and at 15 min, 1, 2, 4, 6, 8, 12, 18, and 24 h after the injection. Samples were placed immediately on ice, centrifuged at 3,000 x g to obtain plasma within 2 h, and stored at –20°C until RIA for leptin. The recombinant oleptin preparation used in both preliminary and formal studies was as reported previously (Gertler et al., 1998; Amstalden et al., 2002).
All doses of leptin increased mean concentrations of plasma leptin within 15 min after injection (Figure 1). The highest dose of oleptin resulted in the greatest increase in mean concentrations of leptin, with the greatest concentrations occurring approximately 1 h after injection (12.01 ± 2.23 ng/mL). Plasma concentrations of leptin in this group remained elevated (P < 0.05) above controls for 12 h after the injection (5.97 ± 0.98 vs. 2.31 ± 0.03 ng/mL; Figure 1), whereas leptin values for the other dose groups did not differ from controls after 6 h. Based on these results, we selected the highest dose (19.2 µg/kg BW), administered twice daily at 12-h intervals, to use in the formal study.
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Figure 1. Mean serum concentrations of leptin during 24 h in control heifers (saline; n = 3) and heifers treated with single injections of Low (4.8 µg/kg BW; n = 3), Mid (9.6 µg/kg BW; n = 3), and High (19.2 µg/kg BW; n = 3) doses of recombinant ovine leptin (oleptin) administered s.c. during a preliminary study. Plasma concentrations of leptin in the High group remained elevated above controls for 12 h (P < 0.05), whereas other groups were elevated (P < 0.05) for 6 h. Pooled SEM were 0.28, 0.53, 0.97, and 1.01 for Control (saline), Low, Mid, and High doses, respectively.
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Animals and Procedures
Fourteen fall-born, prepubertal beef heifers (12 to 13 mo of age, 304.7 ± 4.12 kg BW, Hereford x Brahman, F1) were used for this study. Before the beginning of the experiment, animals were maintained in pens (4 to 5 heifers per pen) measuring 25 x 9 m. Serum concentrations of progesterone were determined in twice-weekly blood samples collected by caudal venipuncture to monitor pubertal status. During the experimental period, all heifers received diets formulated to meet all nutritional requirements and to promote an ADG of approximately 0.68 kg/d (NRC, 1996). Diets consisted of Coastal bermudagrass hay, ground corn, cottonseed meal, limestone, and vitamin A-D-E premix.
Twenty-four hours before the start of the experiment, each heifer was fitted with a jugular catheter (Silastic tubing, 1.4 mm i.d, 1.9 mm o.d.; Dow Corning Corp., Midland, MI) for intensive and daily blood sampling. Heifers were assigned randomly into two groups (seven animals per group): 1) Control; twice daily s.c. injections of saline (0700 and 1900) for 40 d; and 2) Leptin; twice daily s.c. injections (0700 and 1900) of oleptin in saline at a dose rate of 19.2 µg/kg BW for 40 d. The volume of each injection was approximately 2 mL, with the volume varying slightly depending on individual BW. During the experiment, blood samples were collected twice daily (0700 and 1900) just before each saline or leptin injection. Also, on d 0, 5, 10, 20, 30, and 40 of the experiment, heifers were placed in indoor stanchions and blood samples (10 mL) were collected at 10-min intervals for 5 h (0800 to 1300). On d 41, all heifers received an i.v. injection of GnRH (0.001 µg/kg) intended to produce a physiological pulse of LH (Maciel et al., 2004), with blood samples (10 mL) collected every 10 min for 90 min (0800 to 0930). At this time, a second GnRH injection (0.22 µg/kg), intended to release all releasable pools of LH, was administered and intensive bleeding continued for an additonal 4 h (Maciel et al., 2004). During this period, blood samples (10 mL) were collected at 15-min intervals during the first hour (0930 to 1030) and at 1-h intervals during the last 3 h (1030 to 1330).
Blood samples were dispensed into tubes containing a solution of 150 µL of heparin (10,000 UI/mL) and 5% EDTA and immediately placed on ice. During intensive blood sampling, the volume of blood collected (10 mL) was replaced with an equal volume of saline or heparanized (300 IU/mL) saline during cathether flushing. Serum from nonintensively collected tail vein blood samples and plasma from intensively collected samples were obtained by centrifugation (1,200 x g) and stored at –20°C until hormone assays were conducted. After each intensive and daily blood sampling, heifers were returned to outside pens.
Hormone and Biochemical Assays
To confirm the prepubertal status of heifers, serum concentrations of progesterone were assayed in twice-weekly samples collected beginning 70 d before the beginning of the experiment and throughout the study using the Coat-A-Count assay kit (Diagnostic Product Corp., Los Angeles, CA) as reported previously from this laboratory (Fajersson et al., 1999). Heifers were to be considered pubertal if serum concentrations of progesterone was greater than 1 ng/mL for two consecutive samples and accompanied by an ultrasonographically definable corpus luteum. Plasma concentrations of leptin were determined in samples collected twice daily from d 0 to 40 using a highly specific oleptin RIA validated for use in bovine serum or plasma (Delavaud et al., 2002) and reported previously from this laboratory (Amstalden et al., 2000; Garcia et al., 2002). Plasma concentrations of LH were determined in samples collected at 10-min intervals for 5 h on d 0, 5, 10, 20, 30, and 40, with all samples collected after GnRH injections on d 41 assayed for LH as reported previously (McVey and Williams, 1991).
To assess metabolic status in response to leptin treatment, circulating concentrations of GH, insulin, and IGF-I were also monitored. Plasma concentrations of GH were determined in one sample collected every morning just before the treatment injection (0700) on d 0, 1, 2, 3, 4, 5, 10, 20, 30, and 40, as validated previously (Ryan et al., 1994). Circulating concentrations of insulin were determined in samples collected every morning just before the treatment injection (0700) on d 0, 1, 2, 3, 4, 5, 10, 20, 30, and 40 using an assay reported previously (Ryan et al., 1995). Plasma concentrations of IGF-I were determined in samples collected twice weekly from d 0 to 40 (Ryan et al., 1994). Intra- and interassay CV for progesterone, LH, insulin, GH, and IGF-I were 4.0 and 6.0, 7.5 and 9.0, 9.2 and 10.6, 11.0 and 16.2, and 12.0 and 22%, respectively. Leptin was determined in a single assay with an intraassay CV of 4.5%.
Statistical Analysis
The frequency and amplitude of LH pulses were determined using both visual inspection and the aid of a pulse-detection algorithm (Pulsefit 1.2; Kushler and Brown, 1991). The frequency of LH pulses was analyzed by the GLM models for repeated measures using PROC MIXED of SAS (SAS Inst., Inc., Cary, NC). Because of differences in the frequency of LH pulses among groups on d 0, analysis of covariance was used to test main effects on d 5, 10, 20, 30, and 40. Circulating concentrations of LH, GH, IGF-I, insulin, and leptin were analyzed using SAS PROC MIXED for repeated measures. Sources of variation were treatment, day, and their interaction. Day was used as the repeated variable, and heifer within treatment was used as the subject. When differences in circulating concentrations of hormones were detected between groups on d 0, analysis of covariance was performed to compare treatment means on d 5, 10, 20, 30, and 40. The least squares means procedure (PDIFF option) was used to compare means when significant F-value was obtained.
To analyze GnRH-induced release of LH, samples collected before and after both the low and high doses of GnRH were grouped into four periods: Period I, 10-min samples from –90 to 0 min relative to low dose injection; Period II, 10-min samples from 0 to 40 min after the low dose of GnRH; Period III, 10-min samples from 50 to 90 min after the low dose of GnRH; and Period IV, 15-min samples from 15 to 60 min and 1-h samples until 3 h after the high dose of GnRH. Because of differences noted in concentrations of LH among groups during Period I, analyses of covariance were used to test main effects during Periods II, III, and IV. When a significant difference was detected, the least squares means procedure (PDIFF option) of SAS was used to compare means.
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Results
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Plasma Leptin and Onset of Puberty
Recombinant oleptin markedly increased plasma concentrations of leptin in the Leptin group, with mean concentrations greater (P < 0.001) than controls throughout the study (27.8 ± 0.8 vs. 4.9 ± 0.12 ng/mL; Figure 2). Diets promoted a gain of 0.32 ± 0.09 kg/d that did not differ between groups, with final BW at the end of the study averaging 319.18 kg across both groups. Serum concentrations of progesterone remained below 0.2 ng/mL throughout the experiment in both Control and Leptin heifers, indicating that leptin treatment was unable to accelerate the onset of puberty. Although none of the heifers reached puberty during the experimental period, all heifers attained puberty within 45 d after the end of the experiment and were bred at the expected time for heifers of this breed type.
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Figure 2. Mean plasma concentrations (± SEM) of leptin on d 0, 5, 10, 20, 30, and 40. Concentrations of leptin were greater (P < 0.003) in the Leptin group than in the Control group throughout the experiment.
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Pulsatile Patterns of LH Secretion and GnRH-Mediated Release of LH
Mean concentrations of LH, frequency of LH pulses, and amplitude of LH pulses did not differ between groups during the study (Figure 3). However, a treatment x day interaction (P = 0.02) revealed that the frequency of LH pulses (pulses/5 h) was greater (P = 0.03) in controls than in leptin-treated heifers on d 10. Neither mean plasma concentrations of LH after GnRH nor area under the curve was affected by treatment with oleptin (Figure 4).
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Figure 3. Mean frequencies of LH pulses (± SEM) in control (n = 7) and leptin-treated (n = 7) heifers on d 0, 5, 10, 20, 30, and 40. After adjusting for differences in frequencies of LH pulses on d 0, the mean frequency of LH pulses was greater in controls on d 10 (P < 0.03).
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Figure 4. The GnRH-mediated release of LH during Period I: 10-min samples from –90 to 0 min relative to low dose (0.001 µg/kg BW) injection; Period II: 10-min samples from 0 to 40 min after the low dose of GnRH; Period III: 10-min samples from 50 to 90 min after the low dose of GnRH; and Period IV: 15-min samples from 15 to 60 min and 1-h samples until 3 h after the high dose (0.22 µg/kg BW) of GnRH. The GnRH-induced release did not differ between saline- and leptin-treated heifers. Values are mean ± SEM.
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Metabolic Hormones
Mean concentrations of GH, IGF-I, and insulin in plasma were not affected by treatment (Figure 5). However, mean concentrations of insulin (P < 0.002) and IGF-I (P < 0.003) increased transiently from d 0 to 40 of the study in both the control and leptin-treated groups (Figure 6).
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Figure 5. Mean plasma concentrations of GH during Period I (d 0), Period II (d 1 to 5), Period III (d 6 to10), Period IV (d 11 to 20), Period V (d 21 to 30), and Period VI (d 31 to 40) in saline- and leptin-treated heifers. Mean concentrations did not differ between groups during any period. The pooled SEM was 1.04.
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Figure 6. Mean plasma concentrations of IGF-I (Panel A) on d 0, 5, 10, 15, 20, 25, 30, 35, and 40 of the experiment. Plasma concentrations of IGF-I did not differ between saline- and leptin-treated heifers on any d. The pooled SEM was 5.4. Mean plasma concentrations of insulin (Panel B) on d 0, 1, 2, 3, 4, 5, 10, 20, 30, and 40 of the experiment. Plasma concentrations of insulin did not differ between saline- and leptin-treated heifers on any day. The pooled SEM was 0.12.
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Discussion
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Recent studies in this laboratory have demonstrated the ability of peripherally administered, recombinant oleptin to prevent fasting-mediated decreases in the frequency of LH pulses in heifers that were within days or weeks of their first pubertal ovulation (frequency of LH pulses between 0.6 and one pulse/h; Maciel et al., 2004). Such observations imply the ability of leptin to modulate the activity of the GnRH pulse generator in this animal model and are in agreement with previous studies in rodents (Ahima et al., 1997), monkeys (Finn et al., 1998), and male estradiol-implanted sheep (Nagatani et al., 2000). However, in the current study, the peripheral administration of recombinant oleptin for 40 d did not stimulate an increase in LH pulse frequency in prepubertal heifers that were gaining BW at moderate to high rates, were approaching the expected age of pubertal onset, and whose frequency of LH pulses were still relatively low. This confirms a previous report on well-fed prepubertal lambs (Morrison et al., 2002), in which LH, GH, and several other metabolic hormones were not affected by chronic treatment with recombinant oleptin.
The lack of an effect of leptin on LH pulse frequency, and its failure to accelerate the timing of the onset of puberty, suggest that leptin treatment was ineffectual in increasing the frequency of GnRH pulses or in chronically elevating the baseline for LH via direct effects on the pituitary (Amstalden et al., 2002, 2003). Currently, the circumstances and mechanisms by which leptin can stimulate hypothalamic GnRH and/or adenohypophy-seal LH secretion remain to be fully delineated, particularly in ruminants. However, several lines of evidence support the potential for a direct action of leptin at both loci, including the presence of leptin receptors within the arcuate nucleus (Dyer at al., 1997) and on gonadotropes (Iqbal et al., 2000). Importantly, one of the primary factors associated with an increase in the number of leptin receptors in the ventromedial hypothalamus of ewes is malnutrition (Dyer et al., 1997), and numerous reports suggest that leptin may only stimulate LH secretion during nutritional stress in sheep (Nagatani et al., 2000; Henry et al., 2001) and cattle (Amstalden et al., 2002, 2003). Hence, both fasting and chronic, severe dietary energy restriction appear to hypersensitize the hypothalamic-hypophyseal axis to leptin. These findings may explain why exogenous oleptin did not affect LH secretion patterns in well-fed heifers in the current study, which would preclude it from serving as a neuroendocrine trigger for puberty per se.
In vivo studies with well-fed sheep (Henry et al., 1999; Morrison et al., 2002) and anterior pituitary explants from well-fed cows (Zieba et al., 2003b) indicate that leptin is also incapable of consistently influencing the secretion of GH in normally nourished ruminants, although one exception to this view has been published (Henry et al., 2001). In the current study, exogenous oleptin did not affect mean concentrations of plasma GH. However, leptin stimulates GH secretion in fasted sheep (Nagatani et al., 2000), in anterior pituitary explants from cows in the fasted state (Zieba et al., 2003b), and in fasted prepubertal heifers (Maciel et al., 2004). Moreover, leptin receptor mRNA is increased in the pituitary and hypothalamus of fasted rats (Zamorano et al., 1997). Thus, similar to the effects of leptin on LH secretion, it is plausible to conclude that the somato-tropic axis of well-fed heifers in the current study was not sensitized, or was resistant to, the effects of leptin and could not respond to exogenous oleptin with an increase in basal GH secretion.
As expected, mean concentrations of IGF-I and insulin increased from d 0 to 40 of the experiment in all animals. However, neither IGF-I nor insulin was influenced by leptin treatment in the current study. These results are consistent with results obtained in well-fed lambs (Morrison et al., 2002). Moreover, recent studies from this laboratory have demonstrated that the ability of oleptin to normalize fasting-mediated decreases in circulating insulin, similar to both LH and GH, depends on both metabolic status and the dose of oleptin used (Zieba et al., 2003b).
Although the s.c. dose of oleptin used in the current study was based on preliminary experiments in which physiological concentrations of leptin were targeted and achieved, long-term treatment of heifers in this study with the selected dose resulted in mean concentrations of circulating leptin that were between two- and threefold greater than our target. Moreover, these values increased nearly linearly as the experiment progressed in spite of results from preliminary experiments indicating that an appropriate dose of leptin had been chosen. In fasted, mature cows with significant adipose reservoirs, biological responses were inversely proportional to dose of leptin and dose was therefore a critical determinant for achieving sustained increases in LH, GH, and pancreatic insulin release during short-term experiments (Zieba et al., 2003a). Importantly, studies in other species indicate that large doses of leptin may cause the accumulation of excessive amounts of suppressors of cytokine signaling-3, thus creating a state of leptin resistance (Emilsson et al., 1999). Obesity syndromes in humans are also thought to be related to a state of leptin resistance (Caro et al., 1996; Considine et al., 1996). Although we have previously reported that mature, estrous-cycling beef cows can exhibit circulating concentrations of leptin of between 15 and 20 ng/ mL (Garcia et al., 2002), with values similar to those obtained in treated heifers during the first 10 to 15 d of the current study, it is possible that the greater concentrations of circulating leptin created by the prolonged administration of oleptin resulted in a state of leptin resistance. In addition, circulating concentrations of leptin in control heifers in the current study were well within the range of values noted in developing heifers that reached puberty at the expected time (Garcia et al., 2002). Finally, more recent studies in this laboratory (our unpublished observations) indicate that relatively small doses (0.2 µg/kg BW) of oleptin, shown previously to stimulate an increase in LH and insulin secretion in fasted cows (Zieba et al., 2003a), are also incapable of accelerating pulse generator activity in heifers at any development stage before puberty. Thus, collective observations, both published and unpublished, have led us to believe that the major factor contributing to a failure of leptin to modify the function of the hypothalamic-adenohypophyseal axis in the current study is related to metabolic status. Hence, an integration of results across species, particularly ruminants, support the contention that leptin 1) acts mainly as a passive hormone that permits puberty to occur when sexual maturity is reached; and 2) serves as a metabolic signal that can regulate gonadotropin secretion in response to either acute or chronic dietary energy restriction.
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Footnotes
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1 Supported by National Research Inititative Competitive Grant 00-35203-9132 from the USDA Cooperative State Research, Education, and Extension Service, the Foundation for Coordination of Improvement of High Level Scholars (CAPES), the Ministry of Education of Brazil, and the Texas Agric. Exp. Stn. 
2 Correspondence: 3507 Hwy 59E (fax: 361-358-4930; e-mail: glwilliams{at}tamu.edu).
Received for publication March 10, 2004.
Accepted for publication June 8, 2004.
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Abstract
Introduction
