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Temperature and Temperament–Old Stressors, New
Solutions

103 Todd Ave, Yeppoon, QLD 4703, Australia E-mail: [email protected] Take Home Message
8 In human medicine, the traditional paradigm on the mechanism by which heat stress exerts its adverse effects has been abandoned for one in which the integrity of the gut lining plays a central role. 8 Livestock species may be predisposed to heat stress because modern production diets often result in damage to the lining of the gut. Strategic supplementation with compounds that promote gut health may represent a novel way of improving resilience of livestock to heat stress. 8 The traditional approach to decreasing economic losses associated with animals with nervous temperaments is based on genetic selection for breeds and sires with calm temperaments, but progress has been slow. 8 Many studies on fetal programming have established that dietary factors and stress during gestation can affect gene expression of the developing fetus and consequent changes to appetite, growth, body composition, immune competence, reproduction, and susceptibility to stress can persist for the life. 8 Most studies on fetal programming have been conducted with rodent models, but a limited number of trials conducted using livestock under laboratory conditions indicates that fetal programming of stress susceptibility does occur in these species. 8 Comparison of the magnitude of dietary restriction and stress required to induce changes to gene expression in animals held under controlled conditions with those experienced by animals in production systems indicates that it is likely that progeny of pregnant livestock held under the latter conditions are subject to fetal programming. 8 Strategic supplementation of pregnant livestock with methyl donors could have a significant Introduction
In the northern Australian beef industry, resilience against heat stress and the temperament of cattle are commonly given by producers as the primary reasons for their choice of breed and sire, respectively. Heat stress affects livestock productivity in a variety of ways, including reduced feed intake, growth rate, milk production, fertility, embryo survival, libido, and increased susceptibility to disease and parasites. The economic significance of heat stress is evident when one considers that weight gain is reduced by 0.9 lb per day and fertility is decreased by 17% when body temperature is increased by one degree Celsius (Finch 1984). Cattle with excitable temperaments (i.e., animals that display anxiety or aggressive behavior) grow 8% slower at pasture, 9–14% slower in the feedlot, and have 10% lower feed conversion efficiencies (Fordyce et al. 1985; Burrow and Dillon 1997; Voisinet et al. 1997; Petherick et al. 2002). Temperament also has a substantial impact on meat quality: cattle with excitable temperaments exhibit a greater incidence of dark cutting and their meat is tougher. Voisinet et al. (1997) found that meat from 40% of cattle with excitable temperaments exceeded the threshold value for acceptability in food service establishments, compared with 13.7% for animals with calm temperaments. They also found that 25% of carcasses from animals with excitable temperaments were downgraded as dark cutters, in comparison with 6.7% for animals with calm temperaments. Carcasses from animals with excitable temperaments display a higher incidence of bruising, amounting to a loss of 3.3 lb bruise trim per carcass more that that for animals with calm temperaments (Fordyce et al. 1988); moreover, these animals had more bruising in the most valuable cuts. Despite the substantial economic impact of heat stress and temperament, progress in stress physiology has been slow compared to that of other disciplines. That research efforts have not been particularly successful in ameliorating the effects of these stressors is reflected in continued pressure by animal welfare groups and, in some instances, the implementation of prescriptive legislation. The theme of this communication is that progress has been hampered by flaws in paradigms on the mechanisms by which stressors exert their effects. This review examines two new paradigms, which have recently emerged from the discipline of medicine and could hold the key to resolving some apparently intractable problems in livestock production. It is suggested that resilience against heat stress can be improved through gut health, and that temperament can be manipulated by nutrition during fetal life. Heat Stress
Is our old paradigm on heat stress flawed?
The traditional paradigm among the animal scientists is that heat stroke in livestock is caused by heat-induced denaturation of brain proteins or by dehydration-induced heart failure. Although this paradigm is consistent with symptoms such as convulsions, coma, and a sudden drop in blood pressure, it is not consistent with symptoms such as liver necrosis, kidney failure, disseminated blood clotting, gut hemorrhage, and an acute-phase inflammatory immune response. In cases of sub-clinical exposure to heat, the conventional rationale is that the commonly observed reduction in feed intake reflects an attempt by the animal to reduce heat load by decreasing the heat increment associated with the digestion and metabolism of feed. However, this paradigm does not explain why feedlot cattle take five to ten days to attain normal feed intakes after a heat stress event. In the medical field, similar inconsistencies resulted in the recent emergence of a paradigm that places the integrity of the gut lining at the centre of the etiology of heat stress (Bouchama and Knochel 2002). A new paradigm: damage to the lining of the gut plays a central role in
mediating the adverse consequences of heat stress

Exposure of mammals to a high ambient temperature results in redirection of blood flow from the body core to the periphery to facilitate dissipation of body heat to the environment. In order to maintain blood pressure, the increased blood flow to the skin is counter-balanced by reduced blood flow to the splanchnic bed (gut, liver, spleen, and pancreas). The reduction in blood flow to the gut (ischemia) results in depletion of intracellular energy resources. Consequently, energy-dependent ion-pumping mechanisms are impaired, resulting in imbalanced cellular osmotic pressure, increased cytosolic Ca++ concentrations, and generation of reactive oxygen species. The net effect of this progression of events (for details, see Cronjé 2005) is that junctions between the cells that line are damaged, allowing components of the digesta to enter the blood supply. The gut contains large amounts of endotoxin, a component of the cell walls of gram-negative bacteria. When the barrier function of the gut lining is compromised, endotoxin enters the blood stream. The immune system of the body reacts to the presence of endotoxin by releasing a variety of inflammatory cytokines. Endotoxin also induces the secretion of nitrous oxide, a potent vasodilator. The subsequent resumption of blood flow to the gut results in a flood of cytokines, reactive oxygen species, and endotoxin to the rest of the body, precipitating multiple organ failure. This sequence of events is summarized in Figure 1. There are several lines of evidence that support the notion that gut integrity plays a critical role in the etiology of hyperthermia. Elevated concentrations of endotoxin have been detected in heat- stressed monkeys, humans with heatstroke, and in marathon runners (Gisolfi and Mora 2000; Jessen 2001). In a study conducted by Eshel et al. (2001), anaesthetized dogs and monkeys were subject to hyperthermia sufficient to raise body temperature to 42°C for 60 minutes or until cardiac arrest occurred. In animals that died during hyperthermia, the main necropsy findings were gut edema and minor hemorrhages. Animals that were successfully resuscitated following hyperthermia began to show signs of secondary deterioration at times ranging from 4 to 18 hours after resuscitation and return to normal body temperature. These symptoms involved an abrupt drop in blood pressure followed 1 to 2 hours later by massive hemorrhages from the rectum and cardiac arrest. Necropsies revealed the presence of diffuse hemorrhages throughout the tissues of the gut. It was suggested that delayed reaction to hyperthermia indicates that tissue injury continues even after cooling to normal body temperature. It was concluded that the gut edema found in animals that died during hyperthermia reflected the effects of splanchnic ischemia, and the intestinal hemorrhages in animals that survived for longer periods reflected the irreversible effects of cytokine activation and endotoxemia. A new strategy: increasing resilience to heat stress by maintaining a
healthy gut

The effect of heat stress on gut integrity of livestock species has not been documented, but reports of congestion of the mucous membranes of the gut of cattle and sheep that were exposed to hyperthermia (Terui et al. 1980; Khogali et al. 1983) are consistent with impaired gut integrity. The role of the gut in the etiology of heat stress has significant implications for livestock production because concentrate diets, which are frequently used in intensive production systems, result in damage to the gut lining of pigs (ulcers), poultry (gizzard erosion) and ruminants (parakeratosis). It is thus possible that such diets increase the susceptibility of livestock to the adverse effects of heat stress. Cattle and sheep may be particularly vulnerable, as rumen bacteria are a potential source of endotoxin and have been shown to be capable of inducing endotoxic shock. Considerable quantities of endotoxin accumulate in the rumen under conditions conducive to the development of acidosis, which is characteristic of many feedlot diets. Ingestion of concentrate-based diets can double the osmolarity of rumen digesta, leading to a rise in the osmotic pressure gradient between the gut tissues and the rumen contents. This results in rapid movement of water from the blood across the rumen epithelium, causing epithelial cells to separate from the basement membrane. The resulting necrosis affords endotoxin and bacteria entry to the body. The high incidences of liver abscesses among feedlot animals of laminitis among dairy cattle and horses are associated with compromised gut integrity, and suggest that these species would be especially vulnerable to hyperthermia. If gut integrity does play a critical role in susceptibility to heat stress in livestock, then resilience to heat stress could be improved by dietary additives designed to promote gut health. Betaine is one of several compounds that have the potential to improve the integrity of the gut lining in intensively fed livestock. Betaine is an organic osmolyte and is used by mammalian cells to maintain osmotic equilibrium. Studies using gut tissues from poultry chicks supplemented with betaine showed that the treatment altered the movement of water across the intestinal epithelium during hyperosmotic challenges. Histological evidence from broiler chicks showed that the crypt–villus ratio of the small intestine was altered by dietary betaine supplementation, and it was concluded that betaine supplementation stabilizes mucosal structure in healthy birds and alleviates parasite infection when challenged with coccidia (Kettunen et al. 2001 a, b, c). These results show that dietary betaine has a beneficial effect on gut integrity and could thus potentially increase the resilience of livestock against heat load. Stress Responsiveness
As temperament appears to be moderately heritable, the conventional paradigm is to cull animals that display nervous temperaments (Burrow and Corbet, 2000). Recent advances in epigenetics indicate that susceptibility to stress can be influenced by stress and dietary deficiencies experienced during fetal development, which raises the possibility of manipulating temperament by strategic supplementation of pregnant livestock. Epigenetics refers to modifications in gene expression that are mediated by changes in DNA methylation and/or chromatin structure. Exposure of the developing fetus to maternal stress hormones (cortisol) or a deficiency of S-containing amino acids affects DNA methylation of the fetus. The expression of a wide variety of genes may be affected, resulting in changes to growth rate, body composition, appetite, immune competence, reproduction, and blood pressure (see reviews by Cronjé, 2003; McMillen and Robinson, 2005). Because many of these changes persist for life, the concept is commonly referred to as fetal programming. In the case of temperament, the set point at which stress hormones are secreted is lowered, making individuals born to dams that were exposed to stress or dietary protein deficiency more susceptible to stressors. The hormones that determine stress responsiveness are shown in Figure 2. When neural signals reaching the brain are perceived to constitute a threat to the animal, neurons in the paraventricular nucleus of the hypothalamus secrete corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) into the hypophyseal portal system,. These hormones bind to receptors in the anterior pituitary and induce the release of ACTH (adrenocorticotropic hormone). ACTH is secreted into the circulatory system and stimulates the secretion of cortisol from the adrenal cortex. Cortisol binds to intracellular glucocorticoid receptors (GR) in many tissues, promoting or inhibiting the transcription of DNA and hence the synthesis of proteins that alter cell function. The primary effect of the stress response is to mobilize energy resources to enable the animal to cope with stressors. Although the effects shown in Table 1 have utility in a “fight or flight” situation, sustained elevation of stress hormones decreases growth rate, reproduction, and immune competence. The extent and duration of the stress reaction is controlled by a negative feedback loop in which high concentrations of cortisol inhibit the secretion of CRH and ACTH by binding to GR in the hypothalamus and pituitary (Figure 2). At low concentrations, cortisol also functions in a proactive mode, controlling the threshold at which the stress response is initiated. This occurs in the hippocampus, which expresses mineralocorticoid receptors (MR) in addition to GR. Because these receptors have opposing effects on hippocampal excitability and differ in their affinity for high or low concentrations of cortisol, the balance between hippocampal MR and GR and their associated effects determines the set point at which the stress response is initiated. The MR/GR balance is in part determined by genetics, but can be extensively modified by environmental stimuli experienced during prenatal and early neonatal development, and by chronic exposure to stress thereafter. The effect of fetal programming on stress responsiveness
Prenatal stress decreases expression of GR in the hippocampus and increases GR in the liver and amygdala (Seckl 2001). Decreased numbers of GR in the hippocampus impair the effectiveness of the cortisol-mediated negative feedback control of CRH and ACTH secretion, and result in permanently elevated basal and stimulated blood cortisol concentrations. Chronically elevated cortisol impairs the animal’s ability to mount immune responses, utilize nutrients for growth, and successfully synchronize events critical for reproduction. The effects of elevated concentrations of cortisol are potentiated by increased numbers of GR in the amygdala and liver. Cortisol stimulates the synthesis of CRH in the amygdala, which results in the expression of fear and anxiety. As a result, animals that have been subject to prenatal stress are less capable of coping with stress or of habituation to stress and are hyper-responsive to anxiety-provoking stimuli. Cortisol also stimulates the transcription of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting gluconeogenic enzyme in the liver. Consequently, animals that have been exposed to prenatal stress have elevated blood glucose concentrations. Sensitivity to pain is also elevated in prenatally stressed rats. Although most trials on fetal programming have been conducted using rodent models, there is sufficient evidence to indicate that similar effects can be induced in livestock species. Prenatal stress increases stress responsiveness in sheep (Hawkins et al. 2001; Sloboda et al. 2002) and pigs (Haussmann et al. 2000). Prenatal stress also increases disease susceptibility and mortality in pigs and delays wound healing (Haussmann et al. 2000; Otten et al. 2001). In cattle, calves born to cows that had either been subject to transport stress or ACTH injections during pregnancy had increased cortisol responses to stress at the age of five months (Lay et al. 1997a,b). Hawkins et al. (2001) showed that a relatively modest 15% reduction in the feed intake of pregnant ewes from conception until day 70 of gestation was sufficient to alter the expression of CRH, AVP, and GR in the brain of the sheep fetus. At 3 months of age, the lambs born to these ewes exhibited a greater cortisol response to stimulation with CRH (Hawkins et al. 2000). Bloomfield et al. (2003) showed that adult sheep born to ewes subjected to a 50% decrease in feed intake in late gestation had increased ACTH responses to CRH and AVP. There are several trials that show that maternal undernutrition of ewes two months before or after conception alters the stress axis of their lambs during fetal and early postnatal life (see McMillen and Robinson 2005). Nutritional manipulation of stress responsiveness
Pregnant livestock in many extensive farming systems are exposed to protracted periods of low protein intake during pregnancy and to periodic episodes of stress associated with animal husbandry systems. Available evidence on the relative magnitude of stress or undernutrition required to program the stress axis suggests that there are reasonable grounds to conclude that the progeny of pregnant livestock that are exposed to commercial farming systems may have increased susceptibility to stress. One of the most compelling pieces of indirect evidence in support of the existence of effects of maternal nutrition on stress susceptibility in cattle comes from a study in which progeny born to cows fed grass pastures during gestation were shown to have a 14% more excitable temperament than those whose dams were fed legume-grass pastures plus supplements (Hearnshaw and Morris, 1984). The possibility of reducing stress susceptibility of livestock species by nutritional means has not been investigated. Recently, Lillycrop et al. (2005) demonstrated that altered DNA methylation and gene expression of weaned offspring born to dams fed protein deficient diets during pregnancy could be prevented by supplementation of the maternal diet with the methyl donor, folate. Betaine is a methyl donor that participates in the same biochemical pathway as folate, and is commonly included in pig and poultry diets as a functional substitute for methionine and choline. Although the effects of betaine supplementation on programming of fetal gene expression have not been explored, there is no reason to expect that strategic supplementation of pregnant livestock with betaine would not have substantial effects on stress susceptibility, growth, reproduction, appetite, body composition and susceptibility to disease and parasites. Conclusion
The paradigms that we construct to explain the origin of problems predicate our approach to solutions. That our solutions to the problems of heat stress and the effects of excitable temperament in livestock have only been partially successful suggests that it would be worthwhile to re-examine our paradigms in the light of new concepts that have recently emerged from the field of human medicine. These paradigms suggest that the susceptibility of livestock to heat stress and other stressors inherent in production systems could be decreased by strategic dietary supplementation. References
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Implications of nutritional programming of gene expression during early development for livestock production. In: Matching herbivore nutrition to ecosystem biodiversity pp. 321–332 (ed. L. ‘tMannetje). Proceedings of the 6th International Symposium on the Nutrition of Herbivores, Merida, Mexico. Eshel, G.M., Safar, P. and Stezoski, W. (2001). The role of the gut in the pathogenesis of death due to hyperthermia. Am. J. Forensic Med. and Pathol. 22:100–104. Finch, V.A. 1984. Heat stress as a factor in herbivores under tropical conditions. In: Herbivore nutrition in the subtropics and tropics, pp. 89–105 (eds. F.M.C. Gilchrist and R.I. Mackie). The Science Press, Craighall, South Africa. Fordyce, G., Goddard, M.E., Tyler, R., Williams, G. and Toleman, M.A. 1985. Temperament and bruising of Bos indicus cross cattle. Aust. J. Exp. Agric. 25:283–288. Fordyce, G., Wythes, J.R., Shorthose, W.R., Underwood, D.W. and Shepherd, R.K. 1988. 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Maternal undernutrition in early gestation alters molecular regulation of the hypothalamic-pituitary-adrenal axis in the ovine fetus. J. Neuroendocrinol. 13:855–861. Hearnshaw, H. and Morris, C.A. 1984. Genetic and environmental effects on a temperament score in beef cattle. Aust. J. Agric. Res. 35:723–733. Jessen, C. 2001. Temperature regulation in humans and other mammals. Springer, New York. Kettunen, H., Peuranen, S. and Tiihonen, K. (2001a). Betaine aids in the osmoregulation of duodenal epithelium of broiler chicks, and affects the movement of water across the small intestinal epithelium in vitro. Comp. Biochem. Physiol. Mol. Int. Physiol. 129:595–603. Kettunen, H., Peuranen S., Tiihonen K. and Saarinen, M. 2001b. Intestinal uptake of betaine in vitro and the distribution of methyl groups from betaine, choline, and methionine in the body of broiler chicks. Comp. Biochem. Physiol. Mol. Int. Physiol 128:269–278. Kettunen, H., Tiihonen K., Peuranen S., Saarinen M.T. and Remus J.C. 2001c. Dietary betaine accumulates in the liver and intestinal tissue and stabilizes the intestinal epithelial structure in healthy and coccidia-infected broiler chicks. Comp. Biochem. Physiol. Mol. Int. Physiol 130:759–69. Khogali, M., Elkhatib, G., Attia, M., Mustafa, M.K.Y., Gumaa, K., El-Din, A.N. and Al-Adnani, M.S. 1983. Induced heat stroke in sheep: a model in sheep. In: Heat Stroke and Temperature Regulation pp 253–261 (eds. M. Khogali and J.R.S. Hales). Academic Press Australia, Bowen Hills. Lay, D.C. Jr., Randel, R.D. Friend, T.H., Jenkins, O.C., Neuendorff, D.A., Bushong, D.M., Lanier, E.K. and Bjorge, M.K. 1997a. Effects of prenatal stress on suckling calves. J. Anim. Sci. 75:3143–3151. Lay, D.C. Jr., Randel, R.D., Friend, T.H., Carroll, J.A., Welsh, T.H. Jr., Jenkins, O.C., Neuendorff, D.A., Bushong, D.M. and Kapp, G.M. 1997b. Effects of prenatal stress on the fetal calf. Dom. Anim. Endocrin. 14:73–80. Lillycrop, K.A. 2005. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J. Nutr. 135:1382–1386. McMillen, C. and Robinson, J.S. 2005. Developmental origins of the metabolic syndrome: prediction, plasticity and programming. Physiol. Rev. 85:571–633. Otten, W., Kanitz, E., Tuschscherer, M. and Nürnberg, G. 2001. Effects of prenatal restraint stress on hypothalamic-pituitary-adrenocortical and sympatho-adrenomedullary axis in pigs. Anim. Sci. 73:279–287. Petherick, J.C., Holroyd, R.G., Doogan, V.J. and Venus, B.K. 2002. Productivity, carcass and meat quality of lot-fed Bos indicus cross steers grouped according to temperament. Aust. J. Exp. Agric. 42:389–398. Seckl, J.R. 2001. Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. Mol. Cell. Endocrinol. 185:61–71. Sloboda, D.M., Moss, T.J., Gurrin, L.C., Newnham, J.P. and Challis, J.R. 2002. The effect of prenatal betamethasone administration on postnatal ovine hypothalamic-pituitary-adrenal function. J. Endocrinol. 172:71–81. Terui, S., Ishino, S., Matsuda, K., Shoji, Y., Ambo, K. and Tsuda, T. 1980. Clinical hematological and pathological responses in severely heat-stressed steers with special reference to the threshold value for survival. National Institute of Animal Health Quarterly (Japan) 20:138–147. Voisinet, B.D., Grandin, T., Tatum, J.D., O’Connor, S.F. and Struthers, J.J. 1997. Feedlot cattle with calm temperaments have higher average daily gains than cattle with excitable temperaments. J. Anim. Sci. 75:892–896. Figure 1 Summary of the sequence of events during heat stress. Reproduced from Cronjé (2005) with permission. Figure 2 The stress reponse of the hypothalamic-pituitary-adrenal axis. Table 1 Effects of hormones involved in the stress response Increased heart rate and arterial pressure Increased blood flow to brain and skeletal muscles; decreased flow to skin and gut Increased blood glucose concentration Increased blood fatty acid concentration Increased blood lactate concentration Increased metabolic rate Increased insulin secretion Increased glucagon secretion Enhanced memory formation Augmentation of the cardiovascular effects of catecholamines Increased glucose production Decreased glucose uptake and utilization Inhibition of the immune system Fat breakdown Muscle protein breakdown Inhibition of secretion of reproductive hormones

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