Christopher J. Gordon

Thermal biology of the laboratory rat.

The purpose of this paper is to thoroughly review the literature and present a data base of the basic thermoregulatory parameters of the laboratory rat. This review surveys the pertinent papers dealing with various aspects of the thermal biology of the laboratory rat, including: metabolism, thermoneutrality, core and brain temperature, thermal tolerance, thermal conductance and insulation, thermoregulatory effectors (i.e., thermogenesis, peripheral vasomotor tone, evaporation, and behavior), thermal acclimation, growth and reproduction, ontogeny, aging, motor activity and exercise, circadian rhythm and sleep, gender differences, and other parameters. It is shown that many facets of the thermoregulatory system of the laboratory rat are typical to that of most homeothermic species. However, is several instances the rat exhibits unique thermoregulatory responses which are not comparable to other species.

Effects of 3,4-methylenedioxymethamphetamine on autonomic thermoregulatory responses of the rat ☆ ☆☆

3,4-Methylenedioxymethamphetamine (MDMA), a substituted amphetamine analogue which stimulates serotonin release in the CNS, has been shown to induce near lethal elevations in core temperature in the rat. To characterize the effects of MDMA on temperature regulation, we measured metabolic rate (MR), evaporative water loss (EWL), motor activity (MA), and colonic temperature (Tc) in male, Long-Evans rats at 60 min following 30 mg/kg (SC) MDMA or saline at ambient temperature (Ta) of 10, 20 and 30 degrees C. MDMA caused an elevation in MR at Tas of 20 and 30 degrees C but had no effect at 10 degrees C. At a Ta of 30 degrees C, MR of the MDMA group was double that of the saline group. EWL was elevated by MDMA, an effect which was potentiated with increasing Ta. MDMA also elicited an increase in MA at all three Tas. MDMA led to a 3.2 degrees C increase in Tc at 30 degrees C, no change in Tc at 20 degrees C, and a 2.0 degrees C decrease in Tc at 10 degrees C. A second study found that treatment with 20 mg/kg MDMA failed to elicit an increase in blood flow to the tail in spite of a hyperthermic core temperature of 41.4 degrees C. Preliminary studies using radiotelemetry methodology suggested that MDMA lethality is preceded by precipitous elevations in heart rate and core temperature. The data suggest that, at relatively warm Tas. MDMA-induced stimulation of serotonergic pathways causes an elevation in MR and peripheral vasoconstriction, thus producing life-threatening elevations in Tc.(ABSTRACT TRUNCATED AT 250 WORDS)

Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature.

Significance We show that the mandated, subthermoneutral laboratory housing temperature, which is known to cause chronic, metabolic cold stress, induces suppression of the antitumor immune response and promotes tumor growth and metastasis. When mice are housed at thermoneutrality, there are fewer immunosuppressive cells with significantly enhanced CD8+ T cell-dependent control of tumor growth. These findings underscore the fact that investigating mouse models under a single set of environmental temperature conditions may lead to a misunderstanding of the antitumor immune potential. These data also highlight the need for additional study to determine how systemic metabolic stress modulates the functions of immune effector cells, particularly in tumor-bearing mice, and whether cancer therapies, including immunotherapy, are impacted by housing temperature. We show here that fundamental aspects of antitumor immunity in mice are significantly influenced by ambient housing temperature. Standard housing temperature for laboratory mice in research facilities is mandated to be between 20–26 °C; however, these subthermoneutral temperatures cause mild chronic cold stress, activating thermogenesis to maintain normal body temperature. When stress is alleviated by housing at thermoneutral ambient temperature (30–31 °C), we observe a striking reduction in tumor formation, growth rate and metastasis. This improved control of tumor growth is dependent upon the adaptive immune system. We observe significantly increased numbers of antigen-specific CD8+ T lymphocytes and CD8+ T cells with an activated phenotype in the tumor microenvironment at thermoneutrality. At the same time there is a significant reduction in numbers of immunosuppressive MDSCs and regulatory T lymphocytes. Notably, in temperature preference studies, tumor-bearing mice select a higher ambient temperature than non-tumor-bearing mice, suggesting that tumor-bearing mice experience a greater degree of cold-stress. Overall, our data raise the hypothesis that suppression of antitumor immunity is an outcome of cold stress-induced thermogenesis. Therefore, the common approach of studying immunity against tumors in mice housed only at standard room temperature may be limiting our understanding of the full potential of the antitumor immune response.

Temperature regulation in laboratory mammals following acute toxic insult

The purpose of this paper is to provide a concise review of the effects of acute chemical toxicity on thermoregulation in mammals, with particular emphasis on the effects of xenobiotic compounds in laboratory rodents. It has been shown that acute administration of compounds such as nickel, cadmium, lead, and some pesticides causes a reduction in the body temperature of mice when tested at normal room temperatures. When provided with the option of selecting their preferred ambient temperature, the toxic-treated animals generally select cool temperatures which augment the hypothermic effect of the toxic compounds. It would appear that many of the xenobiotic compounds have central as well as peripheral effects on the control of body temperature. That is, the hypothermic animals select cool temperatures, a condition indicative of a centrally mediated decrease in the set-point. This decrease in set-point, or regulated hypothermia, may be beneficial to survival since the lethality of most xenobiotic compounds increases with rising body temperature. The observation that acute doses of various compounds leads to behaviorally and autonomically mediated changes in body temperature may have significant implications for the measurement of other biological effects of these chemical agents (e.g., CNS dysfunction, bradycardia, immunosuppression).

The therapeutic potential of regulated hypothermia.

Reducing body temperature of rodents has been found to improve their survival to ischaemia, hypoxia, chemical toxicants, and many other types of insults. Larger species, including humans, may also benefit from a lower body temperature when recovering from CNS ischaemia and other traumatic insults. Rodents subjected to these insults undergo a regulated hypothermic response (that is, decrease in set point temperature) characterised by preference for cooler ambient temperatures, peripheral vasodilatation, and reduced metabolic rate. However, forced hypothermia (that is, body temperature forced below set point) is the only method used in the study and treatment of human pathological insults. The therapeutic efficacy of the hypothermic treatment is likely to be influenced by the nature of the reduction in body temperature (that is, forced versus regulated). Homeostatic mechanisms counter forced reductions in body temperature resulting in physiological stress and decreased efficacy of the hypothermic treatment. On the other hand, regulated hypothermia would seem to be the best means of achieving a therapeutic benefit because thermal homeostatic systems mediate a controlled reduction in core temperature.

Role of environmental stress in the physiological response to chemical toxicants.

Environmental physiology is the study of the physiological mechanisms that allow animals to cope with and adapt to changes in temperature, humidity, atmospheric pressure, and other natural factors of their physical environment. Nearly all toxicological and pharmacological studies are performed in resting (i.e., nonexercising) experimental animals acclimatized to standard environmental conditions that are usually considered ideal to the animals physiological well-being. These ideal test conditions are clearly not representative of the fluctuations in the natural environment encountered by humans and other animals on a day-to-day basis. It behooves the toxicologist, especially those interested in extrapolating experimental data from laboratory animals to humans, to consider how variations in the natural environment will alter physiological responses to toxicants. Temperature and exercise are the two most well-studied parameters in the fields of environmental physiology and toxicology. In general, high temperatures exacerbate the toxic effects of many environmental toxicants. Moreover, exercising subjects are generally more vulnerable to airborne toxic agents. The prospect of global warming also warrants a better assessment of how higher environmental temperatures may impact on the response of humans and other species to toxic chemicals. Hence, this paper and accompanying papers from the proceedings of a symposium focus on the salient aspects of the interaction between environmental stress and physiological response to toxic agents with particular emphasis on temperature and exercise.

Relationship between autonomic and behavioral thermoregulation in the mouse

Preferred ambient temperature (Ta) was measured in nine mice of the BALB/c strain using a temperature gradient. When tested over four consecutive days the mean preferred Ta was 30.9 degrees C. In another study using the same animals, metabolic rate, evaporative water loss, whole-body thermal conductance, and colonic temperature were measured at specific Tas over a range of 18 to 34 degrees C. The preferred Ta of 30.9 degrees C was associated with the lower critical Ta (i.e., Ta below which metabolic rate increased) a 57% elevation in evaporative water loss when expressed in units of mg water evaporated per ml consumed oxygen, a thermal conductance that was 92% above baseline levels, and a normothermic colonic temperature of between 37.0 to 37.5 degrees C. The data indicate that mice will select an environmental temperature associated with a minimal energy expenditure but a higher than minimal rate of evaporation and higher thermal conductance.

Heat or insulation: behavioral titration of mouse preference for warmth or access to a nest.

In laboratories, mice are housed at 20–24°C, which is below their lower critical temperature (≈30°C). This increased thermal stress has the potential to alter scientific outcomes. Nesting material should allow for improved behavioral thermoregulation and thus alleviate this thermal stress. Nesting behavior should change with temperature and material, and the choice between nesting or thermotaxis (movement in response to temperature) should also depend on the balance of these factors, such that mice titrate nesting material against temperature. Naïve CD-1, BALB/c, and C57BL/6 mice (36 male and 36 female/strain in groups of 3) were housed in a set of 2 connected cages, each maintained at a different temperature using a water bath. One cage in each set was 20°C (Nesting cage; NC) while the other was one of 6 temperatures (Temperature cage; TC: 20, 23, 26, 29, 32, or 35°C). The NC contained one of 6 nesting provisions (0, 2, 4, 6, 8, or 10g), changed daily. Food intake and nest scores were measured in both cages. As the difference in temperature between paired cages increased, feed consumption in NC increased. Nesting provision altered differences in nest scores between the 2 paired temperatures. Nest scores in NC increased with increasing provision. In addition, temperature pairings altered the difference in nest scores with the smallest difference between locations at 26°C and 29°C. Mice transferred material from NC to TC but the likelihood of transfer decreased with increasing provision. Overall, mice of different strains and sexes prefer temperatures between 26–29°C and the shift from thermotaxis to nest building is seen between 6 and 10 g of material. Our results suggest that under normal laboratory temperatures, mice should be provided with no less than 6 grams of nesting material, but up to 10 grams may be needed to alleviate thermal distress under typical temperatures.

Thermoregulation in laboratory mammals and humans exposed to anticholinesterase agents

The regulation of body temperature is one of many homeostatic functions affected by exposure to anticholinesterase (antiChE) pesticides, and related compounds. In the study of antiChE neurotoxicity, thermoregulatory variables are often used as sensitive physiological indices. Hence, a review on the thermoregulatory aspects of antiChE agents would be useful to researchers in a variety of fields. A reduction in body temperature is a commonly used indicator of antiChE poisoning in laboratory rodents. On the other hand, humans and some other species often shown an elevation in body temperature when exposed to antiChE agents. Hyperthermia has also been noted in animals treated with either low levels of antiChEs or during recovery from high doses of antiChEs. In this review, the literature dealing with the central and peripheral effects of cholinergic agonists and antagonists is reassessed because the thermoregulatory effects of antiChEs are thought to be linked to the activation of cholinergic pathways. This is followed by a thorough review of the studies reporting thermoregulatory responses in laboratory rodents and humans exposed to low and high doses of a variety of antiChE agents, including the organophosphate- (OP) and carbamate- (CB) based pesticides and related drugs. Attention is given to the possible mechanism of action of OPs on thermoregulation in the laboratory rodent including the involvement of behavioral and autonomic processes. The incidence of antiChE-induced hyperthermia (fever) in humans exposed to antiChEs is also addressed. Other topics of antiChE-induced thermoregulatory dysfunction discussed in this review include the role of exercise, heat, and cold stress, tolerance to antiChE agents, and genetic variability. Overall, the mechanism of antiChE-induced changes in body temperature cannot always be explained solely by the immediate consequences of ChE inhibition.

Impact of nesting material on mouse body temperature and physiology.

In laboratories, mice are housed at 20-24 °C, which is below their lower critical temperature (≈30 °C). Thus, mice are potentially cold stressed, which can alter metabolism, immune function, and reproduction. These physiological changes reflect impaired wellbeing, and affect scientific outcomes. We hypothesized that nesting material would allow mice to alleviate cold stress by controlling their thermal microenvironment, thus insulating them, reducing heat loss and thermogenic processes. Naïve C57BL/6, CD-1, and BALB/c mice (24 male and 24 female/strain in groups of 3) were housed in standard cages at 20 °C either with or without 8 g nesting material for 4 weeks. Core body temperature was followed using intraperitoneal radio telemetry. The thermal properties of the nests were assessed using a thermal imaging camera, and related to nest quality. Higher scoring nests were negatively correlated with the mean radiated temperature and were thus more insulating. No effects of nesting material on body temperature were found. CD-1 mice with nesting material had higher end body weights than controls. No effect was seen in the other two strains. Mice with the telemetry implant had larger spleens than controls, possibly indicating an immune response to the implant or low level infection from the surgery. BALB/c mice express less mRNA for the UCP1 protein than mice without nesting material. This indicates that BALB/cs with nesting material do not utilize their brown fat to create heat as readily as controls. Nests can alleviate thermal discomfort by decreasing the amount of radiated heat and reduce the need for non-shivering thermogenesis. However, different strains appear to use different behavioral (through different primary modes of behavioral thermoregulation) and physiological strategies (utilizing thermogenesis to different degrees) to maintain a constant body temperature under cool standard laboratory ambient temperatures.