Animal Disorders - W25 PDF

Animal Disorders - W25 Stress and Animal Health ​ Stress is important in animal health because it can reduce production, product quality, and welfare ​ Animal health is of concern because consumers expect high quality, ethically raised with lower price ​ Zoonoses are also of great concern...

Animal Disorders - W25 Stress and Animal Health ​ Stress is important in animal health because it can reduce production, product quality, and welfare ​ Animal health is of concern because consumers expect high quality, ethically raised with lower price ​ Zoonoses are also of great concern - avoiding diseases contracted from animals ​ Zoonotic disease- a disease that goes from animals to humans, reverse is the opposite ○​ Quite a number of livestock pathogens that are considered to be zoonotic ​ Since 1950s, use of antimicrobials to prevent bacterial, fungal, and parasitic infections has increased ○​ Antimicrobial resistance is a growing problem in animal health because antimicrobials are less effective in animals and humans as well ​ Genetic selection for production traits is inversely correlated with health and fertility ○​ All your energy in milk production, less energy for immune system ​ Climate change is expected to effect livestock and aquaculture species as it progresses ○​ Climate is unstable, plants are stressed, mold can grow, mycotoxins can grow ​ Physiological effects of stress are important to study for many reasons, including biomarkers of illness/stress to monitor animal health, phenotypes for selection for stress resistant animals ​ Domestic animals are subjected to physical, chemical, biological and psychological stress Response to stress ​ Response to stress is highly conserved series of reactions shared between mammals ​ Stress response characterized by cardiovascular, metabolic, musculoskeletal, neuroendocrine, and immune changes as body prepared to deal ​ Stress response is often inappropriate due to its primitive nature placed in context of modern day ​ Triggers for stress response vary between species and individuals ​ A stress response is revolutionary, manifests by having responses in different organs and manifests a fight, flight or freeze response dependant on the species and individual ​ A stressor is something that disrupts homeostasis ​ Examples of common stressors to animals include: ○​ Physical: temperature, climate change shipping, air and water quality, light intensity/duration/wavelength, injury, stray voltage, UV radiation, processing, noise, restraint/confinement, surgery, predation ○​ Chemical: mycotoxins, heavy metals, organochlorides, poisonous plants ○​ Biological: nutrient excess/deficiency, feed restriction, parturition, negative energy balance (lactation), acidosis, inadequate rest, over-training, dehydration, infection ○​ Psychological: mixing, weaning, herding, showing ​ Stressful sensory inputs occur externally through five senses and internally through immune system recognition and changes in microbiome ○​ Gut-brain link is an important part of stress response, lots of new research about this field ○​ Touch, taste, smell, hearing, sight, immune system recognition, microbiome  ○​ Microbiome: microbes that are found on epithelial surfaces, provide us with nutrients like vitamin K and we give them an environment for them to survive and feed us, occupy space so a pathogen can’t stick ○​ As we get older, we can't regulate inflammation as well ○​ How our immune system regulates is what determines if we survive or not ○​ Glucocorticoid = anti-inflammatory ​ Sensory inputs are relayed by a neural, endocrine, and immune systems to brain which interprets them and puts out a stress response through conscious and unconscious processing ​ Individuals that are hypersensitive to stressors are more susceptible to disease due to compromised immune function and other dysfunctions in stress response ​ Desensitization to stressors can increase susceptibility to other risks due to lower/impaired processing of stressful inputs ○​ Desensitization is usually an adaptive feature to be able to cope with greater stress ​ Variation= Genetics+Environment+Gene*Environment ○​ V- phenotypic output of stress, determined by internal and external factors ○​ G - genetically determined response ○​ E - environmentally determined response (changes acquired during lifetime) ○​ G*E - interactions between genetics and environment, epigenetics ​ Combination and interactions of stressors can decrease an animals resilience to stress ​ Q0 - estimate of potential infection pressure of a parasitic nematode in ruminants ○​ Increases with climate change due to effect of temperature on growth ○​ Stressors can interact to produce a greater effect on an animal, in this case parasites + climate change ​ Fun fact! 10x more likely to get an infection in the morning than afternoon ​ Circadian rhythm that affects our stress pathways ​ Cortisol levels peak at 9/10am ​ Sympathetic and immune system affect each other ​ BMAL1 gene regulates a whole bunch of circadian cycle genes ​ If we disrupt clockwork genes it makes us more susceptible to infection ​ Jetlag is really hard on your body ​ BMAL1 can be measured in your blood ​ Lowest levels are in the winter, highest levels are in the summer ​ Viral infections can disrupt these genes to their advantage ​ Mismatch of animal to its environment can cause stress and disease ○​ Fainting goats - occur due to Congenital myotonia, a response to stress. A gene encoded temptation (CNCL1 gene) that effects the chloride channel protein causing the pump to stop working and chloride isn’t removed, causing a “freeze” in the muscles ○​ The changing environment of Laying Hens - closed system is restricted in terms of pathogens and going back to free range could be a problem ○​ A proper match of the genotype and epitype to the environment to allow for as little stress as possible - most farmed species are not well matched to intensive farming systems, most endangered species are not well matched to zoos and aquariums where they are kept Stress Physiology ​ Are exotic species such as water buffalo, ostrich and a new aquaculture species matched to current intensive farming systems? ○​ No, breeding can contribute to it but no ​ Are endangered species that have been reintroduced into the wild from zoos/aquariums appropriately matched for optimal survival? ○​ No, they have no survival instincts and would not survive in the wild, better to keep them in their best care and provide with enrichments ​ Many ways to determine if an animal is stressed based on physiological signs such as: ○​ Flock/herd mortality- by then it's probably too late ○​ Weight loss - weighing animals on a regular basis could be helpful but not practical ○​ Reduced fertility - another too late ○​ Clinical disease - good indication, too late hard to assess ○​ Behavioural changes - learned helplessness, aggression, real time monitoring of productivity ○​ stress is a broad term, and not always bad ​ Biomarkers - a measurable substance in an organism whose presence is indicative of some phenomenon such as disease, infection, or environment exposure ​ Biomarkers of stress have certain criteria to be valid measurements ○​ Must be easy to obtain from tissues ​ blood sample if efficient ​ waste products - possible but not easy ​ milk - real time collecting of data ○​ Minimal discomfort to retrieve ○​ Sensitive to changes ○​ Specific to the species and animal ​ SCC - somatic cell count - when a cow develops a mammary infection, SCC will go up very quickly when they have acute mastitis , specific to the mammogram ○​ Systemic vs local? Should be known which it is when performed ​ SCC is localized infection ○​ Repeatable ​ Can collect again and it is still accurate and reliable ○​ Potential for high throughput analysis ​ cost efficient, lots can be processed at the same time ○​ Economical to collect ○​ Assay developed ​ if we have to develop an assay, that’s gonna cost money ○​ Real-time precision monitoring ​ 2 main physiological pathways of stress ​ Sympathetic-adrenal medulla (SAM) axis ○​ activated quickly - within seconds ○​ mediates/ initiates the fight flight or freeze response by causing neuroendocrine and immune function changes  ○​ Stimulus processed by the brain causes release of ACh into bloodstream which binds nicotinic ACh receptors in adrenal medulla ○​ Medullary cells produce epinephrine which prevents degranulation of mast cells to prevent dilation of peripheral blood vessels and keep blood in vicinity of major organs ○​ NOTE: remember L-tyrosine and PNMT ​ Different stressors influence amounts of PNMT (enzyme) which determines intensity of immediate stress response due to its role in conversion of norepinephrine to epinephrine ​ Hypothalamus-pituitary-adrenal cortex (HPA) axis ○​ HPA axis is slower, hormonal response to stress that involves release of corticosteroids ○​ Processing of stressful stimulus in hypothalamus causes corticotropin releasing hormone to be released into pituitary gland and binds receptor (CRH-R1) ○​ Binding causes release of POMC which is converted by enzyme PC1 into ACTH ​ There is no gene for ACTH, only one for POMC and one for PC1 ○​ ACTH released from antipituitary into blood and stimulated receptor in adrenal cortex, MC2R ○​ Adrenal cortex stimulated to synthesize and release glucocorticoids (GCs) ​ Substrate of GCs is cholesterol, which undergoes conversion to pregnenolone by a cytochrome P450 enzyme into pathways for corticosterone or cortisol ○​ Corticosterone is found in birds and rodents, cortisol is found in mammals and humans, important to use correct antibody in appropriate species ​ NOTE: Enzymes to know : 3β-hydroxysteroid dehydrogenase and cytochrome P450 (has different isoforms) ​ Chronic Stress leads to behavioural and immune changes due to effects of Gcs: ○​ Mineralocorticoid receptors (MRs) ​ MRs have a high affinity for mineralocorticoids and GCs ○​ Glucocorticoid receptors (GRs) have low affinity for GCs ​ No GCs bind GRs bind GRs bind until MRs are fully saturated due to differences in affinity ​ Level of MR expression controls sensitivity to stress, whereas GR expression controls entire stress response ​ In a non-stress state, cortisol-binding globulin (CBG) and albumin (ALB) sequester 95% of cortisol released from adrenal glands so only 5% of cortisol is free in blood ○​ During stress, GC,CBG and ALB production occurs to buffer surge in GCs ○​ Around 60% GCs bound and 40% free ​ GC levels are also influences by levels of hydroxysteroid dehydrogenase enzymes which either activate ot inactivate GC depending on isoform of enzyme ○​ 11BHSD-2 converts cortisol into inactive cortisone, whereas 11BHSD-1 activates ​ Suprachiasmatic nuclei (SCN) - region within hypothalamus that is responsive to light and feeding cycles and influences cortisol levels according to these stimuli ​ Splanchnic nerve - sympathetic nerve that stimulates adrenal medulla (produces catecholamines) ○​ Can pick up light signals from optic chiasmata and directly trigger response i n adrenal medulla  ○​ Immediate neural pathway (like SAM axis) unlike neuroendocrine nature of HPA axis ​ Cortisol concentration is typically high in morning and low at night and is regulated by level of expression of MRs which in turn is related to circadian rhythm ​ MR expression > GR expression during normal circadian cycling due to lack of need for GCs ​ During acute stress, GR>MR expression ○​ Negative feedback triggered by binding of GCs to GRs which only occurs once MRs are fully saturated by GCs; prevents GCs from getting way too high ​ Chronic stress - MR and GR expression both decrease as cells become desensitized to GCs ○​ Higher daytime cortisol levels and lack of drop at night means overstimulation ​ Synthesis of epinephrine ​ Synthesized from L-tyrosine by adrenal chromaffin cells through an enzymatic pathway, which ends with the conversion of NEPI to EPI via the enzyme phenylethanolamine N-methyltransferase (PNMT) ​ Rate of catecholamines are so physiologically influential, circulating concentrations are tightly regulated by the enzyme activity and expression levels ​ Catecholamine bioavailability is regulated by different plasma binding proteins - only 50% is bioavailable in human serum ​ Bioactivity is short-lived, and the ½ life is within minutes because enzymes quickly inactivate catecholamines ​ Tissue specific expression of a and b adrenergic receptors can also affect catecholamine bioactivity in target tissues ​ Summary of GC regulation mechanisms during stress: ○​ Increase in CBG and ALB production to buffer amount of CGs ○​ increase in GR expression to induce sensitivity to GCs ○​ Hydroxysteroid dehydrogenase enzymes converting glucocorticoids to active or inactive forms ​ Stressed state: surge in cortisol because of perceived danger ○​ Liver secretes more cortisol but it's not enough ​ Negative feedback loop ○​ Still so low that it binds to MR - MR expressed highly in hippocampus and we think it regulates the circadian cycle ○​ MR determines sensitivity, GR shuts off response ○​ GR is primarily expressed in hippocampus, hypothalamus and pituitary ○​ During chronic stress, cortisol concentration might not be as high, but remains elevated for longer, higher free cortisol affecting the body Biomarkers of Stress ​ Catecholamines - can be analyzed in blood or urine as a marker of immediate stress but its short half-life and high sensitivity makes them difficult to measure ○​ Eg. white coat effect - picking up an animal causes their catecholamines to skyrocket ○​ Used in research to measure stress by catheterizing a blood vessel before the experiment to allow animal to adjust to stress of being handled and then can have trial with less bias ○​ Essentially good for research and not much else  ​ Glucocorticoids - most widely used biomarker of long-term stress, does not degrade quickly but also isn't the fastest response to stressful stimulus ○​ Sampling protocol is important because glucocorticoid levels correspond to circadian rhythm ○​ Sampling over the course of a stress challenge (rather than just morning of night) helps to get a better picture of overall changes and average increases in GCs ○​ GC levels decrease with age until very old age so must be factored into measurements ○​ Barrows (castrated male pigs) have higher average GCs than gilts ( females before 1st litter) ○​ Must specify test to whether you are measuring free ot total cortisol (protein-bound + free) ​ Saliva only has free cortisol vs blood which has free and bound cortisol ○​ There are non-adrenal sources of cortisol that may interfere but these normally contribute very little to overall GC levels ○​ Typically measured with an ELISA or a radioimmunoassay for high sensitivity (for free cortisol) ​ ACTH - can be measured in blood and is stable but since it travels from pituitary to adrenal, its in the middle of the pathway so not really an end result measure ○​ ACTH levels change with circadian rhythm like GCs ○​ Concentration in blood might not be reflective of amount in adrenals so may not be accurate ○​ Skin and leukocytes produce ACTH in amounts that may interfere with measurement ○​ Measured with an ELISA or a radioimmunoassay ​ Chromogranin A - indirect biomarker produced by chromaffin cells of adrenal medulla (along with E and NE) and is positively correlated with NE levels so indicates sympathetic response ○​ Considered indirect because it doesn’t see, to evoke any effect in stress response, just released in parallel with NE ○​ Not affected by sex, age, and time of day so better in that way ​ Blood pressure - use a blood pressure (sphygmomanometer) over brachial artery or catheterize heart and sense (but would have to sedate animal, difficult to do large scale) ​ Heart rate - use a heart rate monitor but these are very expensive and animals usually take them off ○​ Even though a heart rate is a reliable measurement of stress, logistics make it challenging ○​ Considered an indirect biomarker since it isn't necessarily directly related to stress Immunoregulation & Disease ​ Best way to avoid disease is prevention, second best is recognition and elimination of pathogen ​ Infection is a stressor that activates immune system for recognition and elimination ​ Immune system response must be regulated (by HPA and SAM) in order to prevent overzealous response ​ Skin, stomach acid, mucous membranes, body temperature and gut bacteria are some examples of non-immune barriers to prevent microbial growth  ​ If these barriers are breached, innate immune response will kick in and attempt to eliminate pathogen ​ If innate is insufficient, acquired immunity will contribute to response to clear pathogen ​ Commensal microbes are those that live on skin and mucosa without harming health and may contribute to host defense mechanisms ​ Commensal gut bacteria may have many important roles , such as producing vitamins B&K and VFA occupying space and resources that pathogenic microbes might otherwise occupy, and producing antimicrobial toxins against those pathogenic microbes ​ At birth, commensal microbiome is not yet established so must be acquired by receiving from mother’s bodily fluids and other resources in order to establish tolerance to microbes later in life ​ Tolerance to these microbes is key to survival, loss or underdevelopment of tolerance results in disease and potentially death ○​ Microbes that are normally harmless become pathogenic because of a weakened/overly sensitive host ​ Unsuccessful elimination of these pathogens due to lack of defenses, prevention, or treatment leads to disease and potentially death ​ Neuroendocrine stress axes (SAM &HPA) are activated in response to stress and to immune system activity ​ Depending on degree of immune response, immunity may be impaired ○​ Attenuated (weakened) response increases risk of pathogenic disease and cancer ○​ Excessive response leads to inflammatory disease, allergies, autoimmune disease, and cancer Host Defense Definitions: Ab = antibody, Ag = antigen, TNF = tumor necrosis factor, IL = interleukin, PAMP = pathogen associated molecular pattern, DAMP = damage associated molecular pattern, IFN = interferon ​ Immune system is like a sixth sense that signals danger to brain to activate a stress response via SAM and HPA as well as an inflammatory response ​ Signaling between immune system and neuroendocrine systems is bidirectional ​ TNF, IL-1 and IL-6 are most important proinflammatory cytokines for mounting a systemic inflammatory response (across tissues) ○​ Systemic inflammatory response syndrome (SIRS) - aka cytokine storm, an overly enthusiastic response from cytokine that causes tissue damage due to its strength, can cause sepsis → organ failure → death ​ Acute-phase response - systemic response to infection caused by cytokines ○​ Hypothalamus - cytokines elicit fever which induces sickness response ○​ Muscle - cytokines induce protein catabolism in order to synthesize immune cells, antimicrobial proteins and to repair tissues after the pathogen is cleared ​ Many of these are synthesized in liver, called “hepatic acute phase proteins” ​ Increasing strength of barriers (epithelial, pH, temperature,etc) is the first strategy to improve defense ​ Innate immunity - first line of defense following breach of barriers mounted by sentinel cells  ○​ Cells of innate immune response roam around body looking for “foreign” proteins ○​ These cells have pattern recognition proteins (PRPs) on their surfaces such as PAMP receptors that help recognize pathogens and tumour cells ○​ Distressed cells release alarmins to signal to sentinel cells that tissue damage occurred ​ Not pathogenic but still stims innate response to cause inflammation ○​ Innate immunity is a quick and necessary short term response but lacks immunological memory of acquired immunity ​ Acquired immunity - highly specific immune response from T and B lymphocytes that depends on whether pathogen is extracellular (Ab- mediated) or intracellular (cell-mediated) ​ NOTE: T helper cells contribute to AbMIR and CMIR depending on which cytokines are present ​ Antibody-mediated immune response (AbMIR) - targets intracellular pathogens (I.e. viruses, certain bacteria) that causes host cell to release distress signals (DAMPs aka alarmins) ○​ Antigen-presenting cells (APC) recognize and bind Ag and present it to T helper cells ​ APC have major histocompatibility complexes (MHCs) which are surface proteins that bind Ag fragments and present ​ All nucleated cells have MHC-I but only certain immune cells (macrophages, dendritic cells (APC), and B cells) have MHC-II which present Ag fragments to T cells ​ MHC-I help prevent destruction of normal healthy cells (like an ID tag) ○​ Once T helper cells have recognized this MHC-II + Ag complex on the APC surface, they sound the alarm by releasing cytokines (IL-4 and IL-13 which trigger AbMIR and IFN-y for CMIR) ​ Remember that IFN-y is cytokine of interest in CMR ○​ In CMIR, T helper cell signal macrophages to engulf Ag ○​ In AbMIR, T helper cells activate B cells to differentiate into plasma cells and produce Ab ○​ Another cell type in CMIR is cytotoxic T cells which kill cells with Ag on their MHC-I ​ Since all cells have MHC-I, cytotoxic T cells don't require those specific APCs to recognize Ag, they can just recognize it in a normal body cell ​ Memory B and T cells are generated during acquired immune response which facilitate long term immunity by providing immunological memory ​ Acquired immune response takes time to mount because specific Ab need to be produced by B cells ​ Both innate and acquired immunity cause inflammation ​ Immunological biomarkers of stress: innate immunity related proteins and acquired immunity related ○​ Cytokines (innate) - good general indicator (very sensitive to stress) but poor at indicating specific stressor, just general stress ○​ Hepatic acute-phase proteins (innate) - serum amyloid A, C-reactive protein, haptoglobin, complement proteins; same pros and cons as cytokines ○​ Temperature response (innate) - does not occur for everyone ○​ Cytokines assessing AbMIR (Il-4, IL-13) or CMIR (IFN-y) occur in acquired response  ​ Same pros and cons as other cytokines ○​ Antibodies (acquired) - indicator of past or latent infections ​ Ab are highly specific, long-lasting indicators of disease which make them good biomarkers for infection ​ Ab isotypes are species and tissue specific, meaning that sampling location must be considered ○​ IgA present in saliva, IgG-1 present in blood and milk ○​ Bovine IgG1 in blood is indicative of an AbMIR whereas IgG2 in blood indicates a CMIR ​ Due to these different specific responses, we can learn more about the Ag in question ​ Should we measure basal or inducible Ab? ○​ AbMIR may be induced by a novel Ag or vaccine to assess capacity to mount a response ​ Are we measuring total Ab or just specific Ab? Depends on what what you wanna know ​ Sampling time is also of importance: ○​ Level of Ab production depends on how many times you've had the Ag in your system ○​ First infection has a slower, lesser production whereas second and third are faster and more productive; basal and inducible levels of production do not change over time ​ Immune response to stress is influenced by environmental factors which can be somewhat controlled ​ Immune efficacy can be evaluated by an immune challenge ○​ Immune challenge in sheep - if you were to develop a stress-resistant phenotype in an animal, what kind of stressor would you use? ○​ Used a bacterial endotoxin injected into sheep which elicited a cortisol response ○​ Some sheep did not respond at all, which begs the question, how are they different? ○​ Is it that they can process toxins better, or they are less responsive in terms of cortisol release? ○​ Bacterial endotoxin is of interest because heat stress causes gut to become purpose and release bacterial endotoxins into blood ○​ Injected bacterial endotoxin should theoretically cause same response as heat stress but due to individual differences, each animal responds differently ○​ Highly stressed animals responded similarly to different stressors (eg. shipping challenge) so its more about individuals than stressor itself ​ Acute stress has an immunostimulatory effect whereas chronic stress nas an immunosuppressive effect due to change in GC receptor sensitivity and density ○​ Glucocorticoids have immunosuppressive and immunostimulatory effects, depending on dosage and location (local or systemic) ​ E.g. dexamethasone is a steroid cream that treats autoimmune skin conditions by suppressing local immune inflammatory response ​ Bovine Johne’s Diseases - early diagnosis of JD is difficult because Ab levels don’t show up when disease is subclinical ○​ Disease may be subclinical until 3rd stage of infection ○​ Ab only show up when disease becomes clinical, and at that point it can be difficult to stop progress of disease  ○​ IFN-y is the best biomarker for stages 1-3d of disease but it drops after 3rd stage, therefore a panel of biomarkers is better ​ In case of chronic stress, immune challenge can be conducted to assess animals resilience to stress and physiological responses ○​ SAM, HPA, AbMIR and CMIR are monitored over time to assess stress resistance, habituation, recovery, and sensitization to stress ​ Stress challenges can be conducted with a variety of stressors ○​ Physiological - isolation, regrouping ○​ Physical - heat, cold, transport, noise, electricity, restraint ○​ Chemical - toxins or bacterial toxins (MAMPs-LPS), pro-inflammatory cytokines, neuropeptides (corticotropin releasing factor, arginine vasopressin, ACTH) ○​ Biological - acidosis, sleep deprivation, intense exercise, pathogen challenge ​ Microbial stressors require a panel of biomarkers to assess innate and acquired immune responses Genetics of Stress ​ Genetics variants (such as SNPs) predetermine gene activity and are permanent and inherited ​ Epigenetic variants are established by environmental factors during mitosis and provide adaptive mechanism for phenotypic change in the individual ○​ May be inherited so can contribute to phenotypic variation within populations ​ Genetics contributes to variation in sensory input, stress perception and subsequent stress response ○​ Blood cortisol level phenotype has moderate to high heritability and is a food biomarker of stress, hence why it may be selected for/against in trials ​ Measuring epigenetic changes helps to understand long-term effects of stress because the changes are acquired throughout an animals lifetime ​ Epigenetic changes include methylation (adding -Ch3) of cytosine and modification of histones ○​ Me of cytosine - typically silences genes ○​ Modification of histones - histone tail is subject to environmental changes and methylation, acetylation, or phosphorylation of these tails can either prevent or promote DNA transcription ​ These modifications are enzyme regulated and effect which genes are expressed ​ MicroRNA (miRNA) - non-coding RNA that binds to mRNA to negatively regulate its expression ​ All of these modifications influence expression of neuropeptides and therefore have an effect on neuroendocrine stress responses (SAM, HPA) ​ Stress can have a negative effect om CMIR due to effect of glucocorticoids on epigenetics ​ GCs can pause de-acetylation of histones which reduces ability of transcription factors to bind to promoter region of IFN-y (important signal molecule for CMIR) and express it ​ CMIR is very suppressed by Cushing’s disease due to overproduction of GC ○​ Cushings disease is typically caused by cancer of pituitary gland ○​ In humans, polymorphisms in ubiquitin-specific protease 8 (USP8) gene are a risk factor for cushing's disease due to indirect contribution too ACTH production  ​ Addisons disease - autoimmune disease that targets and destroys outer 2 layers of adrenal cortex and causes underproduction of glucocorticoids (opposite of cushings) and aldosterone ○​ ACTH is produced but not absorbed due to destruction of adrenal tissues by immune system, therefore there is free ACTH circulating in blood ○​ Melanocyte-stimulating hormones and ACTH share the same precursor molecule so free ACTH into MSH and melanin production increases ​ Results in hyperpigmentation, common diagnostic symptom of Addisons ​ Does this symptom still have clinical significance for those with darker skin? ​ If a animal is not able to recover from stress, become habituated to stressor, r if it becomes overly sensitive to stressor due to epigenetic modifications, risk of disease is increased ​ Neuroendocrine immune system is especially sensitive to epigenetic modifications during early development which is why microbiome is so important (affects immunological tolerance) ​ Single-nucleotide polymorphisms (SNPs) in cytochrome p450 (CYP) enzymes may have an effect on steroidogenesis of glucocorticoids (think back to steroidogenesis pathway seen last week) Unit 3 - Antimicrobials ​ Antimicrobial usage in animal production has become an accepted practice today to minimize -​ Commensal might share or swap with AMR -​ Group that discovered e coli plasmid(small DNA molecule that replicates on its own and can travel across species) in pork, carrying a gene -​ Antibiotic comes from a mold to control its competition -​ Examples of misuse: -​ Wrong antimicrobial -​ High dose and refuse to follow withdrawal time increases drug residues -​ Use of banned AMR -​ Use of poor quality or expired AMR -​ Shorten recommended treatment period -​ Poorly treated animal waste -​ Administered to prevent disease -​ Unnecessary treatment of humans -​ Conceptual drivers for AMR -​ listen to voice -​ AMR can be found in animal bedding, dust particles, agricultural runoff