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Invited Review: Linking road transportation with oxidative stress in cattle and other species

      ABSTRACT

      Purpose

      The primary objectives of this review were to describe how transportation stress can contribute to the development of oxidative stress and provide a synopsis of the available literature assessing transit-induced oxidative stress in livestock. Nutritional strategies to combat oxidative stress in cattle are also discussed.

      Sources

      Sources of information for this review included peer-reviewed literature, unpublished data from research conducted by the authors, as well as government and industry reports.

      Synthesis

      Transportation is an unavoidable component of beef production and involves both physical and psychological stressors that predispose cattle to disease and negatively affect growth performance and carcass characteristics. These stressors can also result in oxidative stress, which further depresses animal health, feed conversion efficiency, and meat quality.

      Conclusions and Applications

      Although transit has been shown to alter biomarkers of oxidative stress in various livestock species, substantial variation exists regarding study conditions (species, transit duration, distance) and biomarker assessment (tissue, time of sampling, analytical methods). Future research should focus on determining appropriate oxidative stress biomarkers and establishment of a reference panel for livestock species. Furthermore, a more complete characterization of the oxidative stress response in cattle post-transit will help identify targets for the development of nutritional supplementation strategies (e.g., vitamins, minerals, yeast products) to mitigate the negative effects of transit-induced oxidative stress on cattle health and performance.

      Key words

      INTRODUCTION

      Transportation of animals is an essential component of livestock production and presents both economic and animal welfare concerns. Economic costs associated with transport include morbidity, mortality, carcass trim loss, and undesirable meat characteristics. Transportation stress is a predisposing factor for bovine respiratory disease (BRD), which is estimated to cost the US beef industry $1 billion annually (
      • Griffin D.
      Economic impact associated with respiratory disease in beef cattle..
      ). Additionally, economic losses from dark-cutting beef and bruised carcasses have been reported (
      • NBQA (National Beef Quality Audit)
      National Beef Quality Audit Steer and Heifer.
      ). As consumers become increasingly interested in how animals are raised and handled before slaughter, it is important to acknowledge the effects of transit on animal well-being. These include the psychological stress of handling as well as the potential for injury and fatigue during transit. The combination of stressors that accompany transit activate several biological pathways known to lead to the development of oxidative stress (Figure 1).
      Figure 1
      Figure 1Potential sources of transit-induced reactive oxygen species (ROS) production.
      Oxidative stress is defined as a disturbance in the prooxidant–antioxidant balance in favor of prooxidants (
      • Sies H.
      Oxidative stress: Introductory remarks.
      ). Historically, oxidative stress research has focused on aging and disease etiology in humans. However, in the past 20 yr, oxidative stress has gained the attention of animal scientists seeking to understand the implications of oxidative stress on livestock health, efficiency, and meat quality. Although the topics of livestock transport and oxidative stress have been reviewed independently (
      • Schwartzkopf-Genswein K.S.
      • Faucitano L.
      • Dadgar S.
      • Shand P.
      • González L.A.
      • Crowe T.G.
      Road transport of cattle, swine and poultry in North America and its impact on animal welfare, carcass and meat quality: A review..
      ;
      • Knowles T.G.
      • Warriss P.D.
      • Vogel K.
      Stress physiology of animals during transport.
      ;
      • Sies H.
      • Berndt C.
      • Jones D.P.
      Oxidative stress..
      ), to the authors’ knowledge, a review of how these topics relate to one another does not exist. Therefore, the objectives of the current review were to describe how road transportation can contribute to oxidative stress in livestock and provide a synopsis of the available literature regarding transit-induced oxidative stress. This review will also discuss potential nutritional strategies to mitigate oxidative stress and identify future research needs.

      CATTLE TRANSPORTATION PRACTICES

      Transportation of cattle by road is a necessary part of US beef production due to the segmented nature of the beef industry and disparity in geographical locations of industry segments. The cow-calf segment is widely dispersed across the United States to take advantage of forages grown on land typically not suitable for grain production. Alternatively, the feedlot segment is geographically more concentrated in areas where grain and grain by-product availability are high (i.e., the Midwest) or where the climate is suitable for cattle feeding (i.e., the Southern Plains). Therefore, a beef animal may be transported 4 times or more throughout its life: from birthplace to an auction market, stocker or backgrounding operation, feedlot, and finally to a processing facility. In addition to numerous transportation events, cattle may be transported over long distances. Data from 21 feedlots and 14,601 cohorts, defined as a group of cattle that were purchased and managed similarly, indicated the average distance traveled by feeder calves from place of origin to a feedlot was 698 km, with a maximum distance of 3,087 km (
      • Cernicchiaro N.
      • White B.J.
      • Renter D.G.
      • Babcock A.H.
      • Kelly L.
      • Slattery R.
      Associations between the distance traveled from sale barns to commercial feedlots in the United States and overall performance, risk of respiratory disease, and cumulative mortality in feeder cattle during 1997 to 2009..
      ). At an average driving speed of 100 km/h, the average transit duration would be 7 h, with a maximum duration of 31 h. Based on data from the 2016 National Beef Quality Audit, fed cattle were transported an average distance of 219 km (2.7 h) to processing facilities, with a maximum distance of 1,400 km (12 h;
      • NBQA (National Beef Quality Audit)
      National Beef Quality Audit Steer and Heifer.
      ). The effects of various transportation factors (loading density, transportation duration and distance, feed and water withdrawal, weather and trailer environment, and so on) on cattle well-being have been reviewed previously by
      • Schwartzkopf-Genswein K.
      • Ahola J.
      • Edwards-Callaway L.
      • Hale D.
      • Paterson J.
      Symposium Paper: Transportation issues affecting cattle well-being and considerations for the future..
      .
      Transportation stress is often compounded with the stress of weaning and predisposes feeder calves to the development of BRD. According to the
      • USDA
      Types and Costs of Respiratory Disease Treatments in US Feedlot.
      , 16.2% of feedlot cattle displayed signs of respiratory disease at some point during the feeding period and the direct cost of treatment for BRD was $23.60 per case. This does not include the cost of labor associated with handling and treating morbid cattle (
      • Wilkinson A.
      Future of BRD research: An animal health industry perspective..
      ), BRD-associated performance losses (
      • Gifford C.A.
      • Holland B.P.
      • Mills R.L.
      • Maxwell C.L.
      • Farney J.K.
      • Terrill S.J.
      • Step D.L.
      • Richards C.J.
      • Burciaga Robles L.O.B.
      • Krehbiel C.R.
      Growth and Development Symposium: Impacts of inflammation on cattle growth and carcass merit..
      ), or lesser carcass quality and yield for BRD-treated cattle (
      • Wilson B.K.
      • Step D.L.
      • Maxwell C.L.
      • Gifford C.A.
      • Richards C.J.
      • Krehbiel C.R.
      Effect of bovine respiratory disease during the receiving period on steer finishing performance, efficiency, carcass characteristics, and lung scores..
      ). Additional beef quality concerns associated with transit include bruising and dark cutting carcasses. Bruising can result from cattle bumping into one another during transit or from contact with trailer components, primarily during loading and unloading. Of 9,860 carcasses observed at 3 different slaughter facilities in the United States, 68.2% of carcasses were bruised and 53.5% of bruises occurred along the dorsal midline (
      • Lee T.L.
      • Reinhardt C.D.
      • Bartle S.J.
      • Vahl C.I.
      • Siemens M.
      • Thomson D.U.
      Assessment of risk factors contributing to carcass bruising in fed cattle at commercial slaughter facilities..
      ), the region of the carcass with the greatest economic value. Prolonged stress before slaughter depletes muscle glycogen stores, which leads to a phenomenon known as dark cutting carcasses. These carcasses have a higher ultimate pH and yield meat that appears dark and less fresh (
      • MacDougall D.B.
      Changes in the colour and opacity of meat..
      ), making it undesirable to consumers. In 2016, 1.9% of carcasses were classified as dark cutters (
      • NBQA (National Beef Quality Audit)
      National Beef Quality Audit Steer and Heifer.
      ). The potential for transportation to negatively influence carcass and meat characteristics has stimulated interest in transportation beef quality assurance, a program that provides information on best management practices for cattle transporters. As of January 1, 2020, major beef processors such as Cargill and Tyson will require beef quality assurance transportation certification for anyone delivering fed cattle to their facilities.

      OXIDATIVE STRESS

      Oxidative stress was first defined as “a disturbance in the prooxidant–antioxidant balance in favor of the former” (
      • Sies H.
      Oxidative stress: Introductory remarks.
      ). This simplified definition was later expounded to an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling, molecular damage, and impairment of physiological function (
      • Sies H.
      • Jones D.P.
      Oxidative stress.
      ;
      • Sordillo L.M.
      • Aitken S.L.
      Impact of oxidative stress on the health and immune function of dairy cattle..
      ). Under normal cellular conditions, the level of oxidants is balanced by the cell’s antioxidant defense system and thus fluctuates within a certain range referred to as basal oxidative stress or oxidative eustress (
      • Niki E.
      Oxidative stress and antioxidants: Distress or eustress?.
      ). An increase in the production of oxidants, depletion of antioxidants, or a combination of the 2 may increase oxidants above steady-state concentrations and result in different physiological outcomes depending on the intensity (low, intermediate, high) and duration (acute, chronic, repetitive) of the imbalance (
      • Lushchak V.I.
      Free radicals, reactive oxygen species, oxidative stress and its classification..
      ). Low intensity oxidative stress produces an adaptive response via redox regulation of transcription factors that upregulate antioxidant enzymes. In addition to antioxidant defense systems, redox signaling has been implicated in the activation of pathways involved in cell growth, proliferation, and survival (
      • Sundaresan M.
      • Yu Z.-X.
      • Ferrans V.J.
      • Irani K.
      • Finkel T.
      Requirement for generation of H2O2 for platelet-derived growth factor signal transduction..
      ;
      • Bae Y.
      • Kang S.
      • Seo M.
      • Baines I.
      • Tekle E.
      • Chock P.
      • Rhee S.
      Epidermal growth factor (EGF)-induced generation of hydrogen peroxide role in EGF receptor-mediated tyrosine phosphorylation..
      ); the innate and adaptive immune response (
      • Chandel N.S.
      • Trzyna W.C.
      • McClintock D.S.
      • Schumacker P.T.
      Role of oxidants in NF-κB activation and TNF-α gene transcription induced by hypoxia and endotoxin..
      ;
      • Wheeler M.L.
      • Defranco A.L.
      Prolonged production of reactive oxygen species in response to B cell receptor stimulation promotes B cell activation and proliferation..
      ); as well as stem cell self-renewal and differentiation (
      • Ito K.
      • Hirao A.
      • Arai F.
      • Takubo K.
      • Matsuoka S.
      • Miyamoto K.
      • Ohmura M.
      • Naka K.
      • Hosokawa K.
      • Ikeda Y.
      • Suda T.
      Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells..
      ;
      • Malinska D.
      • Kudin A.P.
      • Bejtka M.
      • Kunz W.S.
      Changes in mitochondrial reactive oxygen species synthesis during differentiation of skeletal muscle cells..
      ). Intermediate intensity oxidative stress also produces an adaptive response but may involve damage to cellular components including proteins, lipids, and nucleic acids. These oxidized molecules can further exacerbate oxidative stress and therefore must be repaired or degraded, often via ATP-dependent processes (
      • Lehnman I.R.
      DNA Ligase: Structure, mechanism, and function..
      ;
      • Grune T.
      • Reinheckel T.
      • Davies K.J.
      Degradation of oxidized proteins in mammalian cells..
      ;
      • Menoni H.
      • Gasparutto D.
      • Hamiche A.
      • Cadet J.
      • Dimitrov S.
      • Bouvet P.
      • Angelov D.
      ATP-dependent chromatin remodeling is required for base excision repair in conventional but not in variant H2A.Bbd nucleosomes..
      ). When oxidative stress reaches a high intensity, referred to as oxidative distress, cell death via necrosis, apoptosis, or both may result (
      • Saito Y.
      • Nishio K.
      • Ogawa Y.
      • Kimata J.
      • Kinumi T.
      • Yoshida Y.
      • Noguchi N.
      • Niki E.
      Turning point in apoptosis/necrosis induced by hydrogen peroxide..
      ). Because oxidative stress is defined based on the relationship between oxidants and antioxidants, it is important to consider both sides of this equation when assessing oxidative status in biological samples. Commonly assessed biomarkers include direct measurement of reactive oxygen species (ROS); oxidative modifications to proteins, lipids, and nucleic acids; concentrations of nonenzymatic antioxidants; and activities of antioxidant enzymes (Table 1). For a review of advantages and disadvantages of various oxidative stress biomarkers in ruminants, see the work by
      • Celi P.
      Biomarkers of oxidative stress in ruminant medicine..
      .
      Table 1Commonly measured biomarkers of oxidative stress
      CategoryExamples
      ROM = reactive oxygen metabolites; MDA = malondialdehyde; TBARS = thiobarbituric acid reactive substances; 8-OHdG = 8-hydroxy-2′-deoxyguanosine; FRAP = ferric reducing antioxidant potential.
      Reactive oxygen speciesElectron spin resonance, reactive oxygen metabolites
      Oxidative modificationsProteins: carbonyls, other oxidized AA products

      Lipids: MDA/TBARS, F2-isoprostanes

      Nucleic acids: 8-OHdG, other oxidized base products
      Nonenzymatic antioxidantsGlutathione, bilirubin, uric acid, α-tocopherol, ascorbic acid
      Antioxidant enzymesSuperoxide dismutase, glutathione peroxidase, catalase
      Antioxidant capacityTotal antioxidant capacity, FRAP
      1 ROM = reactive oxygen metabolites; MDA = malondialdehyde; TBARS = thiobarbituric acid reactive substances; 8-OHdG = 8-hydroxy-2′-deoxyguanosine; FRAP = ferric reducing antioxidant potential.

      Oxidants

      Reactive oxygen species can come from exogenous sources or be produced within cells. Exogenous sources of ROS that cattle might be exposed to during transport include exhaust fumes, UV light, and pollutants (
      • Schröder P.
      • Krutmann J.
      Environmental oxidative stress—Environmental sources of ROS.
      ), and endogenous sources of ROS include mitochondria, peroxisomes, and various enzymatic systems. Mitochondria are the major intracellular source of ROS due to the leaking of electrons from coenzyme Q onto oxygen in the electron transport chain to form superoxide radicals (O2•−;
      • Turrens J.F.
      • Alexandre A.
      • Lehninger A.L.
      Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria..
      ). Intracellular O2•− is also produced by cytochrome P-450, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and xanthine oxidase enzymes (
      • Nilsson R.
      • Pick F.M.
      • Bray R.C.
      EPR studies on reduction of oxygen to superoxide by some biochemical systems..
      ;
      • Sligar S.G.
      • Lipscomb J.D.
      • Debrunner P.G.
      • Gunsalus I.C.
      Superoxide anion production by the autoxidation of cytochrome P450cam..
      ;
      • Hohn D.
      • Lehrer R.
      NADPH oxidase deficiency in X-linked chronic granulomatous disease..
      ). Although O2•− is relatively unreactive and membrane impermeable, it is the precursor of most other ROS and propagates oxidative chain reactions (
      • Sawyer D.T.
      • Valentine J.S.
      How super is superoxide?.
      ). Spontaneous or enzymatic dismutation of O2•− produces hydrogen peroxide (H2O2), which can transverse membranes and has a relatively long half-life (1 ms) compared with other ROS, making it suitable as a signaling molecule (
      • Reth M.
      Hydrogen peroxide as second messenger in lymphocyte activation..
      ). In the presence of transition metals, such as Cu and Fe, H2O2 can participate in Fenton and Haber-Weiss reactions, leading to production of the hydroxyl radical (OH;
      • Fenton H.J.H.
      Oxidation of tartaric acid in presence of iron..
      ;
      • Haber F.
      • Weiss J.
      On the catalysis of hydroperoxide..
      ). The hydroxyl radical is highly reactive with a short half-life (10−9 s); thus, OH reacts closely to its site of formation and can oxidize most classes of biomolecules (
      • Halliwell B.
      • Gutteridge J.M.C.
      Biologically relevant metal ion-dependent hydroxyl radical generation An update..
      ). For example, interaction of OH with PUFA results in formation of lipid peroxyl radicals (
      • Gutteridge J.M.C.
      • Richmondt R.
      • Halliwellt B.
      Inhibition of the iron-catalysed formation of hydorxyl radicals from superoxide and of lipid peroxidation by desferrioxamine..
      ). Peroxyl radicals can also be produced by lipoxygenase and cyclooxygenase enzymes during synthesis of arachidonic acid–derived cell signaling molecules (
      • Hamberg M.
      • Samuelsson B.
      On the mechanism of the biosynthesis of prostaglandins E1 and F..
      ;
      • Tang M.S.
      • Copeland R.A.
      • Penning T.M.
      Detection of an Fe 2+-protoporphyrin-IX intermediate during aspirin-treated prostaglandin H2 synthase II catalysis of arachidonic acid to 15-HETE..
      ). Thus, cattle are exposed to increased levels of oxidants from environmental exposure during transit and from activation of ROS-producing biological pathways in response to transit (see section on Transit-Induced Oxidative Stress).

      Antioxidants

      The cellular antioxidant defense system is composed of endogenous nonenzymatic antioxidants and antioxidant enzymes as well as antioxidants obtained exogenously. Endogenously produced nonenzymatic antioxidants include glutathione and ascorbic acid (vitamin C; VC). Glutathione is a tripeptide composed of glutamine, cysteine, and lysine that is synthesized in a 2-step ATP-dependent process in the liver and transported to tissues in the blood (
      • Griffith O.W.
      Biologic and pharmacologic regulation of mammalian glutathione synthesis..
      ). The thiol group of cysteine can donate an H atom to neutralize ROS, maintain protein cysteine residues in their reduced form, and recycle other cellular antioxidants (
      • Meister A.
      • Anderson M.E.
      Glutathione..
      ). Upon H donation, oxidized glutathione can be regenerated to its reduced form by glutathione reductase using NADPH (
      • Racker E.
      Glutathione reductase from bakers’ yeast and beef liver..
      ). Ascorbic acid is the major water-soluble antioxidant present in cells. Several species (e.g., humans, guinea pigs, bats) have lost the ability to endogenously synthesize VC due to mutations in the l-gulonolactone oxidase gene, which codes for the enzyme catalyzing the last step of VC biosynthesis (
      • Drouin G.
      • Godin J.-R.
      • Pagé B.
      The genetics of vitamin C loss in vertebrates..
      ). This enzyme is functional in mammalian livestock species and poultry, allowing for the synthesis of VC from glucose (
      • Chatterjee I.
      Evolution and the biosynthesis of ascorbic acid..
      ) and, in most cases, eliminating the need for exogenous supplementation. Ascorbic acid can reduce ROS through 2 successive electron donations; the first donation results in the formation of the ascorbyl free radical, which can undergo a second electron donation to form dehydroascorbic acid (
      • Bendich A.
      • Machlin L.J.
      • Scandurra O.
      • Burton G.W.
      • Wayner D.D.M.
      The antioxidant role of vitamin C..
      ). Mechanisms of VC recycling include reduction by intracellular dehydroascorbic acid reductases such as thioredoxin reductase (
      • May J.M.
      • Mendiratta S.
      • Hill K.E.
      • Burk R.F.
      Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase..
      ) as well as other endogenous antioxidants such as glutathione (
      • Winkler B.S.
      • Orselli S.M.
      • Rex T.S.
      The redox couple between glutathione and ascorbic acid: A chemical and physiological perspective..
      ).
      The primary antioxidant enzymes within cells include superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase. Superoxide dismutase catalyzes the dismutation of O2•− to form H2O2 and water (
      • McCord J.
      • Fridovich I.
      Superoxide dismutase: An enzymatic function for erythrocuprein (hemocuprein)..
      ). Three SOD isoforms have been characterized in mammalian cells based on the metal cofactor required for activity and cellular localization. Isoforms that require Cu and Zn cofactors include SOD1, located in the cytosol and intermembrane space of mitochondria (
      • Weisiger R.A.
      • Fridovich I.
      Mitochondrial superoxide dismutase site of synthesis and intramitochondrial localization..
      ;
      • Okado-Matsumoto A.
      • Fridovich I.
      Subcellular distribution of superoxide dismutases (SOD) in rat liver..
      ), and SOD3, located in the extracellular space (
      • Marklund S.L.
      • Holme E.
      • Hellner L.
      Superoxide dismutase in extracellular fluids..
      ). The Mn-dependent SOD2 is located within the mitochondrial matrix (
      • Weisiger R.A.
      • Fridovich I.
      Superoxide dismutase: Organelle specificity..
      ). As mentioned previously, mitochondria are the primary endogenous source of O2•−, which gives rise to other ROS. Thus, Mn-SOD represents an important first line of antioxidant defense, demonstrated by embryonic or early postnatal lethality in mice with complete loss of Mn-SOD (
      • Li Y.
      • Huang T.-T.
      • Carlson E.J.
      • Melov S.
      • Ursell P.C.
      • Olson J.L.
      • Noble L.J.
      • Yoshimura M.P.
      • Berger C.
      • Chan P.H.
      • Wallace D.C.
      • Epstein C.J.
      Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase..
      ;
      • Lebovitz R.M.
      • Zhang H.
      • Vogel H.
      • Cartwright J.
      • Dionne L.
      • Lu N.
      • Huang S.
      • Matzuk M.M.
      Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice..
      ). Hydrogen peroxide produced by SOD can be reduced to water by the action of GPX or catalase. Major mammalian GPX isoforms include cytosolic GPX 1 and membrane associated GPX3 (
      • Margis R.
      • Dunand C.
      • Teixeira F.K.
      • Margis-Pinheiro M.
      Glutathione peroxidase family—An evolutionary overview..
      ), both of which require Se as a cofactor and use the reducing power of glutathione (
      • Rotruck J.T.
      • Pope A.L.
      • Ganther H.E.
      • Swanson A.B.
      • Hafeman D.G.
      • Hoekstra W.G.
      Selenium: Biochemical role as a component of glutathione peroxidase..
      ). Catalase is an Fe-dependent enzyme distributed throughout mammalian cells but is found mostly in peroxisomes where high concentrations of H2O2 are produced (
      • De Duve D.
      • Baudhuin P.
      Peroxisomes (microbodies and related particles)..
      ). Phagocytic immune cells also express high concentrations of catalase to protect cells from high concentrations of H2O2 produced to kill pathogens during the respiratory burst (
      • Gee J.B.L.
      • Vassallo C.L.
      • Bell P.
      • Kaskin J.
      • Basford R.E.
      • Field J.B.
      Catalase-dependent peroxidative metabolism in the alveolar macrophage during phagocytosis..
      ).
      Antioxidant compounds that must be consumed or delivered parenterally include tocopherols (vitamin E; VE) and carotenoids (provitamin A compounds found in plant pigments). Vitamin E is the major lipid-soluble antioxidant present in cells and thus plays a vital role in maintenance of cell membrane integrity (
      • Burton G.W.
      • Joyce A.
      • Ingold K.U.
      First proof that vitamin E is major lipid-soluble, chain-breaking antioxidant in human blood plasma..
      ). The antioxidant function of VE is due to its ability to donate a phenolic hydrogen to ROS, most commonly lipid peroxyl radicals within the membrane (
      • Burton G.W.
      • Ingold K.U.
      Autoxidation of biological molecules. 1. The antioxidant activity of vitamin E and related chain-breaking phenolic antioxidants in vitro..
      ). This donation results in formation of the relatively unreactive tocopheroxyl radical, which can be reduced by VC or irreversibly oxidized to tocopherolquinone (
      • van Acker S.A.B.E.
      • Koymans L.M.H.
      • Bast A.
      Molecular pharmacology of vitamin E: Structural aspects of antioxidant activity..
      ). Several lipid-soluble carotenoids (e.g., β-carotene, lycopene) have been shown to exhibit antioxidant activity (
      • Foote C.S.
      • Denny R.W.
      Chemistry of singlet oxygen. VII. Quenching by beta-carotene..
      ;
      • Di Mascio P.
      • Kaiser S.
      • Sies H.
      Lycopene as the most efficient biological carotenoid singlet oxygen quencher..
      ). However, these compounds are present at much lower concentrations in tissues than VE and thus thought to be less significant in cellular antioxidant defense (
      • Burton G.
      • Ingold K.
      beta-Carotene: An unusual type of lipid antioxidant..
      ). Although the cellular antioxidant defense system is extremely redundant to protect cells from the detrimental effects of oxidative stress (
      • Jacob R.A.
      The integrated antioxidant system..
      ), there may be situations, such as transit, where cattle may benefit from nutritional intervention to improve antioxidant status before or after transit (see section on Oxidative Stress Mitigation Strategies).

      Implications for Animal Health, Efficiency, and Meat Quality

      Oxidative status is critical to immune cell function and integrity, evidenced by decreased immunocompetence in animals that exhibit deficiencies in vitamins or trace minerals (TM) that support antioxidant defense (
      • Fernandes G.
      • Nair M.
      • Onoe K.
      • Tanaka T.
      • Floyd R.
      • Good R.A.
      Impairment of cell-mediated immunity functions by dietary zinc deficiency in mice..
      ;
      • Bendich A.
      • Gabriel E.
      • Machlin L.J.
      Dietary vitamin E requirement for optimum immune responses in the rat..
      ;
      • Smith S.M.
      • Levy N.S.
      • Hayes C.E.
      Impaired immunity in vitamin A-deficient mice..
      ). Thus, it is not surprising that oxidative stress has been implicated in several pathological conditions relevant to livestock (reviewed by
      • Lykkesfeldt J.
      • Svendsen O.
      Oxidants and antioxidants in disease: Oxidative stress in farm animals..
      ;
      • Armstrong D.
      Oxidative Stress in Applied Basic Research and Clinical Practice.
      ). Most relevant to the current review is the role of oxidative stress in BRD.
      • Urban-Chmiel R.
      The influence of transport stress on oxidative stress parameters in bovine leukocytes. 7th Middle Eur. Buiatric Congr.
      evaluated the oxidative status of leukocytes, immune cells that generate ROS as part of their phagocytic mechanism, isolated from transported calves. Lipid peroxidation and antioxidant capacity were increased 71 and 12% after transit, respectively, suggesting transit resulted in oxidative damage that may have stimulated upregulation of cellular antioxidants. When compared with nontransported calves, lipid peroxidation was 218% greater and antioxidant capacity was 186% lesser in leukocytes isolated from transported calves (
      • Urban-Chmiel R.
      • Kankofer M.
      • Wernicki A.
      • Albera E.
      • Puchalski A.
      The influence of different doses of α-tocopherol and ascorbic acid on selected oxidative stress parameters in in vitro culture of leukocytes isolated from transported calves..
      ); these differences were ablated when cells were incubated with antioxidants (α-tocopherol or ascorbic acid) at concentrations greater than 0.1 mg/mL.
      • Chirase N.K.
      • Greene L.W.
      • Purdy C.W.
      • Loan R.W.
      • Auvermann B.W.
      • Parker D.B.
      • Walborg E.F.
      • Stevenson D.E.
      • Xu Y.
      • Klaunig J.E.
      Effect of transport stress on respiratory disease, serum antioxidant status, and serum concentrations of lipid peroxidation biomarkers in beef cattle..
      also observed increased lipid peroxidation (177%) and decreased antioxidant status (11%) in the serum of beef calves after transit relative to pretransit values. Furthermore, post-transit serum malondialdehyde (MDA) concentrations were 43% greater in calves that later died of acute BRD, and calves that experienced ≥3 episodes of BRD had 2-fold greater MDA concentrations after transit than healthy calves.
      • Eitam H.
      • Vaya J.
      • Brosh A.
      • Orlov A.
      • Khatib S.
      • Izhaki I.
      • Shabtay A.
      Differential stress responses among newly received calves: Variations in reductant capacity and Hsp gene expression..
      observed greater linoleoyl tyrosine oxidation products before and after transit in blood samples from calves that eventually had pulmonary adhesions at slaughter, providing evidence that oxidative status may be a contributing factor in the development of BRD. Reactive oxygen species produced by immune cells to eliminate pathogenic bacteria can damage and kill pulmonary cells, resulting in respiratory inflammation and dysfunction (
      • Martin II, W.J.
      Neutrophils kill pulmonary endothelial cells by a hydrogen-peroxide-dependent pathway. An in vitro model of neutrophil-mediated lung injury..
      ;
      • Wright D.T.
      • Cohn L.A.
      • Li H.
      • Fischer B.
      • Ming Li C.
      • Adler K.B.
      Interactions of oxygen radicals with airway epithelium..
      ). These data indicate that transit-induced oxidative damage can impair immune-cell and respiratory function, which ultimately increases morbidity and mortality.
      Oxidative stress induced by transit may be energetically expensive as ATP is often required to repair or degrade oxidatively damaged molecules and to support production of cellular antioxidants. Indeed, a negative relationship between oxidative stress and feed efficiency in livestock has been observed (reviewed by
      • Bottje W.G.
      • Carstens G.E.
      Association of mitochondrial function and feed efficiency in poultry and livestock species..
      ;
      • Bottje W.G.
      Board Invited Review: Oxidative stress and efficiency: The tightrope act of mitochondria in health and disease..
      ). Oxidative damage to proteins, assessed by protein carbonyls, was greater in breast, leg, heart, liver, gut, and lymphocytes of lowly versus highly feed efficient broilers (
      • Bottje W.
      • Pumford N.R.
      • Ojano-Dirain C.
      • Iqbal M.
      • Lassiter K.
      Feed efficiency and mitochondrial function..
      ). Multiple studies have also reported greater protein oxidation and mitochondrial ROS production in broilers exhibiting a low feed efficiency phenotype (
      • Bottje W.
      • Iqbal M.
      • Tang Z.X.
      • Cawthon D.
      • Okimoto R.
      • Wing T.
      • Cooper M.
      Association of mitochondrial function with feed efficiency within a single genetic line of male broilers..
      ;
      • Iqbal M.
      • Pumford N.R.
      • Tang Z.X.
      • Lassiter K.
      • Wing T.
      • Cooper M.
      • Bottje W.
      Low feed efficient broilers within a single genetic line exhibit higher oxidative stress and protein expression in breast muscle with lower mitochondrial complex activity..
      ;
      • Ojano-Dirain C.P.
      • Iqbal M.
      • Cawthon D.
      • Swonger S.
      • Wing T.
      • Cooper M.
      • Bottje W.
      Determination of mitochondrial function and site-specific defects in electron transport in duodenal mitochondria in broilers with low and high feed efficiency..
      ;
      • Iqbal M.
      • Pumford N.R.
      • Tang Z.X.
      • Lassiter K.
      • Ojano-Dirain C.
      • Wing T.
      • Cooper M.
      • Bottje W.
      Compromised liver mitochondrial function and complex activity in low feed efficient broilers are associated with higher oxidative stress and differential protein expression..
      ). Alternatively,
      • Russell J.R.
      • Sexten W.J.
      • Kerley M.S.
      • Hansen S.L.
      Relationship between antioxidant capacity, oxidative stress, and feed efficiency in beef steers..
      observed greater plasma protein carbonyl concentrations and a greater ratio of oxidized to reduced glutathione concentrations in red blood cell lysate from highly versus lowly feed efficient steers. The authors suggested that this finding may be indicative of greater tolerance for oxidative stress by highly feed efficient steers. Indeed, antioxidant enzyme (Mn-SOD and GPX) activity was greater in lowly feed efficient steers, suggesting these steers were potentially using energy to combat oxidative stress rather than to promote tissue accretion (
      • Russell J.R.
      • Sexten W.J.
      • Kerley M.S.
      • Hansen S.L.
      Relationship between antioxidant capacity, oxidative stress, and feed efficiency in beef steers..
      ). The discrepancies observed among studies suggest that the type of tissue measured may have significant effects on interpretation of results. In addition to increasing energy requirements, oxidative stress can hinder cellular energy production by signaling for the diversion of substrates from glycolysis to the pentose phosphate pathway (
      • Kuehne A.
      • Emmert H.
      • Soehle J.
      • Winnefeld M.
      • Fischer F.
      • Wenck H.
      • Gallinat S.
      • Terstegen L.
      • Lucius R.
      • Hildebrand J.
      • Zamboni N.
      Acute activation of oxidative pentose phosphate pathway as first-line response to oxidative stress in human skin cells..
      ). This pathway produces reducing equivalents (i.e., NADPH), which are vital to maintaining the cellular antioxidant defense system. Although the studies presented herein provide mechanistic insight into the negative effects of oxidative stress on efficiency at the cellular level, the challenges of delivering a specific oxidative insult at the whole-animal level (
      • Koch R.E.
      • Hill G.E.
      An assessment of techniques to manipulate oxidative stress in animals..
      ) have made it difficult to quantify the effect of oxidative stress on growth performance and production efficiency.
      Premortem oxidative stress has the potential to affect postmortem oxidative status and meat quality (
      • Xing T.
      • Gao F.
      • Tume R.K.
      • Zhou G.
      • Xu X.
      Stress effects on meat quality: A mechanistic perspective..
      ) as muscle loses the ability to maintain the cellular antioxidant defense system postmortem, which can lead to an accumulation of ROS (
      • Renerre M.
      • Dumont F.
      • Gatellier P.
      Antioxidant enzyme activities in beef in relation to oxidation of lipid and myoglobin..
      ). Lipid oxidation is a primary cause of quality defects in meat products, including changes in flavor, color, texture, and nutritive value (
      • Gray J.I.
      • Gomaa E.A.
      • Buckley D.J.
      Oxidative quality and shelf life of meats..
      ). Protein oxidation also plays a vital role in meat quality. Proteins can be oxidized in several ways including oxidation of AA residues and the protein backbone as well as formation of protein carbonyls and protein–protein crosslinks (
      • Berlett B.S.
      • Stadtman E.R.
      Protein oxidation in aging, disease, and oxidative stress..
      ). These oxidative modifications alter protein structure and function, which negatively influence water-holding capacity and tenderness of meat products (
      • Zhang W.
      • Xiao S.
      • Ahn D.U.
      Protein oxidation: Basic principles and implications for meat quality..
      ). The activity of calcium-dependent proteases (calpains) influences meat tenderness as these enzymes are involved in postmortem proteolysis of key myofibrillar proteins (
      • Goll D.E.
      • Thompson V.F.
      • Li H.
      • Wei W.
      • Cong J.
      The calpain system..
      ). Calpains are susceptible to oxidation and subsequent inactivation because their active site contains a cysteine residue (
      • Guttmann R.P.
      • Elce J.S.
      • Bell P.D.
      • Isbell J.C.
      • Johnson G.V.W.
      Oxidation inhibits substrate proteolysis by calpain I but not autolysis..
      ).
      • Rowe L.J.
      • Maddock K.R.
      • Lonergan S.M.
      • Huff-Lonergan E.
      Oxidative environments decrease tenderization of beef steaks through inactivation of u-calpain..
      observed beef steaks exposed to oxidizing conditions (irradiation) had decreased μ-calpain activity, lesser proteolysis, and greater Warner Bratzler shear force values, indicating a less tender steak. Eating satisfaction, specifically tenderness and flavor, as well as visual characteristics of meat are quality factors that are of high priority to consumers (
      • NBQA (National Beef Quality Audit)
      National Beef Quality Audit Steer and Heifer.
      ). Therefore, efforts have been made to lessen lipid and protein oxidation in meat through antemortem antioxidant supplementation, addition of antioxidants to the meat product, or incorporation of antioxidants into the packaging material (
      • Mitsumoto M.
      • Arnold R.N.
      • Schaefer D.M.
      • Cassens R.G.
      Dietary versus postmortem supplementation of vitamin E on pigment and lipid stability in ground beef..
      ;
      • Buckley D.J.
      • Morrissey P.A.
      • Gray J.I.
      Influence of dietary vitamin E on the oxidative stability and quality of pig meat..
      ;
      • Nerín C.
      • Tovar L.
      • Djenane D.
      • Camo J.
      • Salafranca J.
      • Beltrán J.A.
      • Roncalés P.
      Stabilization of beef meat by a new active packaging containing natural antioxidants..
      ).

      TRANSIT-INDUCED OXIDATIVE STRESS

      Understanding transit-induced oxidative stress may be crucial to understanding the negative effects of transit on producer profitability (animal health and feed efficiency) and consumer experiences (meat quality). This section will focus on how the physiologic responses to transit (psychological stress, food deprivation, and physical exertion) contribute to the production of ROS (Figure 1). Over the past 20 yr, the effects of transit on oxidative stress biomarkers have been examined in various species; a summary of these transit-induced changes is presented in Table 2.
      Table 2Summary of the scientific literature examining changes in oxidative stress biomarkers due to transportation of livestock
      ReferenceAnimal description
      The values in parentheses are weights ±SD.
      Transit duration, distanceTissueBiomarker
      FRAP = ferric reducing antioxidant potential; GSH = glutathione; GSH-Px = glutathione peroxidase; GR = glutathione reductase; MDA = malondialdehyde; ROS = reactive oxygen species; SOD = superoxide dismutase; TBARS = thiobarbituric acid reactive substances; dROM = derivatives of reactive oxygen metabolites; GST = glutathione S-transferase.
      Effect of transit
      In reference to baseline (pretransit) values or a nontransported control group.
      • Chirase N.
      • Green L.
      • Purdy C.
      • Loan R.
      • Briggs R.
      • Mcdowell L.
      Effect of environmental stressors on ADG, serum retinol and alpha-tocopherol concentration and incidence of bovine respiratory disease of feeder steers..
      120 Crossbred beef steers (185 kg)18 h, 1,890 kmSerumα-TocopherolDecrease
      • Chirase N.K.
      • Greene L.W.
      • Purdy C.W.
      • Loan R.W.
      • Auvermann B.W.
      • Parker D.B.
      • Walborg E.F.
      • Stevenson D.E.
      • Xu Y.
      • Klaunig J.E.
      Effect of transport stress on respiratory disease, serum antioxidant status, and serum concentrations of lipid peroxidation biomarkers in beef cattle..
      105 Crossbred beef steers (207 ± 21.2 kg)19 h 40 min, 1,930 kmSerumTotal antioxidant capacityDecrease
      SerumMDA (HPLC)Increase
      • Urban-Chmiel R.
      The influence of transport stress on oxidative stress parameters in bovine leukocytes. 7th Middle Eur. Buiatric Congr.
      9 Heifer calves (150 kg)1.5 h, 80 kmLeukocytesMDA (TBARS)Increase
      LeukocytesFRAPIncrease
      LeukocytesROS productionIncrease
      • Wernicki A.
      • Urban-Chmiel R.
      • Kankofer M.
      • Mickucki P.
      • Puchalski A.
      • Tokarzewski S.
      Evaluation of plasma cortisol and TBARS levels in calves after short-term transportation..
      9 Heifer calves (100 kg)2 h, 120–140 kmPlasmaMDA (TBARS)Increase
      • Nazifi S.
      • Saeb M.
      • Baghshani H.
      • Saeb S.
      Influence of road transportation during hot summer conditions on oxidative status biomarkers in Iranian dromedary camels (Camelus dromedarius)..
      10 Iranian dromedary camels (300 kg)5 h, 300 kmPlasmaMDAIncrease
      Plasmaα-TocopherolNumerical decrease
      ErythrocytesSOD activityNone
      Whole bloodGSH-Px activityIncrease
      • Burke N.C.
      • Scaglia G.
      • Boland H.T.
      • Swecker Jr., W.S.
      Influence of two-stage weaning with subsequent transport on body weight, plasma lipid peroxidation, plasma selenium, and on leukocyte glutathione peroxidase and glutathione reductase activity in beef calves..
      36 Crossbred beef steers (243 ± 20.8 kg)2 h, 172 kmPlasmaMDADecrease
      LeukocytesGSH-Px activityNone
      LeukocytesGR activityDecrease
      PlasmaSeDecrease
      • Zhong R.Z.
      • Liu H.W.
      • Zhou D.W.
      • Sun H.X.
      • Zhao C.S.
      The effects of road transportation on physiological responses and meat quality in sheep differing in age..
      24 Ujumqin sheep (23–29 kg)8 hSerumMDA (TBARS)Increase
      • Aktas M.S.
      • Ozkanlar S.
      • Karakoc A.
      • Akcay F.
      • Ozkanlar Y.
      Efficacy of vitamin E + selenium and vitamin A + D + E combinations on oxidative stress induced by long-term transportation in Holstein dairy cows..
      30 Holstein cows (400–600 kg)22 h, 1,250 km (1-h break every 8 h)SerumMDA (TBARS)Increase
      • Onmaz A.C.
      • Van Den Hoven R.
      • Gunes V.
      • Cinar M.
      • Kucuk O.
      Oxidative stress in horses after a 12-hours transport period..
      10 Horses (480 ± 33 kg)12 h, 538 kmPlasmaMDA (TBARS)Increase
      PlasmaSOD activityDecrease
      • Piccione G.
      • Casella S.
      • Giannetto C.
      • Bazzano M.
      • Giudice E.
      • Fazio F.
      Oxidative stress associated with road transportation in ewes..
      20 Comisana ewes (55 ± 4 kg)6 h, 490 kmSerumReactive oxygen species (dROM)Increase
      SerumAntioxidant barrier (oxy-adsorbent)Increase
      SerumThiol antioxidant barrier (SHp)Increase
      • Niedźwiedź A.
      • Nicpoń J.
      • Zawadzki M.
      • Słuzewska-Niedźwiedź M.
      • Januszewska L.
      The influence of road transport on the activities of glutathione reductase, glutathione peroxidase, and glutathione-S-transferase in equine erythrocytes..
      60 Horses (680 ± 50 kg)8 hErythrocytesGR activityDecrease
      ErythrocytesGSH-Px activityDecrease
      ErythrocytesGST activityNone
      • Niedźwiedź A.
      • Kubiak K.
      • Nicpoń J.
      Plasma total antioxidant status in horses after 8-hours of road transportation..
      60 Horses (680 ± 50 kg)8 h, 560 kmPlasmaFRAPIncrease
      • Adenkola A.Y.
      • Ayo J.O.
      Physiological and behavioural responses of livestock to road transportation stress: A review..
      7 Rams8 h, 300 kmSerumMDA (TBARS)Increase
      • EL-Deeb W.M.
      • El-Bahr S.M.
      Acute-phase proteins and oxidative stress biomarkers in water buffalo calves subjected to transportation stress..
      50 Water buffalo calves (165 ± 13 kg)4 h, 250 kmPlasmaMDAIncrease
      PlasmaNitric oxideDecrease
      PlasmaSOD activityDecrease
      PlasmaReduced GSHDecrease
      • Wernicki A.
      • Urban-Chmiel R.
      • Puchalski A.
      • Dec M.
      Evaluation of the influence of transport and adaptation stress on chosen immune and oxidative parameters and occurrence of respiratory syndrome in feedlot calves..
      60 Beef bull calves (110 kg)120 kmSerumMDA (TBARS)Increase
      • Polycarp T.N.
      • Obukowho E.B.
      • Yusoff S.M.
      Changes in haematological parameters and oxidative stress response of goats subjected to road transport stress in a hot humid tropical environment..
      35 Boer goats (23–25 kg)7 h, 350 kmPlasmaMDA (TBARS)Increase
      ErythrocytesSOD activityDecrease
      PlasmaReduced GSHDecrease
      • Padalino B.
      • Raidal S.L.
      • Carter N.
      • Celi P.
      • Muscatello G.
      • Jeffcott L.
      • de Silva K.
      Immunological, clinical, haematological and oxidative responses to long distance transportation in horses..
      16 Horses94 h (51 h in transit)PlasmaTotal antioxidant statusIncrease
      PlasmaReactive oxygen metabolitesNone
      • Deters E.L.
      • Hansen S.L.
      Effect of supplementing a Saccharomyces cerevisiae fermentation product during a preconditioning period prior to transit on receiving period performance, nutrient digestibility, and antioxidant defense by beef steers..
      48 Crossbred beef steers (257 ± 18 kg)19 h, 1,748 kmPlasmaMDA (TBARS)None
      ErythrocytesMn-SOD activityIncrease
      ErythrocytesCu, Zn-SOD activityDecrease
      E. L. Deters and S. L. Hansen (unpublished data)72 Crossbred beef steers (356 ± 18 kg)18 h, 1,675 kmPlasmaMDA (TBARS)Decrease
      PlasmaFRAPDecrease
      PlasmaAscorbateDecrease
      1 The values in parentheses are weights ±SD.
      2 FRAP = ferric reducing antioxidant potential; GSH = glutathione; GSH-Px = glutathione peroxidase; GR = glutathione reductase; MDA = malondialdehyde; ROS = reactive oxygen species; SOD = superoxide dismutase; TBARS = thiobarbituric acid reactive substances; dROM = derivatives of reactive oxygen metabolites; GST = glutathione S-transferase.
      3 In reference to baseline (pretransit) values or a nontransported control group.

      Psychological Stress

      Livestock are exposed to a variety of psychological stressors during transport including handling during loading and unloading, unfamiliar noises and environments, as well as commingling. The body responds to stress by activating 2 major hormonal axes. In the short term, activation of the sympathetic-adrenal-medullary axis initiates the release of catecholamines including epinephrine (i.e., adrenaline) and norepinephrine. These hormones support the fight-or-flight response by increasing heart rate, blood pressure, and glucose availability via stimulation of hepatic glycogenolysis (
      • Himms-Hagen J.
      Sympathetic regulation of metabolism..
      ). The long-term stress response is maintained by the hypothalamic-pituitary-adrenal axis. Briefly, corticotrophic-releasing hormone and vasopressin released from the hypothalamus stimulate the release of adrenocorticotrophic hormone from the pituitary, which ultimately signals the release of glucocorticoids (primarily cortisol in mammals) from the adrenal cortex (
      • Charmandari E.
      • Tsigos C.
      • Chrousos G.
      Endocrinology of the stress response..
      ). Glucocorticoids stimulate the release of glycerol and fatty acids from adipose tissue as well as AA from muscle, directing these nutrients toward the liver for enzyme synthesis and gluconeogenesis (
      • Baxter J.D.
      • Forsham P.H.
      Tissue effects of glucocorticoids..
      ). The uptake and aerobic metabolism of these substrates by other tissues increases mitochondrial-derived ROS simply as a result of greater electron flow through the electron transport chain and electron leakage to oxygen.
      Both cortisol and MDA in calves have been shown to increase following a 2-h transit event: cortisol peaked on d 1 and returned to baseline by d 16 after transit, and MDA peaked on d 3 and returned to baseline by d 9 after transit (
      • Wernicki A.
      • Urban-Chmiel R.
      • Kankofer M.
      • Mickucki P.
      • Puchalski A.
      • Tokarzewski S.
      Evaluation of plasma cortisol and TBARS levels in calves after short-term transportation..
      ). Numerous (14 of 19) studies presented in Table 2 assessed MDA concentrations, and 11 of those 14 studies reported increased MDA concentrations due to transit. Transit-induced increases in markers of oxidative damage coincide with decreases in concentrations of nonenzymatic antioxidants (
      • Chirase N.
      • Green L.
      • Purdy C.
      • Loan R.
      • Briggs R.
      • Mcdowell L.
      Effect of environmental stressors on ADG, serum retinol and alpha-tocopherol concentration and incidence of bovine respiratory disease of feeder steers..
      ;
      • Burke N.C.
      • Scaglia G.
      • Boland H.T.
      • Swecker Jr., W.S.
      Influence of two-stage weaning with subsequent transport on body weight, plasma lipid peroxidation, plasma selenium, and on leukocyte glutathione peroxidase and glutathione reductase activity in beef calves..
      ;
      • Nazifi S.
      • Saeb M.
      • Baghshani H.
      • Saeb S.
      Influence of road transportation during hot summer conditions on oxidative status biomarkers in Iranian dromedary camels (Camelus dromedarius)..
      ;
      • EL-Deeb W.M.
      • El-Bahr S.M.
      Acute-phase proteins and oxidative stress biomarkers in water buffalo calves subjected to transportation stress..
      ;
      • Polycarp T.N.
      • Obukowho E.B.
      • Yusoff S.M.
      Changes in haematological parameters and oxidative stress response of goats subjected to road transport stress in a hot humid tropical environment..
      ) and antioxidant enzyme activity (
      • Burke N.C.
      • Scaglia G.
      • Boland H.T.
      • Swecker Jr., W.S.
      Influence of two-stage weaning with subsequent transport on body weight, plasma lipid peroxidation, plasma selenium, and on leukocyte glutathione peroxidase and glutathione reductase activity in beef calves..
      ;
      • Onmaz A.C.
      • Van Den Hoven R.
      • Gunes V.
      • Cinar M.
      • Kucuk O.
      Oxidative stress in horses after a 12-hours transport period..
      ;
      • Niedźwiedź A.
      • Nicpoń J.
      • Zawadzki M.
      • Słuzewska-Niedźwiedź M.
      • Januszewska L.
      The influence of road transport on the activities of glutathione reductase, glutathione peroxidase, and glutathione-S-transferase in equine erythrocytes..
      ;
      • EL-Deeb W.M.
      • El-Bahr S.M.
      Acute-phase proteins and oxidative stress biomarkers in water buffalo calves subjected to transportation stress..
      ;
      • Polycarp T.N.
      • Obukowho E.B.
      • Yusoff S.M.
      Changes in haematological parameters and oxidative stress response of goats subjected to road transport stress in a hot humid tropical environment..
      ). Most authors concluded the observed decrease in enzyme activity is a result of increased ROS production and subsequent consumption of the enzyme for antioxidant reactions. However,
      • Deters E.L.
      • Hansen S.L.
      Effect of supplementing a Saccharomyces cerevisiae fermentation product during a preconditioning period prior to transit on receiving period performance, nutrient digestibility, and antioxidant defense by beef steers..
      observed increased red blood cell lysate Mn-SOD activity in beef steers after a 19-h transit event. Similarly,
      • Nazifi S.
      • Saeb M.
      • Baghshani H.
      • Saeb S.
      Influence of road transportation during hot summer conditions on oxidative status biomarkers in Iranian dromedary camels (Camelus dromedarius)..
      observed an increase in whole-blood GPX activity 24 h after transit in camels and concluded this was a compensatory response of cells to mitigate increased oxidant concentrations. As positive or negative changes in antioxidant enzyme activity can be interpreted as being a result of increased oxidative stress, it is important to pair enzyme activity with direct markers of oxidative damage. Identification of appropriate biomarkers of oxidative stress in livestock species will continue to be a rate-limiting step in our understanding of the effect of oxidative stress on production.

      Food Deprivation

      Commercial livestock trailers are typically not equipped to hold feed and water; thus, animals are deprived of feed and water for at least the duration of transit, resulting in loss of BW (i.e., shrink). Although cattle recover lost BW relatively quickly (average 10.6 d; range 3–30 d;
      • Self H.L.
      • Gay N.
      Shrink during shipment of feeder cattle..
      ), there may be longer effects of transit that are not yet fully understood. Food deprivation necessitates the use of body reserves to supply the animal with energy. In a fasted state, blood glucose concentrations decline due to less glucose availability from the gastrointestinal tract and depletion of liver glycogen stores. The decline in blood glucose leads to decreased insulin secretion and increased glucagon secretion from the pancreas (
      • Gerich J.E.
      • Charles M.A.
      • Grodsky G.M.
      Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused rat pancreas..
      ,
      • Gerich J.E.
      • Schneider V.
      • Dippe S.E.
      • Langlois M.
      • Noacco C.
      • Karam J.H.
      • Forsham P.H.
      Characterization of the glucagon response to hypoglycemia in man..
      ), which stimulates the liver to increase glycogenolysis and gluconeogenesis to maintain blood glucose concentrations (
      • Wagle S.R.
      • Ingebretsen Jr., W.R.
      Stimulation of glycogenolysis by epinephrine and glucagon and its inhibition by insulin in isolated rat liver hepatocytes..
      ;
      • Eisenstein A.B.
      • Strack I.
      • Steiner A.
      Glucagon stimulation of hepatic gluconeogenesis in rats fed a high-protein, carbohydrate-free diet..
      ). Additionally, glucagon stimulates the hydrolysis of triglycerides into glycerol and nonesterified fatty acids to facilitate their mobilization from adipose tissue and use as metabolic fuel in other tissues including the liver and muscle (
      • Perea A.
      • Clemente F.
      • Martinell J.
      • Villanueva-Peñacarrillo M.
      • Valverde I.
      Physiological effect of glucagon in human isolated adipocytes..
      ). The subsequent aerobic metabolism of these nutrients increases mitochondrial ROS production; thus, feed deprivation is a contributing factor to transit-induced oxidative stress.
      Before feedlot arrival, cattle may experience periods of fasting lasting up to 72 h. This includes time in transit as well as time spent at auction markets, where feed may not be provided. Furthermore, cattle may self-restrict feed intake upon arrival, which could further exacerbate oxidative stress conditions depending on the severity of the restriction. For example,
      • Stankovic M.
      • Mladenovic D.
      • Ninkovic M.
      • Vucevic D.
      • Tomasevic T.
      • Radosavljevic T.
      Effects of caloric restriction on oxidative stress parameters..
      compared the effects of different degrees of chronic restriction (80–90, 60–70, 40–50, or 20–30% of daily caloric needs for 5 wk) and acute fasting (1 wk without food intake) on oxidative stress parameters in rat liver. Rats exposed to severe caloric restriction (<50% of daily caloric needs) or acute fasting displayed increased concentrations of MDA and nitric oxide as well as decreased SOD activity and glutathione concentrations. Alternatively, moderate caloric restriction (60–70% of daily caloric needs) did not cause hepatocyte damage and increased antioxidant capacity based on greater Mn-SOD activity and glutathione concentrations (
      • Stankovic M.
      • Mladenovic D.
      • Ninkovic M.
      • Vucevic D.
      • Tomasevic T.
      • Radosavljevic T.
      Effects of caloric restriction on oxidative stress parameters..
      ).
      • Sorensen M.
      • Sanz A.
      • Gómez J.
      • Pamplona R.
      • Portero-Otín M.
      • Gredilla R.
      • Barja G.
      Effects of fasting on oxidative stress in rat liver mitochondria..
      also observed detrimental effects of fasting, where liver mitochondria from rats fasted for 72 h exhibited increased electron leak and free radical generation at complex III of the electron transport chain, which resulted in a greater degree of lipid and protein oxidative damage.
      Feed restriction alone, as well as transit, have been shown to increase inflammatory biomarkers in cattle (
      • Marques R.S.
      • Cooke R.F.
      • Francisco C.L.
      • Bohnert D.W.
      Effects of twenty-four hour transport or twenty-four hour feed and water deprivation on physiologic and performance responses of feeder cattle..
      ). Although inflammation increases nutritional demands, dietary induction of a negative energy balance in dairy cows for 7 d before a bacterial injection had minimal effects on the inflammatory response when compared with nonrestricted cows (
      • Moyes K.M.
      • Drackley J.K.
      • Salak-Johnson J.L.
      • Morin D.E.
      • Hope J.C.
      • Loor J.J.
      Dietary-induced negative energy balance has minimal effects on innate immunity during a Streptococcus uberis mastitis challenge in dairy cows during midlactation..
      ). This could be explained by similar blood glucose concentrations among treatments, indicating that restricted cows had greater rates of glycogenolysis and gluconeogenesis to supply immune cells with glucose. Inflammation is initiated by macrophage recognition of endogenous danger signals or intracellular pathogens (
      • Zhang X.
      • Mosser D.
      Macrophage activation by endogenous danger signals..
      ). Macrophages then recruit other phagocytic immune cells via secretion of chemokines and cytokines (
      • Vieira S.
      • Lemos H.
      • Grespan R.
      • Napimoga M.
      • Dal-Secco D.
      • Freitas A.
      • Cunha T.
      • Verri Jr., W.
      • Souza-Junior D.
      • Jamur M.
      • Fernandes K.
      • Oliver C.
      • Silva J.
      • Teixeira M.
      • Cunha F.
      A crucial role for TNF-α in mediating neutrophil influx induced by endogenously generated or exogenous chemokines, KC/CXCL1 and LIX/CXCL5..
      ;
      • Griffin G.K.
      • Newton G.
      • Tarrio M.L.
      • Bu D.
      • Maganto-Garcia E.
      • Azcutia V.
      • Alcaide P.
      • Grabie N.
      • Luscinskas F.W.
      • Croce K.J.
      • Lichtman A.H.
      IL-17 and TNF-α sustain neutrophil recruitment during inflammation through synergistic effects on endothelial activation..
      ). Upon phagocyte activation, assembly of the NADPH oxidase complex at the cell membrane is stimulated (
      • Nauseef W.M.
      Assembly of the phagocyte NADPH oxidase..
      ). This enzyme uses an electron from intracellular NADPH to reduce extracellular O2 to O2•− (
      • Babior B.M.
      • Kipnes R.S.
      • Curnutte J.T.
      Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent..
      ). The production of ROS by phagocytes to kill pathogens has received much attention in the literature (
      • Gabig T.G.
      • Babior B.M.
      The killing of pathogens by phagocytes..
      ;
      • Babior B.M.
      Phagocytes and oxidative stress..
      ). The signaling role of phagocyte-derived ROS has also been investigated, as O2•− is rapidly dismutated to H2O2 either nonenzymatically or enzymatically by SOD (
      • Salin M.L.
      • McCord J.M.
      Superoxide dismutases in polymorphonuclear leukocytes..
      ). The pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NFκβ) signaling pathway is a potential target of ROS produced by the NADPH oxidase system (
      • Schreck R.
      • Rieberl P.
      • Baeuerle P.A.
      Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-κB transcription factor and HIV-1..
      ). Additional inflammatory mediators include eicosanoids, which are molecules derived from arachidonic acid or other PUFA released from membrane phospholipids by phospholipase enzymes, especially phospholipase A2 (
      • Funk C.D.
      Prostaglandins and leukotrienes: Advances in eicosanoid biology..
      ). The enzymatic oxidation of PUFA by cyclooxygenase, lipoxygenase, and cytochrome P-450 monooxygenase enzymes can produce O2•− and intermediate compounds (e.g., 15-hydroperoxyeicosatetraenoic acid) that act as potent hydroperoxides, which can cause oxidative damage to cells (
      • Weaver J.A.
      • Maddox J.F.
      • Cao Y.Z.
      • Mullarky I.K.
      • Sordillo L.M.
      Increased 15-HPETE production decreases prostacyclin synthase activity during oxidant stress in aortic endothelial cells..
      ;
      • Sordillo L.M.
      • Weaver J.A.
      • Cao Y.Z.
      • Corl C.
      • Sylte M.J.
      • Mullarky I.K.
      Enhanced 15-HPETE production during oxidant stress induces apoptosis of endothelial cells..
      ). Because ROS are both products and stimulators of inflammatory processes, a deleterious feedback loop can exacerbate conditions of inflammation and oxidative stress.

      Physical Exertion

      Cattle tend not to lie down while trucks are moving (
      • Warriss P.D.
      • Brown S.N.
      • Knowles T.G.
      • Kestin S.C.
      • Edwards J.E.
      • Dolan S.K.
      • Phillips A.J.
      Effects on cattle of transport by road for up to 15 hours..
      ), but long transit durations (>24 h) may cause more animals to lie down if adequate space is available (
      • Knowles T.G.
      A review of the road transport of cattle..
      ). Transportation may contribute to muscle fatigue and damage as cattle are standing for long periods of time and trying to maintain their balance, and they may experience bumping and falls that result in bruising (
      • Schwartzkopf-Genswein K.
      Cattle transport by road.
      ). Muscle fatigue is defined as a decreased ability to generate appropriate amounts of contractile force and can occur shortly after onset of exercise (acute) or after exercise has been carried out for a prolonged period of time (delayed). Alternatively, muscle damage is accompanied by structural damage to muscle fibers and usually takes longer to recover (
      • Finsterer J.
      Biomarkers of peripheral muscle fatigue during exercise..
      ). Recovery from muscle damage involves inflammatory and immune responses as well as regeneration via stimulation of satellite cells (
      • Tiidus P.M.
      Can oestrogen influence skeletal muscle damage, inflammation, and repair?.
      ). Satellite cells are multipotent stem cells capable of becoming myocytes and exist in a quiescent state between the basal lamina and plasma membrane of muscle fibers (
      • Seale P.
      • Asakura A.
      • Rudnicki M.A.
      The potential of muscle stem cells..
      ). Recruitment of satellite cells is the primary mechanism by which bovine skeletal muscle grows postnatally as muscle fiber number is relatively fixed at birth (
      • Rowe R.W.D.
      • Goldspink G.
      Muscle fibre growth in five different muscles in both sexes of mice I. Normal mice..
      ). Although satellite cell activation is necessary for skeletal muscle growth and repair, overactivation may lead to depletion of the satellite cell pool (
      • Dayanidhi S.
      • Lieber R.L.
      Skeletal muscle satellite cells: Mediators of muscle growth during development and implications for developmental disorders..
      ).
      As skeletal muscle energy expenditure represents 25 to 30% of total body energy expenditure in cattle (
      • Lobley G.E.
      Protein turnover-what does it mean for animal production?.
      ), it is likely that muscle-derived ROS make a large contribution to whole-body oxidative status. Similar to other cells, muscle cells generate endogenous ROS via mitochondria (
      • Davies K.J.A.
      • Quintanilha A.T.
      • Brooks G.A.
      • Packer L.
      Free radicals and tissue damage produced by exercise..
      ), NADPH oxidase enzymes (
      • Xia R.
      • Webb J.A.
      • Gnall L.L.M.
      • Cutler K.
      • Abramson J.J.
      Skeletal muscle sarcoplasmic reticulum contains a NADH-dependent oxidase that generates superoxide..
      ), phospholipase A2–dependent processes (
      • Gong M.C.
      • Arbogast S.
      • Guo Z.
      • Mathenia J.
      • Su W.
      • Reid M.B.
      Calcium-independent phospholipase A2 modulates cytosolic oxidant activity and contractile function in murine skeletal muscle cells..
      ), and nitric oxide synthases (
      • Kobzik L.
      • Reid M.B.
      • Bredt D.S.
      • Stamler J.S.
      Nitric oxide in skeletal muscle..
      ). Since the 1950s the field of exercise redox biology has worked to characterize exercise-induced oxidative stress and determine the effect of ROS on muscle function. This research may provide valuable insight into the effects of transit on livestock muscle physiology. Exercise has been shown to increase whole-body indicators of oxidation in the blood (
      • Sen C.K.
      • Rankinen T.
      • Väisänen S.
      • Rauramaa R.
      Oxidative stress after human exercise: Effect of N-acetylcysteine supplementation..
      ;
      • Wierzba T.H.
      • Olek R.A.
      • Fedeli D.
      • Falcioni G.
      Lymphocyte DNA damage in rats challenged with a single bout of strenuous exercise..
      ), with the general consensus that exercised-induced ROS production occurs predominantly by contracting heart and skeletal muscle (
      • Powers S.
      • Jackson M.
      Exercise-induced oxidative stress: Cellular mechanisms and impact on muscle force production..
      ). Mitochondria were originally thought to be the primary source of ROS produced in skeletal muscle during exercise. However, mitochondria produce more ROS during state 4 (basal) respiration than during state 3 (maximal ADP-stimulated) respiration (
      • Cortassa S.
      • O’Rourke B.
      • Aon M.A.
      Redox-optimized ROS balance and the relationship between mitochondrial respiration and ROS..
      ), which is the predominant state of mitochondria during aerobic contractions. Similar to the effects of caloric restriction, regular and moderate aerobic exercise is beneficial, whereas unaccustomed or exhaustive exercise can be detrimental. For example, rats trained on a treadmill for 1 h/d, 3 d/wk for 14 wk displayed increased fiber diameter in oxidative (soleus) muscle and increased fiber number in glycolytic (tibialis anterior) muscle (
      • Abruzzo P.M.
      • Esposito F.
      • Marchionni C.
      • di Tullio S.
      • Belia S.
      • Fulle S.
      • Veicsteinas A.
      • Marini M.
      Moderate exercise training induces ROS-related adaptations to skeletal muscle..
      ). The authors proposed this was a result of ROS activation of redox-sensitive transcription factors (NFκβ, activator protein-1, and mitogen-activated protein kinase) that regulate muscle regulatory factors, which in turn regulate satellite cell proliferation and differentiation. Alternatively, endurance exercise promotes muscle damage, which stimulates an inflammatory response (
      • Suzuki K.
      • Totsuka M.
      • Nakaji S.
      • Yamada M.
      • Kudoh S.
      • Liu Q.
      • Sugawara K.
      • Yamaya K.
      • Sato K.
      Endurance exercise causes interaction among stress hormones, cytokines, neutrophil dynamics, and muscle damage..
      ) and subsequently increases ROS production by macrophages and other phagocytic cells within the muscle tissue. As the effects of both feed restriction and physical exertion on ROS production are dependent on duration and intensity, length of transit is likely a vital determinant of the oxidative stress response after transit.

      OXIDATIVE STRESS MITIGATION STRATEGIES

      It is evident that transportation of livestock may influence oxidative status, which can subsequently hinder animal health, efficiency, and meat quality. Several supplementation strategies exist to enhance antioxidant status in cattle including vitamins with antioxidant properties and TM that participate as critical cofactors in antioxidant enzymes. However, due to the lack of understanding of the oxidative stress response of cattle after transit, it is currently impossible to develop optimum nutritional supplementation strategies to increase resilience or aid in recovery of transit-induced oxidative stress. Because feeder calves often change ownership between the cow-calf and feedlot segment, most strategies to mitigate the negative effects of transit stress are implemented upon or within the first 2 wk after arrival at a feedlot. Pharmacological strategies frequently used by feedlot operators to improve BRD treatment outcomes include synthetic glucocorticoids such as dexamethasone and nonsteroidal anti-inflammatory drugs such as flunixin or aspirin (
      • USDA
      Types and Costs of Respiratory Disease Treatments in US Feedlot.
      ). The effects of administering these drugs on oxidative stress biomarkers in cattle has not been directly investigated. Although nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase and subsequent ROS produced from this eicosanoid biosynthetic pathway (
      • Meade E.A.
      • Smith W.L.
      • DeWitt D.L.
      Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs..
      ), there is evidence that they can also induce ROS generation (
      • Adachi M.
      • Sakamoto H.
      • Kawamura R.
      • Wang W.
      • Imai K.
      • Shinomura Y.
      Nonsteroidal anti-inflammatory drugs and oxidative stress in cancer cells..
      ). Preconditioning is a practice implemented by cow-calf producers that has been found to decrease feedlot morbidity and typically ensures that calves have been weaned for 30 to 45 d, vaccinated against clostridial and viral pathogens, castrated, dehorned, and accustomed to feed bunks and waterers before feedlot entry (
      • Duff G.C.
      • Galyean M.L.
      Board-invited review: Recent advances in management of highly stressed, newly received feedlot cattle..
      ). Identification of nutritional strategies to combat transit stress may help add value to preconditioning programs and lessen antibiotic use during feedlot receiving. This section will focus on how vitamins, TM, and other supplements have the potential to mitigate transit-induced oxidative stress with emphasis on mode of delivery (oral vs. injection) and timing of supplementation (before vs. after transit).

      Vitamins

      Vitamin E and C have direct antioxidant activity due to their ability to scavenge free radicals, making them essential components of the cellular antioxidant defense system. Supplemental VE recommendations for newly received calves (400 to 500 IU/d or 1.6 to 2.0 IU/kg of BW) were established based on previous evidence that increased concentrations of VE during periods of high stress may promote animal health (
      • NASEM (National Academies of Sciences, Engineering, and Medicine)
      Nutrient Requirements of Beef Cattle.
      ). Alternatively, there is no established VC requirement for cattle as cattle can synthesize VC from glucose in the liver. However, livestock species have undergone intense genetic selection for production traits, which may necessitate exogenous VC supplementation to support optimal animal health and productivity. Furthermore, it has been demonstrated that VC can mitigate the negative effects of glucocorticoids (such as dexamethasone) on bovine neutrophil function (
      • Roth J.A.
      • Kaeberle M.L.
      In vivo effect of ascorbic acid on neutrophil function in healthy and dexamethasone-treated cattle..
      ), making VC a potential ancillary therapy for BRD. Vitamin E and VC may be orally supplemented to cattle, but VC must be supplemented in ways that avoid destruction in the rumen such as encapsulation (
      • Knight C.A.
      • Dutcher R.A.
      • Guerrant N.B.
      • Bechdel S.I.
      Utilization and excretion of ascorbic acid by the dairy cow..
      ;
      • Zinn R.A.
      • Owens F.N.
      • Stuart R.L.
      • Dunbar J.R.
      • Norman B.B.
      B-vitamin supplementation of diets for feedlot calves..
      ). Additionally, feed intake of newly received calves can be quite low: 0.5 to 1.5% of their BW during the first week and 1.5 to 2.5% of their BW during the second week (
      • Hutcheson D.P.
      • Cole N.A.
      Management of transit-stress syndrome in cattle: Nutritional and environmental effects..
      ), making it difficult to ensure adequate vitamin intake. To overcome these obstacles, both VE and VC can be supplemented via injection (intramuscular, subcutaneous, or intravenous), but this method may require additional supplies (needles, syringes) and labor.
      Several studies have reported stress decreases circulating and tissue concentrations of VE and VC. For example, plasma α-tocopherol concentrations of commingled and transported cattle decreased from 7.2 μg/mL (adequate) to 2.0 μg/mL (marginal) within 14 d of arrival when dietary VE was supplemented at 15 IU/kg of DM (
      • Han H.
      • Stovall T.C.
      • Wagner J.T.
      • Gill D.R.
      Impact of Agrado on Tocopherol Metabolism by Transport-Stressed Heifers.
      ).
      • Chirase N.
      • Green L.
      • Purdy C.
      • Loan R.
      • Briggs R.
      • Mcdowell L.
      Effect of environmental stressors on ADG, serum retinol and alpha-tocopherol concentration and incidence of bovine respiratory disease of feeder steers..
      and
      • Nazifi S.
      • Saeb M.
      • Baghshani H.
      • Saeb S.
      Influence of road transportation during hot summer conditions on oxidative status biomarkers in Iranian dromedary camels (Camelus dromedarius)..
      also observed transit-induced decreases in circulating α-tocopherol concentrations. Dietary VE supplementation at 151 IU/animal daily (25 IU/kg of DM) to newly received beef steers was adequate to prevent the decline in VE status (serum and liver α-tocopherol) that was observed in steers not supplemented VE during the first month after feedlot arrival (
      • Deters E.L.
      • Hansen S.L.
      Vitamin E supplementation strategies during feedlot receiving: Effects on beef steer performance, antibody response to vaccination and antioxidant defense..
      ). Increasing VE also decreased liver glutathione concentrations, demonstrating a sparing effect on other cellular antioxidants (
      • Deters E.L.
      • Hansen S.L.
      Vitamin E supplementation strategies during feedlot receiving: Effects on beef steer performance, antibody response to vaccination and antioxidant defense..
      ). Stress has also been shown to decrease tissue VC concentrations and stimulate VC biosynthesis in capable species (
      • Nakano K.
      • Suzuki S.
      Stress-induced changes in tissue levels of ascorbic acid and histamine in rats..
      ;
      • Chan T.S.
      • Shangari N.
      • Wilson J.X.
      • Chan H.
      • Butterworth R.F.
      • O’Brien P.J.
      The biosynthesis of ascorbate protects isolated rat hepatocytes from cumene hydroperoxide-mediated oxidative stress..
      ). Decreases in circulating ascorbate concentrations have been observed in cattle exposed to heat stress (
      • Padilla L.
      • Matsui T.
      • Kamiya Y.
      • Kamiya M.
      • Tanaka M.
      • Yano H.
      Heat stress decreases plasma vitamin C concentration in lactating cows..
      ) and housing stress (metal pen vs. commercial calf hutch;
      • Cummins K.A.
      • Brunner C.J.
      Effect of calf housing on plasma ascorbate and endocrine and immune function..
      ). Plasma ascorbate concentrations of crossbred beef steers were decreased 10% immediately after an 18-h transit, but providing steers with a pretransit i.m. VC injection (5 g of sodium ascorbate per steer) prevented this decline (E. L. Deters and S. L. Hansen, unpublished data). Plasma ascorbate concentrations returned to pretransit values by d 7 after transit. However, steers that received a pretransit VC injection had greater ADG and final BW during the 56-d post-transit period compared with steers that did not receive a VC injection or steers that received a VC injection after transit (E. L. Deters and S. L. Hansen, unpublished data). These data suggest injectable VC administration is a viable option for overcoming transit-induced performance losses, but timing of injection is important for optimal effectiveness.

      Trace Minerals

      The combination of events occurring during transit (feed restriction, physical and oxidative stress, and so on) collectively increase demand on the TM stores of an animal. This may be further exacerbated by low feed intake (and thus low TM intake) upon arrival to the feedlot. The net effect is lesser availability of TM to support dependent enzymes that are essential in immunity and defense against oxidative stress. For example, steers receiving a TM-deficient diet for 89 d had impaired neutrophil killing ability and greater cytochrome C reduction, an indicator of extracellular O2•−, suggesting that SOD activity may have also been impaired (
      • Genther O.N.
      • Hansen S.L.
      A multielement trace mineral injection improves liver copper and selenium concentrations and manganese superoxide dismutase activity in beef steers..
      ). Therefore,
      • NASEM (National Academies of Sciences, Engineering, and Medicine)
      Nutrient Requirements of Beef Cattle.
      recommends increasing TM concentrations in receiving cattle diets to ~150% of requirements to overcome limitations of low feed intake during this time and replenish cattle stores of TM. Alternatively, injectable TM products can rapidly improve TM status in beef cattle (
      • Pogge D.J.
      • Richter E.L.
      • Drewnoski M.E.
      • Hansen S.L.
      Mineral concentrations of plasma and liver after injection with a trace mineral complex differ among Angus and Simmental cattle..
      ;
      • Genther O.N.
      • Hansen S.L.
      A multielement trace mineral injection improves liver copper and selenium concentrations and manganese superoxide dismutase activity in beef steers..
      ), which may be beneficial when the TM status of incoming cattle is unknown. Injectable TM have been shown to positively influence feedlot performance, BRD morbidity rates, and antibody response to vaccination (
      • Richeson J.T.
      • Kegley E.B.
      Effect of supplemental trace minerals from injection on health and performance of highly stressed, newly received beef heifers..
      ;
      • Arthington J.D.
      • Havenga L.J.
      Effect of injectable trace minerals on the humoral immune response to multivalent vaccine administration in beef calves..
      ).
      Steers mildly deficient in TM, including Cu and Se, lost more weight after a 20-h transit event and took longer to return to pretransit rates of feed intake than steers of adequate TM status (
      • Genther O.N.
      • Hansen S.L.
      Effect of dietary trace mineral supplementation and a multi-element trace mineral injection on shipping response and growth performance of beef cattle..
      ). In that study, steer weight loss during the transit period was negatively correlated with liver Cu concentrations, suggesting TM status of cattle may be crucial in response to the stress of transit. Still, the use of TM supplementation to temper negative effects of transit-induced oxidative stress requires refinement as limited studies have focused on this area and results are likely dependent on age and initial TM status of the cattle, duration of the transit event, timing relative to transit, as well as route and type of TM supplementation (
      • Dorton K.L.
      • Engle T.E.
      • Enns R.M.
      Effects of trace mineral supplementation and source, 30 days post-weaning and 28 days post receiving, on performance and health of feeder cattle..
      ;
      • Kegley E.B.
      • Pass M.R.
      • Moore J.C.
      • Larson C.K.
      Supplemental trace minerals (zinc, copper, manganese, and cobalt) as Availa-4 or inorganic sources for shipping-stressed beef cattle 1..
      ;
      • Arthington J.D.
      • Moriel P.
      • Martins P.G.M.A.
      • Lamb G.C.
      • Havenga L.J.
      Effects of trace mineral injections on measures of performance and trace mineral status of pre- and postweaned beef calves..
      ;
      • Genther O.N.
      • Hansen S.L.
      Effect of dietary trace mineral supplementation and a multi-element trace mineral injection on shipping response and growth performance of beef cattle..
      ;
      • Genther-Schroeder O.N.
      • Hansen S.L.
      Effect of a multielement trace mineral injection before transit stress on inflammatory response, growth performance, and carcass characteristics of beef steers..
      ). Ultimately, TM supplementation may be important in both the resiliency to and recovery from transit-induced oxidative stress. However, because TM may take a longer period of time to be incorporated into antioxidant enzymes, direct antioxidant supplementation, such as VE or VC, may offer more immediate protection. When designing TM supplementation strategies, it is also important to note that TM can be prooxidant at high concentrations.

      Other Supplements

      In addition to vitamins and TM, synthetic antioxidants, such as ethoxyquin, may be useful in mitigating transit-induced oxidative stress. Steers supplemented with ethoxyquin (Agrado; Novus International, St. Louis, MO) during a 42-d backgrounding period before transit had greater serum VE after transit than control steers (
      • McBride K.
      • Greene L.
      • Chirase N.
      • Kegley E.
      • Cole N.
      The effects of ethoxyquin on performance and antioxidant status of feedlot steers..
      ). Additionally, steers that received ethoxyquin after transit had greater DMI and ADG over the 182-d feeding period. Other nutritional supplements that could influence antioxidant capacity include phytochemicals such as polyphenols (reviewed by
      • Rice-Evans C.A.
      • Miller N.J.
      • Paganga G.
      Antioxidant properties of phenolic compounds..
      ), probiotics (reviewed by
      • Wang Y.
      • Wu Y.
      • Wang Y.
      • Xu H.
      • Mei X.
      • Yu D.
      • Wang Y.
      • Li W.
      Antioxidant properties of probiotic bacteria..
      ), and yeast fermentation products. Saccharomyces cerevisiae fermentation products (SCFP) have been found to exhibit high ROS scavenging activity (
      • Schauss A.
      • Vojdani A.
      Discovery of edible fermentation product with unusual immune enhancing properties in humans..
      ) and increase antioxidant capacity in vitro and in vivo. In vitro antioxidant capacity of SCFP (XP; Diamond V, Cedar Rapids, IA) was greatest in red blood cells at the highest dose tested (10 mg/mL) but in neutrophils at the lowest dose tested (0.0001 mg/mL) (
      • Jensen G.S.
      • Patterson K.M.
      • Yoon I.
      Yeast culture has anti-inflammatory effects and specifically activates NK cells..
      ). The authors hypothesized that the inverse dose response observed in neutrophils was due to the presence of both pro-inflammatory (β-glucans) and antioxidant compounds. In support of this hypothesis,
      • Deters E.L.
      • Stokes R.S.
      • Genther-Schroeder O.N.
      • Hansen S.L.
      Effects of a Saccharomyces cerevisiae fermentation product in receiving diets of newly weaned beef steers II: Digestibility and response to a vaccination challenge..
      observed a quadratic response of SCFP (XPC; Diamond V) on antioxidant defense of newly weaned beef steers, where steers supplemented SCFP at 14 g·steer−1·d−1 tended to have greater concentrations of reduced glutathione on d 27 and 56 of supplementation compared with steers supplemented SCFP at 0 or 28 g·steer−1·d−1. Nutritional strategies that improve antioxidant capacity of cattle may lead to better post-transit performance, as steers with greater liver glutathione concentrations exhibited greater ADG early in the receiving period after a 19-h transit event (
      • Deters E.L.
      • Hansen S.L.
      Effect of supplementing a Saccharomyces cerevisiae fermentation product during a preconditioning period prior to transit on receiving period performance, nutrient digestibility, and antioxidant defense by beef steers..
      ). A potential challenge with yeast fermentation products is that their mechanism of action is not well understood (
      • Newbold C.J.
      Microbial feed additives for ruminants.
      ), and thus, effects of these products on inflammation and oxidative stress may not be highly predictable.

      APPLICATIONS

      Transportation of cattle can contribute to the development of oxidative stress in several ways. Psychological stress and food deprivation stimulate fatty acid and AA mobilization for use as metabolic fuel, which increases mitochondrial ROS production. Additionally, food deprivation and physical exertion can stimulate an inflammatory response, which results in ROS production by phagocytic immune cells and as a by-product of eicosanoid biosynthesis. In the literature presented herein, transit generally increased ROS production and markers of oxidative damage while decreasing antioxidant concentrations and antioxidant enzyme activity. Despite these trends, discrepancies in species, age, environmental conditions, transit duration and distance, tissue or biomarker measured, and analytical methods make it difficult to determine what a characteristic oxidative stress response to transit might be. Furthermore, few studies relate transit-induced changes in oxidative stress biomarkers to animal health or production parameters. Future research should focus on the following:
      • determination of appropriate oxidative stress biomarkers and establishment of a reference panel for livestock species,
      • development of a model to specifically induce oxidative stress in livestock that induces measurable changes in oxidative stress biomarkers without causing adverse side effects,
      • characterization of the oxidative stress response in cattle after transit, including time to recovery and implications for long-term health and performance, and
      • identification of targets for the development of nutritional and pharmacological strategies to mitigate the negative effects of transit-induced oxidative stress on cattle health and performance.

      ACKNOWLEDGMENTS

      The authors acknowledge Diamond V (Cedar Rapids, IA), DSM Nutritional Products (Heerlen, the Netherlands), and the Iowa Beef Checkoff for their financial support of some of the research discussed in this review. Additional thanks are extended to Allison VanDerWal (Iowa State University, Ames, IA) for editing this manuscript prior to submission.

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