The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

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How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

The influence of diet on the distribution of nitrogen isotopes in animals was investigated by analyzing animals grown in the laboratory on diets of constant nitrogen isotopic composition. 
The isotopic composition of the nitrogen in an animal reflects the nitrogen isotopic composition of its diet. The δ^(15)N values of the whole bodies of animals are usually more positive than those of their diets. Different individuals of a species raised on the same diet can have significantly different δ^(15)N values. The variability of the relationship between the δ^(15)N values of animals and their diets is greater for different species raised on the same diet than for the same species raised on different diets. Different tissues of mice are also enriched in ^(15)N relative to the diet, with the difference between the δ^(15)N values of a tissue and the diet depending on both the kind of tissue and the diet involved. The δ^(15)N values of collagen and chitin, biochemical components that are often preserved in fossil animal remains, are also related to the δ^(15)N value of the diet. 
The dependence of the δ^(15)N values of whole animals and their tissues and biochemical components on the δ^(15)N value of diet indicates that the isotopic composition of animal nitrogen can be used to obtain information about an animal's diet if its potential food sources had different δ^(15)N values. The nitrogen isotopic method of dietary analysis probably can be used to estimate the relative use of legumes vs non-legumes or of aquatic vs terrestrial organisms as food sources for extant and fossil animals. However, the method probably will not be applicable in those modern ecosystems in which the use of chemical fertilizers has influenced the distribution of nitrogen isotopes in food sources. 
The isotopic method of dietary analysis was used to reconstruct changes in the diet of the human population that occupied the Tehuacan Valley of Mexico over a 7000 yr span. Variations in the δ^(15)C and δ^(15)N values of bone collagen suggest that C_4 and/or CAM plants (presumably mostly corn) and legumes (presumably mostly beans) were introduced into the diet much earlier than suggested by conventional archaeological analysis.

Influence of Diet On the Distribtion of Nitrogen Isotopes in Animals

The stress response in teleost fish shows many similarities to that of the terrestrial vertebrates These concern the principal messengers of the brain-sympathetic-chromaffin cell axis (equivalent of the brain-sympathetic-adrenal medulla axis) and the brain-pituitary-interrenal axis (equivalent of the brain-pituitary-adrenal axis), as well as their functions, involving stimulation of oxygen uptake and transfer, mobilization of energy substrates, reallocation of energy away from growth and reproduction, and mainly suppressive effects on immune functions There is also growing evidence for intensive interaction between the neuroendocrine system and the immune system in fish Conspicuous differences, however, are present, and these are primarily related to the aquatic environment of fishes For example, stressors increase the permeability of the surface epithelia, including the gills, to water and ions, and thus induce systemic hydromineral disturbances High circulating catecholamine levels as well as structural damage to the gills and perhaps the skin are prime causal factors This is associated with increased cellular turnover in these organs In fish, cortisol combines glucocorticoid and mineralocorticoid actions, with the latter being essential for the restoration of hydromineral homeostasis, in concert with hormones such as prolactin (in freshwater) and growth hormone (in seawater) Toxic stressors are part of the stress literature in fish more so than in mammals This is mainly related to the fact that fish are exposed to aquatic pollutants via the extensive and delicate respiratory surface of the gills and, in seawater, also via drinking The high bioavailability of many chemicals in water is an additional factor Together with the variety of highly sensitive perceptive mechanisms in the integument, this may explain why so many pollutants evoke an integrated stress response in fish in addition to their toxic effects at the cell and tissue levels Exposure to chemicals may also directly compromise the stress response by interfering with specific neuroendocrine control mechanisms Because hydromineral disturbance is inherent to stress in fish, external factors such as water pH, mineral composition, and ionic calcium levels have a significant impact on stressor intensity Although the species studied comprise a small and nonrepresentative sample of the almost 20,000 known teleost species, there are many indications that the stress response is variable and flexible in fish, in line with the great diversity of adaptations that enable these animals to live in a large variety of aquatic habitats

The stress response in fish

The fish gill is a multipurpose organ that, in addition to providing for aquatic gas exchange, plays dominant roles in osmotic and ionic regulation, acid-base regulation, and excretion of nitrogenous wastes Thus, despite the fact that all fish groups have functional kidneys, the gill epithelium is the site of many processes that are mediated by renal epithelia in terrestrial vertebrates Indeed, many of the pathways that mediate these processes in mammalian renal epithelial are expressed in the gill, and many of the extrinsic and intrinsic modulators of these processes are also found in fish endocrine tissues and the gill itself The basic patterns of gill physiology were outlined over a half century ago, but modern immunological and molecular techniques are bringing new insights into this complicated system Nevertheless, substantial questions about the evolution of these mechanisms and control remain

https://people.clas.ufl.edu/devans/files/PRVGill.pdf

The Multifunctional Fish Gill: Dominant Site of Gas Exchange, Osmoregulation, Acid-Base Regulation, and Excretion of Nitrogenous Waste

Cortisol is the principal corticosteriod in teleost fishes and its plasma concentrations rise dramatically during stress. The relationship between this cortisol increase and its metabolic consequences are subject to extensive debate. Much of this debate arises from the different responses of the many species used, the diversity of approaches to manipulate cortisol levels, and the sampling techniques and duration. Given the extreme differences in experimental approach, it is not surprising that inconsistencies exist within the literature. This review attempts to delineate common themes on the physiological and metabolic roles of cortisol in teleost fishes and to suggest new approaches that might overcome some of the inconsistencies on the role of this multifaceted hormone. We detail the dynamics of cortisol, especially the exogenous and endogenous factors modulating production, clearance and tissue availability of the hormone. We focus on the mechanisms of action, the biochemical and physiological impact, and the interaction with other hormones so as to provide a conceptual framework for cortisol under resting and/or stressed states. Interpretation of interactions between cortisol and other glucoregulatory hormones is hampered by the absence of adequate hormone quantification, resulting in correlative rather than causal relationships.

Cortisol in teleosts: dynamics, mechanisms of action, and metabolic regulation

We investigated short-term eVects (up to 24 h) of air exposure and confinement, and long-term eVects (up to 11 days) of confinement, to elucidate signalling pathways in the stress response of gilthead sea bream Sparus aurata L. Plasma glucose and lactate were taken as indicators of sympathetic activation, and AE-melanocyte stimulating hormone (AE-MSH), adrenocorticotrophic hormone (ACTH) and cortisol as indicators of activation of the brain‐ pituitary‐interrenal (BPI) axis. Air exposure for 3 min resulted, within 30 min, in an increase in plasma concentrations of cortisol, AE-MSH, glucose, lactate, osmolality and plasma Na, Cl and Mg. Plasma ACTH and ‚-endorphin and plasma K, Ca and P did not change. We conclude that air exposure mainly activates the brain‐ sympathetic‐chromaYn cell (BSC) axis. In fish confined at a density of 70 kg/m 3 (compared with 4 kg/m 3 in controls), cortisol, ACTH and AE-MSH increased within 1 h, indicating activation of the BPI axis. Plasma glucose, Na, Cl and Mg increased with an 8 h delay compared with the response to air exposure. No changes in plasma lactate, osmolality, K, Ca and P were observed. Long-term confinement induced a biphasic cortisol response with peaks at 1 h and at 2 and 3 days. A gradual increase in plasma ‚-endorphin concentrations peaked at 7 days; the concentration of AE-MSH increased rapidly within 1 h and then declined to control values 4 days after the onset of confinement. No changes in ACTH were detected. Our data provide evidence that a stressor-specific activation of the BSC and BPI axes may occur in Sparus aurata.

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The stress response of the gilthead sea bream (Sparus aurata L.) to air exposure and confinement

Exposure of freshwater trout ( Salmo gairdneri ) to waterborne Cd 2+ results in accumulation of the metal in the branchial epithelial cells and its appearance in the blood. Cd 2+ apparently enters the cells via Ca 2+ channels in the apical membrane. Transfer of Cd 2+ through the basolateral membrane is probably by diffusion. Inhibition by Cd 2+ of transepithelial Ca 2+ influx is time- and Cd 2+ -concentration-dependent. The inhibition of transepithelial Ca 2+ influx is accompanied by blockage of apical Ca 2+ channels. In line with the assumption that cytosolic Cd 2+ inhibits Ca 2+ uptake by inhibiting the basolateral Ca 2+ pump, we hypothesize that the blockage of Ca 2+ channels is an indirect effect of Cd 2+ and results from a rise in cytosolic Ca 2+ level caused by inhibition of the basolateral membrane Ca 2+ pump.

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The movement of cadmium through freshwater trout branchial epithelium and its interference with calcium transport

The effects of cadmium (Cd2+) on calcium (Ca2+) transport in the gills of rainbow trout (Salmo gairdneri) were studied. The gill epithelium of freshwater fish represents a model for a Ca2+-transporting tight epithelium. Unidirectional Ca2+ fluxes in the gills were estimated in an isolated saline-perfused head preparation. Ca2+ influx was not affected when up to 10 microM Cd were added to the ventilatory water at the start of flux determinations (in vitro exposure). However, after 16 h in vivo preexposure of the fish to 0.1 microM Cd in the water, a 79% inhibition of Ca2+ influx was observed. Ca2+ efflux was not affected when up to 10 microM Cd were added to the ventilatory water during the flux determination. Ca2+ efflux in fish preexposed to 0.1 microM Cd for 16 h was also not affected; a preexposure to 1 microM Cd, however, resulted in a 173% increase in Ca2+ efflux rates. Tracer retention in the gill tissue indicated that both Ca2+ and Cd2+ enter the gill epithelium via a lanthanum (La3+)-inhibitable pathway. It is concluded that Cd2+ readily enters the branchial epithelial cells, similarly as Ca2+ does via La3+-sensitive apical Ca2+ channels. The inhibitory action of Cd2+ on transepithelial Ca2+ influx seems to result from an inhibition of the basolateral Ca2+ transport, occurring after a critical intracellular Cd2+ concentration has been reached.

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Cadmium inhibition of Ca2+ uptake in rainbow trout gills

Publisher Summary This chapter discusses the control of calcium regulating hormones in the vertebrates. Control of ionic calcium levels of the extracellular fluids is mandatory for all vertebrates because only minor changes of calcium, in particular the ionized calcium fraction, have pronounced effects on the permeability of cell membranes to ions and, consequently, on important physiological processes, such as muscle contraction, nerve signal transduction, and control of cellular metabolism. Calcium uptake is balanced by renal calcium excretion, with exception of periods of body growth or, in females, periods of reproduction and parental care. Parathyroid hormone (PTH) dominates the control of the Ca2+ concentration of the extracellular fluid by its calcium-mobilizing action on bone and, indirectly, via its control of the synthesis of 1,25(OH)2D3, intestinal calcium absorption. Calcitonin (CT) reduces the extracellular calcium concentration by inhibiting osteoclastic bone resorption and by promoting calcium deposition in the skeleton. In the terrestrial vertebrates, the evidence for the involvement of prolactin (PRL) in calcium metabolism is limited to calcium handling during gestation and lactation in mammals.

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S.E. Wendelaar Bonga

Papers

The stress response in fish

The stress response of the gilthead sea bream (Sparus aurata L.) to air exposure and confinement

The movement of cadmium through freshwater trout branchial epithelium and its interference with calcium transport

Cadmium inhibition of Ca2+ uptake in rainbow trout gills

Control of calcium regulating hormones in the vertebrates: parathyroid hormone, calcitonin, prolactin, and stanniocalcin.