# Review: Implication of redox imbalance in animal health and performance at critical periods, insights from different farm species

Denys Durand, Anne Collin, Elodie Merlot, Elisabeth Baéza, Laurence A.

Guilloteau, Nathalie Le Floc'H, Thomas Armand, Stéphanie

Fontagné-Dicharry, Florence Gondret

► To cite this version:

Denys Durand, Anne Collin, Elodie Merlot, Elisabeth Baéza, Laurence A. Guilloteau, et al. Review: Implication of redox imbalance in animal health and performance at critical periods, insights from different farm species. Animal, 2022, 16 (6), pp.100543. 10.1016/j.animal.2022.100543. hal-03681823

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https://hal.inrae.fr/hal-03681823v1

Submitted on 22 Jul 2024

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1 **Review: Implication of redox imbalance in animal health and performance at critical periods, insights from different farm species**

3 D. Durand<sup>a</sup>, A. Collin<sup>b</sup>, E. Merlot<sup>c</sup>, E. Baéza<sup>b</sup>, L. A. Guilloteau<sup>b</sup>, N. Le Floc'h<sup>c</sup>, A.

4 Thomas<sup>a</sup>, S. Fontagné-Dicharry<sup>d</sup>, F. Gondret<sup>c</sup>

5

6 <sup>a</sup> INRAE, Université Clermont Auvergne, VetAgro Sup, UMR Herbivores, 63122

7 Saint-Genès-Champanelle, France

8 <sup>b</sup> INRAE, Université de Tours, BOA, 37380 Nouzilly, France

9 <sup>c</sup> PEGASE, INRAE, Institut Agro, 35590 Saint-Gilles, France

10 <sup>d</sup> INRAE, Université de Pau et des Pays de l'Adour, E2S UPPA, NUMEA, 64310, Saint-Pée-sur-Nivelle, France

12

13 Corresponding author: Denys Durand, denis.durand@inrae.fr

14

15 **Abstract**

16 The process of oxidative stress occurs all over the production chain of animals and
17 food products. This review summarizes insights obtained in different farm species
18 (pigs, ruminants, poultry, and fishes) to underpin the most critical periods for the
19 venue of oxidative stress, namely birth/hatching and weaning/start-feeding phase.
20 Common responses between species are also unravelled in periods of high
21 physiological demands when animals are facing dietary deficiencies in specific
22 nutrients, suggesting that nutritional recommendations must consider the
23 modulation of responses to oxidative stress for optimizing production performance
24 and quality of food products. These conditions concern challenges such as heat
25 stress, social stress, and inflammation. The magnitude of the responses is partly
26 dependent on the prior experience of the animals before the challenge, reinforcing
27 the importance of nutrition and other management practices during early periods to
28 promote the development of antioxidant reserves in the animal. When these
29 practices also improved performance and health of the animal, this further confirms
30 the central role played by oxidative stress in physiologically and
31 environmentally-induced perturbations. Difficulties in interpreting responses to
32 oxidative stress arise from the fact that the indicators are only partly shared between
33 studies, and their modulations may also be challenge-specific. A consensus about
34 the best indicators to assess pro-oxidative and antioxidant pathways is of huge
35 demand to propose a synthetic index measurable in a non-invasive way and
36 interpretable along the productive life of the animals.

37

38 **Keywords:** Oxidative stress, Physiological transition, Inflammation, Challenge,
39 Animal performance.

40

41 Implications

42 The agro-ecological transition in farming practices stimulates natural processes in
43 biological systems. Oxidative stress is considered as a pivotal mechanism
44 underlying the adaptation of animals to management practices and acclimation to
45 environmental constraints. This reinforces the importance of monitoring and
46 understanding the responses to pro-oxidant challenges in farm animals. An overview
47 in different farm species from different ecosystems (terrestrial, aquatic) may be
48 helpful to obtain a consensus on the best biomarkers to measure the redox status
49 and evaluate and propose management practices able to limit the short and
50 long-term consequences of oxidative stress on animal performance, health and
51 welfare.

52 **Introduction**

53 Farm animals are facing many environmental conditions and constraints that
54 challenge their physiology during their whole productive life. Oxidative stress has
55 emerged as an important issue to explain dis-adaptation and dysfunctions (Abuelo et
56 al., 2019) leading to impaired survival, bad production performance or compromised
57 health and immunity (Al-Gubory et al., 2010). Oxidative stress arises from the
58 imbalance between the production of reactive oxygen species (ROS) and the
59 neutralizing capacity of the antioxidant system. The ROS family includes free
60 radicals which are often small and diffusible molecules with one or more unpaired
61 electrons (peroxides, superoxide, hydroxyl radical) and no-radical molecules
62 (hydrogen peroxide, peroxinitrite, etc.) which are by-products of the metabolism of
63 oxygen in animal cells. The ROS have beneficial effects for many biological
64 processes such as stem cell differentiation, lineage commitment, self-renewal and
65 cell homeostasis (Ren et al., 2015), because they act as signals inside and between
66 cells to regulate gene expressions involved in cell development and growth (Dalton
et al., 2002). However, exaggerated and even uncontrolled ROS production induces oxidative damage to proteins, lipids and DNA, and results in the deterioration of cellular structure and functions, and even cell death. Damaged and destroyed macro-biomolecules can also trigger inflammatory responses as a starting point of altered health. Both enzymatic and non-enzymatic molecules produced by the animal (uric acid, glutathione GSH) or brought by the diet (vitamins E and C, carotenoids, flavonoids, polyphenols, selenium, zinc) act as antioxidants to prevent or repair the oxidative damages. Oxidative stress is then defined as a distress situation corresponding to an overexposure to oxidants which results in non-specific oxidation of biomolecules and disruption of redox signalling (Sies and Jones, 2020).
This can induce transient or permanent perturbations which generate physiological consequences within the cells and at the whole animal level (Pignatelli et al., 2018).

A better knowledge of the critical periods when exaggerated ROS production occurs and (or) elements in the antioxidant defence system are lacking, is required in farm animals to pay attention on aggravating events during these periods, with the objectives to limit consequences on production performance, health, and welfare.
This review enlightens critical periods for the venue of oxidative stress in different farm species, including mammals and oviparous species living in terrestrial or aquatic environments. Detailed mechanisms underlying oxidative issue for a given species can be found in other reviews (Lushchak, 2011; Birnie-Gauvin et al., 2017; Chowdhury and Saikia, 2020; Hoseinifar et al., 2021). However, enlightening common or specific responses across species may allow a better anticipation of the
89 risk events for each species when the conventional management practices must
90 evolve to cope with climatic pressure and environmental or societal expectations.

91 For instance, quality issues for all species can be foreseen when considering meat
92 quality degradation of broilers due at least in part to the physiological challenge
93 imposed by rapid growth on oxidative metabolism. Pastoral ruminant systems can
94 provide examples for risks underlying outdoor productions in pigs or other species.

95 Inter-species comparison in the modulation of pro- and antioxidant molecules and its
96 relationships with variations of performance and health may also underpin the best
97 indicators (when, how, what, where, frequency) to monitor oxidative stress in farm
98 animals.

99 **Critical physiological transition periods in early life**

100 Physiological transition periods are associated with many obligatory changes in
types of nutrients, environmental temperature, physical activity, etc... These induce
101 many metabolic changes in cell physiology, notably for mitochondria responsible for
102 energy production and controlling many processes from signalling to cell death
103 (Salin et al., 2015; Bottje, 2019).
104

105 **Birth or hatching and start-feeding phases**

106 Birth in mammals is the most striking shared period for the venue of acute oxidative
107 stress, due to the abrupt switch from a fetal environment with a lower oxygen supply
108 (maternal-mediated respiration in the uterus) than that after birth (autonomous
109 pulmonary respiration). Whereas hypoxia is necessary for the development and
110 growth of the fetus, the aerobic metabolism is needed to efficiently provide enough
111 energy for the newborn to ensure survival and development (Morton and Brodsky, 2016). This switch is obligatory associated with large amounts of ROS generated by the neonatal cells (Friel et al., 2004). This period is also concomitant with a transition in gut activity from amniotic fluid to colostrum feeding, which is another source of oxidative stress (Osorio, 2020; Rosa et al., 2021). In oviparous species, many similarities at hatching are found with these events at birth. In poultry where the embryo derives nutrient requirements from the egg, changes in oxygen availability and nutrition at hatching also induce alterations in the redox status. The role of oxygen in the venue of oxidative stress was proved by the fact that hypoxia/re-oxygenation protocol to pre-hatching ducklings resulted in a higher susceptibility to ROS monitored in red blood cells of these animals (Rey et al., 2010).

121 In situation of aqueous life for fishes, the hatching period is also critical but this is likely more due to the nutritional transition and the dramatic morphological changes in the larvae which both increase the energy demand at this moment, than due to changes in oxygen availability. A specificity of fish is also the high concentrations of long chain n-3 polyunsaturated fatty acids in feed and in animal tissues, which are thus particularly prone to oxidation. In the absence of a suitable antioxidant protection, lipid peroxidation in fish tissues due to the ingestion of oxidized feeds during the early developmental stages thus led to depressed growth and bad survival (Fontagné-Dicharry et al., 2014), inflammatory response (Fontagné-Dicharry et al., 2018) and various pathologies including muscular dystrophy (Boglione et al., 2013).
In all species, internal defence actors against ROS are prepared by the cells in
before birth or hatching. For instance in pigs, proteins of the peroxiredoxins family
were up-regulated with advancing gestational age in adipose tissue (Gondret et al.,
2018). The global antioxidant capacity only slightly increases during the few days
after birth, in a moment when plasma concentration of hydroperoxides dramatically
increases (Buchet et al., 2017). This explains why newborns suffer from oxidative
stress in the days after birth. With the gradual development of the antioxidant
system, the oxidative balance can be recovered in 7 days after birth in pigs (Yin et
al., 2013). Similarly, most neonatal calves are experiencing oxidative stress during
the first few weeks of age (Abuelo et al., 2019). During the early developmental
stages in fishes such as trout, the antioxidant protection rather relies on antioxidant
vitamins in the earliest embryonic stages, and after first-feeding, of antioxidant
enzymes (Fontagné et al., 2008). However, similarly to mammals, the endogenous
antioxidant defence system is not fully responsive, leading to pronounced lipid
peroxidation when oxidized feed is ingested during this period (Fontagné-Dicharry et
al., 2014).

Importantly, the consequences of the redox imbalance during the first days after
birth or hatching are more detrimental in situations where prior tissue development is
impaired. In pigs, intrauterine growth restriction, a common feature observed in a
subset of littermates for sows selected for high prolificacy, was associated with
impaired mitochondrial biogenesis and energy homeostasis and with greater hepatic
malondialdehyde (MDA) concentration, a marker of lipid peroxidation (Zhang et al.,
2017). Depressed levels of proteins that regulate oxidative defence and increased levels of proteins involved in the response to oxidative stress have been reported by proteomic studies on intestine, liver and muscle from intrauterine growth retarded piglets (Wang et al., 2008). This means that a particular attention must be paid on stimulating the antioxidant capacities of piglets during the perinatal period, and especially those of the lightest weight. In ruminants, suboptimal intrauterine conditions can similarly affect the foetus (Abuelo et al., 2019). As compared with single foetuses, twinning in ewes led to intrauterine growth restriction, and this was associated with higher oxidative stress monitored in the cord blood (Sales et al., 2018). Artificial feeding after birth to compensate for an insufficient milk production by the ewe in the large litters, further depressed the antioxidant capacity of the lambs when compared with those fed by their mothers, together with other negative indicators of animal health and welfare (Mialon et al., 2021). In poultry, oxidative stress was also increased by management practices before hatch. For instance, egg storage longer than 7 days, which is a common practice in farms for logistical reasons, negatively influenced the embryonic development and resulted in early embryonic mortality and lower hatchability (Fasenko, 2007; Pokhrel et al., 2018). Long egg storage influenced the redox balance, as illustrated by the lower total antioxidant status (TAS) in serum (Pertusa et al., 2017) and greater MDA concentrations in the serum and yolk sac (Yang et al., 2020). After hatching, birds have to cope with specific husbandry conditions and transports. Delayed placement in hatchery resulted in an increase in lipid peroxidation as proved by higher
thiobarbituric acid reactive substances (TBARS) in blood and the liver (Foury et al., 2020), and negatively affected animal performance (Guilloteau et al., 2019). This dis-adaptive oxidative profile was also manifested by altered concentrations in metabolites involved in the antioxidant status and energy metabolism in the fecal metabolome, until at least 13 days after the delayed placement (Beauclercq et al., 2019). Whereas no difference was detected in the redox balance indicators in blood at this time and later in age (Beauclercq et al., 2019; Foury et al, 2020), expression levels of various genes involved in oxidative stress (such as the transcription factors NFE2L2 and MEF2A) were modified. The differences were accentuated for males, which have a lower systemic anti-oxidative activity including lower uric acid concentration, TAS and ferric reducing ability of plasma (FRAP) than females.

Altogether, these comparisons between species not only underline birth or hatching as a critical period for the venue of oxidative stress, but they also reveal how selection for reproduction traits and practices to manage it, further accentuate the redox imbalance and consequences in the young animals. Besides identifying these risk factors, possibilities during prenatal/pre-hatching periods may be shared in the different species to sustain the development of antioxidant capacities of animal tissues, and thereby to preserve health. Because intrauterine growth restricted piglets and lambs serve as animal models for a better understanding of the development of the human embryo and complication of pregnancy, there is a considerable literature dealing with orally-treated pups to correct oxidative stress soon after birth. Neonatal formula rich in proteins have been tested to accelerate
growth recovery, with consequences in the abundance of redox proteins such as
peroxiredoxins, glutathione S-transferase and cyclophilin-A in tissues of growing
intrauterine growth restricted piglets (Sarr et al., 2012). In pigs and ruminants as in
Humans (Manuelian et al., 2021; Fardet and Chardigny, 2013), other tested
solutions include specific aminoacids with antioxidant and functional properties, and
plants extracts rich in lipotropic and antioxidant compounds to improve antioxidant
capacities during the postnatal period. Dietary antioxidant supplementations than
can routinely be used in farms, have been also tested for gestating and lactating
females to improve the redox status of their young (Abuelo et al., 2019). However,
effects are not always conclusive, depending on the level and timing of
supplementation and on the active principles tested. Reducing maternal stress may
also have beneficial consequences on oxidative stress in the female and the young
(Merlot et al., 2019; see section 5.1). In laying hens, supplying diets with exogenous
antioxidants such as vitamin E, has positive effects on antioxidant status of the egg
yolks and newly hatched chicks (Yang et al., 2020), showing again the benefit of
preparing antioxidant defence through the nutrition of the female. Supplementation
of broiler feeds with herbal plant extract like *Melissa officinalis* L. also has beneficial
effects on the redox balance, with improved performance during the growth phase
and different health effects (Travel et al., 2021). The antioxidant defence system
during the early developmental stages in fish can be also sustained by
supplementing diets of the broodstock with aminoacids such as methionine
(Fontagné-Dicharry et al., 2017) and with selenium (Wischhusen et al., 2019). If the
221 parental selenium supplementation can improve antioxidant status and performance
222 of the progeny, this may however induce a lower stress resistance in the longer term
223 (Wischhusen et al., 2020a) due to alteration of the Methionine cycle and epigenetic
224 changes (Wischhusen et al., 2020b). Therefore, any strategies for parental feeding
225 must be investigated at short and long term before definitive recommendations can
226 be formulated.

227 Juvenile transitions

228 Other critical periods for the venue of oxidative stress occur later in the development,
229 when physiological transitions are abruptly imposed to the young animals (Table 2).
230 In these situations, oxidative stress is more likely the consequence of systemic
231 inflammation rather than the cause of systemic disorders. Indeed, in conventional
232 farming systems for pigs and dairy calves, weaning is lived as the abrupt separation
233 from the mother, and this is also associated with a dietary switch from milk to solid
234 feeds rich in plant raw materials. Weaning may generate immune and inflammatory
235 responses that can reach a systemic dimension (McCracken et al., 1999; Gilbert et
236 al., 2019). For instance, intestinal dysfunction is often observed just after weaning
237 and it is clearly associated with inflammatory response and oxidative stress at both
238 the systemic and intestinal levels, which are manifested by changes in the
239 expression levels of cytokines and antioxidant enzymes together with increased
240 concentrations of lipid oxidation markers in pigs (Zhou et al., 2018). In pigs,
241 hydroperoxides concentrations increased whereas the blood antioxidant potential
242 (BAP) decreased during the days just after weaning, leading an increase in the
243 oxidative stress index (hydroperoxides / BAP ratio) between 5 and 12 days after weaning (Buchet et al., 2017). Other redox indicators such as plasma MDA, FRAP and erythrocyte GSH content indicate that consequences of oxidative stress may last at least 28 days after weaning (Degroot et al., 2020). The local and systemic inflammatory responses are probably the main cause of the production of oxidation products during the days after weaning. In support, oxidative stress was higher in piglets with post-weaning diarrhoea than in those with no diarrhea (Buchet et al., 2017). Importantly, antioxidant defence and clearance of dysfunctional mitochondria at weaning were more compromised in intrauterine growth restricted piglets than in their normal littermates (Novais et al., 2021), reinforcing the importance of prenatal events in the adaptation capacity to postnatal challenges. Indicators of oxidative stress were also observed in the exhaled breath condensate in calves soon after weaning. Indeed, oxidative stress may result from respiratory infections due to stress-induced alterations in the immune function at this moment (Ranade et al., 2014). In both species, another cause of oxidative stress may be the anorexia observed during the first days after weaning. Anorexia reduces the intake of all nutrients, and among them, of those with antioxidant properties at the time when their use is precisely needed to neutralize the oxidative products generated by inflammation (Amazan et al., 2012). For instance in pigs, blood concentration of vitamin E declined sharply, and to a lesser extent, that of vitamin A (Buchet et al., 2017) in the days following weaning.
Even if oxidative stress might be the consequence rather than the cause of stress and disorders observed just after weaning, it is important to improve antioxidant defence before weaning to limit the post-weaning alterations of performance. Indeed, piglets whose growth was the less affected during the 3 weeks following weaning in commercial farms, were those whose oxidative stress increased the least, and for which blood vitamin E concentration before weaning was the highest (Buchet et al., 2017). Moreover, the oxidative status of piglets was improved thanks to the reduction of hydroperoxides concentration in the blood when the starter diet included a premix combining vitamins E, A, C, polyphenols and trace elements such as zinc and selenium, and this was associated with increased post-weaning growth rate of the supplemented piglets (Robert et al., 2009). In calves, parenteral supplementation of minerals and vitamins with antioxidant effects also prevented the decrease in variables related to the immune system, improved antibody responses and had positive effects on BW (Mattioli et al., 2020). Moreover, monitoring changes in salivary biomarkers of anti-oxidant capacity, such as Trolox equivalent antioxidant capacity (TEAC), FRAP and cupric ion reducing antioxidant capacity (Cuprac), seems a promising approach to characterize stressful conditions in calves at weaning (Rubio et al., 2021). These examples in the two species suggest that robustness of an animal might be associated, at least in part, with its own ability to limit oxidative stress. In support to this assumption, later in growth, it was observed that BAP as an antioxidant measure in plasma combined with circulating concentrations of metabolic and immune indicators provided an
286 animal-centred index to predict the extent of reduction in growth rate when growing
287 pigs are facing sanitary (inflammatory) challenges (Le Floc'h et al., 2021).

288 Challenges during rearing periods

289 Physiological challenge: the pro-oxidant effects of high growth rate

290 Since many decades, farm animals have been selected for productive performance,
291 such as growth rate and yield of edible products (meat or flesh, eggs, milk) which are
292 high-nutrient-demanding processes. At the cellular level, ROS generation takes
293 place at the electron transport chain during the process of oxidative phosphorylation,
294 so that ROS are normal by-products of mitochondrial metabolism associated to
295 energy production. Any increase in cellular metabolism that generates greater
296 energy and oxygen demands would then increase the activity of the mitochondrial
297 respiratory chain and the production of ROS. This suggests that accelerated growth
298 rate would be obligatory associated with accentuated risks for oxidative stress. In
299 support, plasma concentrations of hydroperoxides continuously increased in
300 growing pigs (Buchet et al., 2017). In addition, fast-growing lines and breeds have a
301 deteriorated redox status when compared with slow-growing lines or breeds
302 (Brambilla et al., 2002; Merlot et al., 2012). However, no particular diseases are
303 observed in these situations, although high selected breeds are suggested to be less
304 robust than unselected breeds. On the opposite, the extraordinary achievements of
305 selection for fast growth rate and high breast meat yield in poultry resulted in the
306 apparition of spontaneous myopathies (white striping, wooden breast, spaghetti
307 muscles) in broilers and turkeys (Petracci et al., 2015). In these situations, the breast
308 muscle of the chickens displayed inflammation and oxidative stress (Baéza et al., 309 2018; Petracci et al., 2019), as revealed by greater levels of lipids (MDA content) and 310 proteins (carbonyls content) oxidation products (Soglia et al., 2016; Baldi et al., 311 2018). When compared with normal muscles, they also had lower contents in 312 anserine and carnosine, two dipeptides having antioxidant effects (Sundekilde et al., 313 2017). Comparison between species thus suggests the existence of a physiological 314 limit after which any improvement of growth rate would have detrimental effects on 315 health.

316 Studies dealing with lines selected for residual feed intake, a measure of feed 317 efficiency, provide more insights on the role of mitochondrial functionalities in 318 managing the balance between oxidative products and antioxidants in animals 319 selected for production performance. In pigs, the protein profile of mitochondria 320 isolated from skeletal muscle in the low residual feed intake pigs (the more efficient) 321 indicated an increase in anti-oxidant defence capacity as compared with high 322 residual feed intake pigs (Grubbs et al., 2017). In good hygiene housing conditions, 323 low residual feed intake pigs have lower antioxidant enzymes activities such as the 324 glutathione reductase and catalase in adipose tissue and superoxide dismutase in 325 muscle, and when reared in degraded hygiene conditions inducing an inflammatory 326 response, the low residual feed intake pigs produced lower ROS than the high 327 residual feed intake pigs (Sierzant et al., 2019). Similarly, low residual feed intake 328 bulls (more efficient) had a lower antioxidant activity in the liver, which is interpreted 329 as the consequence of a lower ROS production in those animals as compared with
330 high residual feed intake bulls (McKenna et al., 2021). Taken together, mitochondrial 331 functionality can modify the venue of oxidative stress, so that there is no absolute 332 relationships high production performance and the venue of oxidative stress. 333

333 **Dietary challenges: beyond the role of nutrients in growth performance**

334 Due to the close relationships between nutrient use for cellular energy production, 335 oxidative phosphorylation and the oxido-reduction metabolism, any deficiency or 336 excess in macro- and micro-nutrients can generate an imbalance between ROS 337 production and antioxidant defense in tissues. The roles of the sulfur-containing 338 aminoacids such as methionine (Table 3) and cysteine have been particularly 339 examined. Indeed, these aminoacids are limiting for growth and lactation 340 performance due to their involvement in protein synthesis in the different species, 341 and considering that most forages and soybean meal have a low content in 342 methionine. In aquaculture, plant ingredients included in aqua-feeds to reduce the 343 use of ingredients derived from feed grade fisheries (i.e., fishmeal and fish oil) also 344 contain less micronutrients such as methionine. Importantly, these aminoacids can 345 directly modulate the redox status of animal tissues due to their involvement in the 346 synthesis of GSH and taurine, two cellular compounds with antioxidant properties. 347

347 In growing pigs, dietary methionine deficiency reduced the GSH content in the 348 muscle and liver, increased the enzymatic antioxidant activities in muscle and 349 adipose tissues, and lowered the total anti-oxidant power (FRAP and 350 1,1-diphényl-2-picrylhydrazyl) in plasma (Castellano et al., 2015; Conde-Aguilera et 351 al., 2020). Conversely, feeding finishing pigs with extra dietary methionine supply
352 above growth requirements increased the muscle content in total GSH and
353 dipeptides with antioxidant properties such as anserine, but without any changes in
354 the antioxidant enzyme activities in muscle (Lebret et al., 2018; Gondret et al., 2021).

355 In addition, the lower TBARS values generated during a forced oxidation kinetics in
356 muscle of pigs fed extra methionine supply further indicated lower oxidative stress in
357 those pigs (Lebret et al., 2018). In ruminants, a rumen-protected form of methionine
358 may be supplemented to the diet which is of special interest for improving
359 performance of high-yielding dairy cows and liver metabolism (Durand et al., 1992;
360 Bauchart et al., 1998). However, in growing bulls receiving high forage diet
361 supplemented by methionine (Cantalapiedra et al., 2020), there was no
362 improvement in endogenous antioxidants nor changes in the systemic redox status
363 (Durand Denys, unpublished data). In broilers, suboptimum supply of Methionine
364 also resulted in lower antioxidant concentrations in plasma and body tissues.
365 However, although a higher content in GSH in the liver was observed with increased
366 methionine concentrations in the diet (Conde-Aguilera et al., 2016), liver
367 concentrations of TBARS and protein carbonyls were not responsive to dietary
368 methionine concentration (Zeitz et al., 2018).

369 In various fish species at different life stages, dietary methionine deficiency was
370 also associated with an imbalance between oxidative products and antioxidants,
371 with a decrease in GSH to oxidized glutathione (GSSG) ratio and an increase in lipid
372 peroxidation and protein oxidation observed in rainbow trout juveniles and in the fry
373 fed a deficient methionine diet for 12 weeks (Fontagné-Dicharry Stéphanie,
374 unpublished data). These changes were associated with higher expression levels of
375 genes coding for the antioxidant enzyme glutathione S-transferase π, and for the
376 tumor necrosis factor, a pro-inflammatory cytokine, in the flesh (Alami-Durante et al.,
377 2018). Expression levels of genes coding for antioxidants such as glutathione
378 S-transferase π, glutathione reductase and methionine sulfoxide reductase A1, were
379 induced either directly by dietary methionine deficiency in the liver of the broodstock
380 and in whole fry, or indirectly by the parental methionine intake as observed in the
381 swim-up fry. Long-lasting parental effects of broodstock methionine-intake were
382 observed in the fry, 21 days after first-feeding and irrespective of the fry diet, for the
383 genes coding for methionine sulfoxide reductases A1 and B2 and superoxide
384 dismutase 2 (Fontagné-Dicharry et al., 2017). However, in some studies, dietary
385 methionine deficiency in rainbow trout juveniles decreased rather than increased
386 carbonyls and GSH. This may be due to the sharp increase in mitochondrial
387 degradation through mitophagy which decreased ROS production (Séité et al.,
388 2018). Similarly, feeding extra methionine decreased protein oxidation in rainbow
389 trout juveniles but increased lipid peroxidation and antioxidant genes expression in
390 rainbow trout fry (Fontagné-Dicharry Stéphanie, unpublished data). Discrepancies
391 between studies may be related to the specific needs in methionine depending of
392 age and growth period of the trout.

393 These experiments illustrate the potential of dietary aminoacid contents for
394 modulating oxidative stress in farm species, and further suggest that nutritional
395 recommendations could be revised to better account for the effects on redox status
396 and not only on growth requirements. Other imbalanced feeding conditions such as
397 glycemic index and balance in polyunsatured fatty acids (n-6 /n-3), can be also
398 concerned, but are not detailed in this review.

399 **Environmental challenges**

400 The environment in which farm animals are reared is subjected to uncontrolled
401 events that tackle the animal physiology. Different situations can be encountered in
402 farm animals.

403 Maybe not enough considered, the level of oxygen in the environment is of
404 importance due to its role in the venue of oxidative stress. Hypoxia occurs in most
405 aquatic environments, especially those with a high stocking density. In rainbow trout
406 juveniles, chronic hypoxia reduced blood GSH content and increased hepatic activity
407 and transcript expression of the antioxidant enzyme catalase (Fontagné-Dicharry et
408 al., 2020). Acute hypoxic challenge also induced oxidative stress with increased lipid
409 peroxidation and glutathione disulfide content and transcriptional regulation of
410 antioxidant enzymes in rainbow trout fry (Wischhusen et al., 2020a). Water
411 oxygenation is thus a common recommended practice in aquaculture systems.
412 However, if not adequate, it can conversely lead to hyperoxia that also induced
413 physiological stress responses, characterized by a higher TBARS content in flesh
414 and lower antioxidant enzyme activities in the liver of rainbow trout juveniles
415 (Kalinowski et al., 2019). The situation in fish may question the consequences of
416 inadequate oxygen supply in terrestrial species. Although rare, this may concern
417 extensive farming systems in hard mountain conditions (cows or sheep) and poultry
houses in altitude. Differences in oxygen availability to tissues can also be due to external and inner events. In poultry, ascites is a frequent metabolic disorder manifested by the abnormal build-up of fluid in the peritoneal spaces, which can be induced by several factors such as continuous light, insufficient ventilation in the poultry house, high altitude and cold environment (Decuypere et al., 2000). Ascites is caused by an imbalance between the oxygen requirement of tissues and the oxygen supply to tissues. In addition, lipid peroxidation further played an important role in the pathogenesis of pulmonary hypertension associated with ascites, since free radicals led to endothelial damage in both heart and lung cells (Aksit et al., 2008). Controlling the early chick embryo environment may be a way to avoid these oxidative damage. The use of cold temperatures during egg incubation was proven to limit cold sensitivity later in age and the incidence of ascites (Shinder et al., 2011). Furthermore, chicks exposed to cyclically cold incubation temperatures exhibited increased antioxidant capacity, such as 8-fold higher catalase activity in the liver at hatch as compared to control-incubated chicks (Loyau et al. 2014).

Due to relationships between environmental availability of oxygen and heat tolerance of the animals, it is also of interest to consider the effects of heat stress on redox status of the animals. Considering the global warming, severity and frequencies of heat waves will be more frequent in the coming years, which further justifies to undergo specific studies to investigate the effects of chronic heat stress on oxidative stress in farm species. As examples, the effects of heat stress on different indicators of oxidative stress have been characterized in chicken and laying
hens (Lin et al., 2006; 2008). In laying hens, a moderate heat exposure (32°C during 440 21 days) at the end of the laying period (60 weeks) increased ROS concentration in 441 blood during heat exposure, and triggered blood antioxidants, on a temporary basis 442 (superoxide dismutase activity) or during the whole period (FRAP) (Lin et al., 2008). 443

In meat type chicken, acute heat stress also led to an increase in TBARS 444 concentrations in the liver but not in the heart (Lin et al., 2006). Solutions to mitigate 445 oxidative stress due to heat conditions can reside in improving the long-term 446 thermo-tolerance of the animals. In poultry, cyclic increases in incubation 447 temperature of the eggs led to a better survival to acute heat exposure at 35-days of 448 age in male chickens (Piestun et al., 2008), and this was associated with many 449 changes in expression levels of genes involved in stress response and 450 vascularization acting in tissue oxygenation (Loyau et al., 2016). These examples 451 obtained in fishes and chicken underline the importance of environmental events in 452 the venue of oxidative stress, and these events may be more frequent in the coming 453 years and have wider effects on a large broad of farm systems, and especially those 454 in loose and harsh conditions. 455

## Pro-inflammatory and stressful conditions 456

### Housing conditions 457

Poor hygiene conditions and the lack of respecting biosecurity recommendations 458 have been clearly identified as risk factors for health of animals reared indoors. Poor 459 hygiene conditions often induce a systemic inflammatory response due to carbon 460 dioxide, ammonia, temperature and(or) bacterial pressure. Among other problems 461
such as pulmonary diseases, the poor sanitisation levels have been associated with the generation of oxidative stress, as attested by a lower total antioxidant capacity in plasma (FRAP), greater plasma levels of hydroperoxides and an activation of antioxidant enzymes in tissues of growing pigs (Buchet et al., 2018; Sierzant et al., 2019). During reproduction, stressful housing situations can also generate oxidative stress. For example, moving young nulliparous sows from group-housing pens to individual crates increased salivary cortisol, and this was associated with an increased expression of oxidative stress enzymes in serum (Marco-Ramell et al., 2016). Greater plasma concentrations of hydroperoxides were also observed in sows housed in groups on concrete slatted floor during gestation when compared with sows housed in larger pens with deep straw litter favouring animal welfare (Merlot et al., 2019). After farrowing, the one-day old piglets born from the sows housed on concrete slatted floor have a lower blood antioxidant potential than piglets born from mothers that had been housed on straw (Quesnel et al., 2019). The cortisol whose secretion was increased in the group on concrete slatted floor, might play a role in this response, because studies in the avian species showed that glucocorticoids stimulated the production of oxidative products (Lin et al., 2004). In sheep, forced physical activity and transportation led to a higher cortisol concentration, an increase in the metabolism of carbohydrates and lipids; this resulted in the occurrence of oxidative stress proved by an increased MDA production and lower TAS (Gladine Cécile, unpublished data).
483 Self-medication behavior appears as an interesting strategy to reduce the consequences of production diseases. Self-medication has been defined as the ability of animals to select and use specific plants or substrates with medicinal properties to control or to prevent diseases or situations of discomfort.

487 Self-medication is reported in ruminants which can consume plants associated with anti-parasitic properties to maintain health (Villalba et al, 2014). In cows and sheep, plant extracts rich in polyphenols, vitamin E or the combination of the two additives supplemented to n-3 polyunsaturated fatty acid-rich diets have been tested to reduce the oxidative stress induced by forced physical activity and transport.

492 Although the dietary administration of polyphenols or Vit E did not prevent the induction of lipoperoxidation, the dietary administration of the two antioxidants reduced the increase in MDA production in sheep (Gladine Cécile, unpublished data). This synergic effect of the antioxidants cocktail has been confirmed in dairy cows (Gobert et al., 2009). This can be explain by the dual abilities of the lipophilic (vitamin E) and hydrophilic (polyphenols) antioxidant properties to break the lipoperoxidation chain and reduce the amounts in oxygenated radical species (Delosière et al., 2020). Plant extracts combined with vitamin E can be supplemented to polyunsaturated fatty acid-rich diets to limit oxidative stress in cull cows, even for pre-slaughter animal stress (Gobert et al., 2010; Delosière et al., 2020). Strategies based on self-medication in ruminants have been also tested in poultry. For instance, lame chickens have a preference for a feed supplemented with an anti-inflammatory and analgesic drug rather than the same feed without the drug
505 (Danbury et al, 2000) and chicks can adjust essential oil consumption after a delayed
506 placement by uptake of lemon verbena essential oil, which is known to have
507 antioxidant, anti-inflammatory, sedative, and digestive effects (Guilloteau et al.,
508 2019).

509 **Surgical procedures**

510 Surgeries are used in farm animals at specific periods for castration, caesarian,
511 visceral interventions, etc. For instance, during a high invasive surgery in sheep,
512 although the antioxidant status estimated by TAS and the lipoperoxidation were not
513 significantly altered, greater nitric oxide and lower GSH/GSSG ratio both indicated
514 that the oxidation was triggered (Faure et al., 2017). To monitor the efficacy of
515 drug-based pain alleviation protocols to surgeries, responses can be followed by
516 using both behavioural and physiological indices. In addition to the most commonly
517 used indicators (cortisol, haptoglobin, clinical signs), oxidative stress indicators are
518 also well correlated with the efficacy of analgesia strategies. For instance, the
519 multimodal analgesia (local anesthesia + non-steroidal anti-inflammatory drug) led
520 to the lowest impact on redox status, thus limiting post-traumatic event (Durand et
521 al., 2019). Painful procedures similarly induce changes in biochemical markers of
522 oxidative stress (Ting et al., 2003), and of inflammation such as haptoglobin and
523 serum amyloid A (Eckersall et al., 2001) in calves and lambs. Oxidative stress
524 markers have also been proposed as relevant indicators of pain in pigs. In this
525 species, salivary cortisol, ferric reducing ability of saliva and advanced oxidation
526 protein products in saliva are correlated with the pain score measured in lame and
527 prolapsed animals (Contreras-Aguilar et al., 2019). These different examples further
528 highlight the close relationships between stress hormones (cortisol or corticosterone
529 depending on the species), inflammation and oxidative stress.

530 **Conclusion**

531 This review highlights several relationships between redox status and animal
532 performance and health at critical periods (Fig. 1). Of note, the level of oxidative
533 stress and its consequences are modulated by additional factors inherent to the
534 animal (genotype, physiological maturity) and to management practices prior, during
535 and after the challenges. The data from different species pointed to the central role
536 of energy metabolism at the origin of pro-oxidative metabolites generation, whereas
537 the antioxidant capacities orchestrated between various tissues are of importance to
538 limit their deleterious effects. Therefore, the evaluation of the redox imbalance can
539 be used as a non-specific but valuable indicator to evaluate the intensity of stressful
540 events encountered by the animals. When measured before a well-known but
541 inevitable challenge, it can be used to predict the robustness and more specifically
542 the resilience of the animal. A synthetic index to estimate oxidative stress would be
543 thus a valuable tool to rank animals according to risk and to evaluate acute or
544 long-term effects of management practices on performance and health. However,
545 this supposes a consensus about the best measures of pro-oxidative and antioxidant
546 pathways and their interpretation along the productive life. It seems premature to
547 identify a simple, generic and robust indicator of oxidative stress. However, specific
548 indicators of the level of oxidative stress and of the level of antioxidants that the
549 animals can mobilise to respond to diverse challenges can be foreseen. They
550 include the measurement of oxidation products such as lipid oxidation products
551 (MDA, lipoperoxides), protein oxidation products (carbonyls) and GSH/GSSG ratio
552 to evaluate the intensity of oxidative processes. Similarly, available antioxidant
553 defence can be assessed by global test (FRAP, BAP, TAS, TEAC, Cuprac) in blood
554 or plasma but must likely be associated with measurements of endogenous
555 (catalase, superoxide dismutase, glutathione peroxidase) enzymatic defenses in
556 different tissues. To data, there is no gold standard approach between species. In
557 humans, considering the complexity of redox status evaluation, the 5R redox
558 principles are recommended with different factors measured at the same time to
559 achieve real precision (Meng et al., 2021). The development of agro-ecological
560 practices in farm animals reinforces the needs to better understand the internal
561 levers from animal physiology to control the level of oxidative stress. Genetic
562 selection for robustness but also the ability of the animals to self-regulate their
563 physiology through feeding preferences are possible strategies to be explored and
564 combined in the future.

565 Ethics approval

566 Not applicable

567 Data and model availability

568 This review cites data that have been published in peer-reviewed journals or
569 conference proceedings. For the majority of them, they are not deposited in official
570 repositories. For data referred as unpublished, none of these data were deposited in
571 an official repository. The data that support the concepts are available from the
572 authors upon request.

573 Author ORCIDs

574 Denis Durand: 0000-0001-8381-8999

575 Florence Gondret: 0000-0001-7997-1560

576 Nathalie Le Floc'h: 0000-0001-9858-1584

577 Elodie Merlot: 0000-0003-2300-0970

578 Stéphanie Fontagné-Dicharry: 0000-0002-4366-4590

579 Elisabeth Baéza: 0000-0001-7658-3394

580 Laurence A. Guilloteau: 0000-0001-7089-2196

581 Anne Collin: 0000-0002-3410-6108

582

583 **Author Contributions:** D. Durand and F. Gondret conceptualized the review; all
584 co-authors wrote and edited the manuscript. All co-authors read and agreed to the
585 final version of the manuscript.

586 Declaration of interest

587 The authors declare no conflict of interest.

588 Acknowledgements

589 Not applicable

590 Financial support statement

591 Not applicable
592

593

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898 Séité, S., Mourier, A., Camougrand, N., Salin, B., Figueiredo-Silva, A.C.,
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969
<caption>**Table 1**</caption>

Post-natal period events with increased oxidative process in pigs, ruminants, poultry and fishes.

<table><thead><tr><th>Species<sup>1</sup></th><th>Critical stage</th><th>Main challenge</th><th>Additional challenge</th><th>Redox status involvement</th><th>Aggravating factors</th><th>Levers to limit oxidative stress</th></tr></thead><tbody><tr><td>Pig</td><td>Birth</td><td>Hypo- to hyperoxia</td><td>Amniotic fluid to colostrum feeding</td><td>Blood hydroperoxides ↑<br>Expression of peroxiredoxins in adipose tissue ↑<br>Hepatic MDA content ↑</td><td>Low BW of piglets</td><td>Neonatal diet rich in proteins</td></tr><tr><td>Ruminant</td><td>Birth</td><td>Hypo- to hyperoxia</td><td>Amniotic fluid to colostrum feeding</td><td>Blood ROS ↑</td><td>Feeding newborns with milk replacer</td><td>Dietary supplementation of lactating females and calves with antioxidants and selenium</td></tr><tr><td>Poultry</td><td>Hatching</td><td>Hypo- to hyperoxia</td><td>Yolk sac to concentrate diet feeding</td><td>Lipid peroxidation in skeletal muscles and heart</td><td>Long egg storage before incubation<br>Delayed placement of chicks in farms</td><td>Short egg storage before incubation<br>Short delay between hatching and placement in farms<br>Dietary supplementation of breeders with antioxidants</td></tr><tr><td>Fish</td><td>Hatching</td><td>Active feeding</td><td>Egg yolk to larval diet</td><td>Lipid peroxidation ↑<br>Vitamins A, C and E ↓<br>GSH/GSSG ↓<br>Antioxidant enzyme activities ↑</td><td>High concentration of long chain n-3 polyunsaturated fatty acids in diet and animal tissues.<br>Incomplete development of the endogenous antioxidant</td><td>Dietary supplementation of broodstock with vitamin A, methionine, selenium</td></tr></tbody></table>
Abbreviations: GSH = reduced glutathione; GSSG = oxidized glutathione disulphide; MDA = malondialdehyde; ROS = Reactive oxygen species.

¹Examples in different species are mainly based on our own works, and not an overview of all references. This underlines that depending of the lab history and skills, the used indicators may vary and no systematic studies have been considered for one or more challenges.
<caption>**Table 2**</caption>

Juvenile transition events with increased oxidative process in pigs and ruminants.

<table><thead><tr><th>Species<sup>1</sup></th><th>Critical stage</th><th>Main challenge</th><th>Additional challenge</th><th>Redox status involvement</th><th>Aggravating factors</th><th>Levers to limit oxidative stress</th></tr></thead><tbody><tr><td>Pig</td><td>Weaning</td><td>Dietary transition, separation from the mother, social stress</td><td>New environment, high rearing density, animal mixing, cold stress</td><td>Hydroperoxides in blood and liver ↑ Hepatic MDA content ↑ Glutathione peroxidase activity in liver ↓ Vitamins A and E in blood ↓</td><td>Early stage, low BW, additional gut health disorders</td><td>Dietary supplementation with antioxidants</td></tr><tr><td>Ruminant</td><td>Weaning</td><td>Dietary transition, separation from the mother</td><td>New environment, social stress</td><td>Hydroperoxides in exhaled breath condensate ↑</td><td></td><td>Dietary supplementation with minerals and antioxidants</td></tr></tbody></table>

Abbreviations: MDA = malondialdehyde.

<footnote n="1">¹Examples in different species are mainly based on our own works, and not an overview of all references. This also underlined that depending of the labs history and skills, indicators may vary and no systematic studies have been considered for one or more challenges</footnote>
<caption>**Table 3**</caption>

Synthesis on dietary methionine deficiency and redox status of pigs, ruminants, poultry and fishes.

<table><thead><tr><th>Species<fnref n="1" /></th><th>Redox status</th></tr></thead><tbody><tr><td>Pig</td><td>Glutathione content in muscles and liver ↓<br>Antioxidant enzyme activities (catalase, superoxide dismutase or glutathione peroxidase) in muscle and adipose tissues ↑</td></tr><tr><td>Ruminant</td><td>glutathione peroxidase and glutathione reductase mRNA in placenta</td></tr><tr><td>Poultry</td><td>Glutathione and vitamin E contents in liver ↓<br>TBARS value and carbonyl contents in blood ↑<br>Vitamin E in blood ↓<br>Antioxidant enzyme activities (Catalase, superoxide dismutase, and glutathione peroxidase) in jejunum ↑</td></tr><tr><td>Fish</td><td>Glutathione content in plasma and liver ↓<br>Protein carbonyls in liver ↑<br>Glutathione transferase-π transcript expression in liver, muscle and fry ↑</td></tr></tbody></table>

Abbreviations: TBARS = thiobarbituric acid reactive substances.

<footnote n="1">¹Examples in different species are mainly based on our own works, and not an overview of all references. This also underlined that depending of the labs history and skills, indicators may vary and no systematic studies have been considered for one or more challenges</footnote>
**Figure captions**

**Fig. 1.** Schematic representation of the main internal and external factors inducing oxidative stress in pigs, ruminants, poultry or fishes.
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