Cortisol, stress and robustness in cattle. Pierre MORMEDE Génétique, Physiologie et Systèmes d Elevage GenPhySE UMR1388 Castanet-Tolosan

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1 Cortisol, stress and robustness in cattle Pierre MORMEDE Génétique, Physiologie et Systèmes d Elevage GenPhySE UMR1388 Castanet-Tolosan

2 CORTISOL IS NOT STRESS CORTISOL AND STRESS CORTISOL AND ROBUSTNESS

3 The concept of stress Walter B. Cannon ( )

4 Strain: change in form or size, or both, resulting from stress, or force Adaptation and stress, mechanical model The Hooke law ADAPTATION Homeostasis STRESS Allostasis Zone of elastical deformation Zone of permanent deformation Robert Hooke rupture Stress: force exerted upon a body, that tends to strain of deform its shape

5 «I wish to try to make clear that it is the peculiar function of the sympatho-adrenal mechanism to preserve and assure a homeostatic condition in the internal environment» When the stimulus intensity increases, we observe a non specific generalization of the response. [In these conditions] «the stress might be regarded as becoming excessive or critical, i.e., inducing a breaking strain in the homeostatic mechanisms» This generalization of the response leads to a mobilization of energy preparing the organism to action (fight/flight reaction)

6 The wrong start of the HPA axis The focus on adrenal glands comes from Hans Selye s description of A syndrome produced by diverse nocuous agents, a one-column paper published in Nature in The general adaptation syndrome

7 The HPA axis, a major neuroendocrine system Adrenal glands have long been been mentioned in anatomical records (Tabulae anatomicae by Bartholomaei Eustachii, 1716) but their precise role was ignored except in rare clinical conditions (Cushing, Addison) isolation by Reichstein of Kendall s compound E (cortisone, 1939) from adrenal glands discovery of the anti-inflammatory effects of cortisone by Hench 1950 Edward C. Kendall, Tadeus Reichstein and Philip S. Hench receive the Nobel Price of Physiology and Medicine for the discovery of adrenal steroids and of their biological (anti-inflammatory) effects. it s the beginning of a long story

8 The HPA axis in cattle Hypothalamus (CRH, AVP), anterior pituitary (ACTH), adrenal cortex Cortisol is the main glucocorticoid hormone in cattle It circulates mainly as bound to corticosteroid-binding globulin (CBG, ~80 %) and albumin (~10 %) CBG acts mainly as a reservoir that releases active (free) hormone in the tissues Glucocorticoid receptors (gene NR3C1 and NR3C2) are present in all tissues Following hormone binding they are translocated to the nucleus where they act as regulators of gene transcription through binding on specific DNA sequences (GRE = glucocorticoid response elements) or by interaction with other transcription factors (FOS, JUN, NFκB, STAT) Glucocorticoid hormones regulate the expression of more than 500 genes They regulate a wide range of physiological processes: metabolism, brain functions, inflammation and immune responses,

9 Physiological variations in HPA axis activity - Ultradian and diurnal cycles Nadir 1800 h 3.10 ng/ml Zenith 0530 h 4.48 ng/ml Period of the ultradian rhythm 120 min Feeding 0900 h Feeding 0900 h Hour Lefcourt et al. J Dairy Sci 76:2607, 1993

10 Stimulation tests: ACTH Changes in plasma metabolites: amino acids, glucose - Protein catabolism (muscle) - Gluconeogenesis (Ndibualonji et al. 1995) Changes in white blood cells: leucocytosis with lymphopenia and granulocytosis Changes in gene expression Verkerk et al. 1994

11 ACTH stimulation test: pigs White dots: females Black dots: males r = Larzul et al. 2015

12 Physiological variations in HPA axis activity - age, sex, hormonal and reproductive status Gifford et al., 2015

13 Hormonal status: ACTH stimulation test Boissy & Bouissou, 1994

14 Plasma cortisol Physiological variations in HPA axis activity - Temperature: adaptation and stress ADAPTATION cold heat STRESS Acute exposure Progressive exposure Basal levels Non specific response hours Specific adjustments days TIME Cattle: Johnson & Vanjonack, 1976 Lee et al Pigs: Marple et al. 1972

15 Individual variations in HPA axis activity Genetic factors Breed differences Family studies Genetic selection Early influences and epigenetic factors Life history: allostatic changes wear and tear of adaptation (McEwen & Stellar 1993)

16 NO, CORTISOL IS NOT STRESS

17 Cortisol and stress Stress is the non-specific response of the body to any demand made upon it (Selye, 1950) The HPA axis is activated by stress factors to meet the metabolic demands of adaptation ( fight or flight ) However, any difference in cortisol level or in HPA axis function does not necessarily reflects a stress response How is my measure related to HPA axis activity? If yes, is the change is HPA axis activity a stress response?

18 ROBUSTNESS In engineering science, a robust conception aims at the optimization of product performance together with the lowest sensitivity to disturbances In animal breeding, robustness is the ability to combine a high production potential with resilience to stressors, allowing for unproblematic expression of a high production potential in a wide variety of environmental conditions (Knap 2005) ROBUSTNESS is clearly a synthetic concept combining production potential with the sensitivity a animals to disturbances (resistance) and their adaptation potential (resilience) to avoid negative consequences of stress or suboptimal environments on production, health and welfare

19 Effects of cortisol on production and robustness traits Selection for Fast growth rate High feed efficiency Lean carcasses - Production traits Growth rate Feed efficiency Protein/lipid ratio (carcass composition) Cortisol Robustness traits Resistance to stress Resistance to diseases Newborn survival

20 Cortisol and feed efficiency: sheep In pigs: Hennessy & Jackson 1987

21 Cortisol and feed efficiency: cattle Montanholi et al., 2010, 2013

22 Cortisol and carcass composition Slaughter weight Carcass weight Note %LD %fat Plasma cortisol Noradrenaline urine Adrenaline urine Cortisol urine Cortisone urine Beef cattle, Limousine breed, n = 358 Hocquette, Mormede et al. unpublished data

23 Cortisol and milk production at dry-off ± 6.8 ng/g 94.0 ± 6.3 ng/g 71.1 ± 6.1 ng/g Bertulat et al.,

24 Cortisol health??? Liver inflammation reduces CBG? High HPA axis activity increases robustness? Trevisi et al. 2013

25 lcort CURRENT RESEARCH Genetic selection for a more active HPA axis to improve robustness in pigs The adrenal sensitivity to ACTH is the main source of genetic variability Selection trait: plasma cortisol concentration 1 h after ACTH at 6 weeks Heritability 0.68 (Larzul et al. Animal 2015) Third generation: cortisol post-acth x 2.34 no time x genotype interaction Reproduction G piglet/litter in G2+ vs G2- Much more to come What about cattle? Plasma cortisol - response to ACTH H 1H 4H 24H temps factor(lot) G3- G3+