Stress often occurs during toxicity studies. The perception of sensory stimuli as stressful primarily results in catecholamine release and activation of the hypothalamic-pituitary-adrenal (HPA) axis to increase serum glucocorticoid concentrations. Downstream effects of these neuroendocrine signals may include decreased total body weights or body weight gain; food consumption and activity; altered organ weights (e.g., thymus, spleen, adrenal); lymphocyte depletion in thymus and spleen; altered circulating leukocyte counts (e.g., increased neutrophils with decreased lymphocytes and eosinophils); and altered reproductive functions. Typically, only some of these findings occur in a given study. Stress responses should be interpreted as secondary (indirect) rather than primary (direct) test article-related findings. Determining whether effects are the result of stress requires a weight-of-evidence approach. The evaluation and interpretation of routinely collected data (standard in-life, clinical pathology, and anatomic pathology endpoints) are appropriate and generally sufficient to assess whether or not changes are secondary to stress. The impact of possible stress-induced effects on data interpretation can partially be mitigated by toxicity study designs that use appropriate control groups (e.g., cohorts treated with vehicle and subjected to the same procedures as those dosed with test article), housing that minimizes isolation and offers environmental enrichment, and experimental procedures that minimize stress and sampling and analytical bias. This article is a comprehensive overview of the biological aspects of the stress response, beginning with a Summary (Section 1) and an Introduction (Section 2) that describes the historical and conventional methods used to characterize acute and chronic stress responses. These sections are followed by reviews of the primary systems and parameters that regulate and/or are influenced by stress, with an emphasis on parameters evaluated in toxicity studies: In-life Procedures (Section 3), Nervous System (Section 4), Endocrine System (Section 5), Reproductive System (Section 6), Clinical Pathology (Section 7), and Immune System (Section 8). The paper concludes (Section 9) with a brief discussion on Minimizing Stress-Related Effects (9.1.), and a final section explaining why Parameters routinely measured are appropriate for assessing the role of stress in toxicology studies (9.2.).

https://journals.sagepub.com/doi/pdf/10.1177/0192623312466452

Interpreting Stress Responses during Routine Toxicity Studies: A Review of the Biology, Impact, and Assessment

The development of the hypothalamic-pituitary-adrenal (HPA) response to stress is influenced by the early mother-infant relationship. In rats, early handling (brief daily mother-offspring separations) attenuates the adult offspring's HPA and fear responses compared to both nonhandling (no separations) and maternal separation (prolonged daily separations). It has been proposed that variation in the amount of maternal care mediates these effects of neonatal manipulations on the adult offspring's stress and fear responses. Here we tested this hypothesis by assessing maternal care and the adult offspring's HPA and fear responses in Lister hooded rats which were subjected to either early handling (EH) or maternal separation (MS) from postnatal day 1-13, or were left completely undisturbed (nonhandled, NH) throughout this period. Both EH and MS induced a more active nursing style and elevated levels of maternal care compared to NH. Total levels of maternal care were indistinguishable between EH and MS, but diurnal distribution differed. MS dams showed elevated levels of maternal care following the 4-h separation period, thereby fully compensating for the amount of maternal care provided by EH dams during the time MS dams were separated from their pups. However, while EH resulted in reduced HPA and fear responses in the adult offspring compared to NH, MS and NH offspring did not differ. Our findings therefore demonstrate dissociation in the effects of EH and MS on maternal care and on the stress and fear responses in the offspring. This indicates that maternal care cannot be the sole mediator of these effects.

/pdf/dissociation-in-the-effects-of-neonatal-maternal-separations-1wir96mu0q.pdf

Dissociation in the effects of neonatal maternal separations on maternal care and the offspring's HPA and fear responses in rats

Previous work has indicated that acute and repeated stress can alter thyroid hormone secretion. Corticosterone, the end product of hypothalamic-pituitary-adrenal (HPA) axis activation and strongly reg

Relation between the Hypothalamic-Pituitary-Thyroid (HPT) axis and the Hypothalamic-Pituitary-Adrenal (HPA) axis during repeated stress

Iodine deficiency is generally recognized as the most commonly preventable cause of mental retardation and the most common cause of endocrinopathy (goiter and primary hypothyroidism). Iodine deficiency becomes particularly critical in pregnancy due to the consequences for neurological damage during fetal development as well as during lactation. The safety of therapeutic doses of iodine above the established safe upper limit of 1 mg is evident in the lack of toxicity in the Japanese population that consumes 25 times the median intake of iodine consumption in the United States. Japan’s population suffers no demonstrable increased incidence of autoimmune thyroiditis or hypothyroidism. Studies using 3.0- to 6.0-mg doses to effectively treat fibrocystic breast disease may reveal an important role for iodine in maintaining normal breast tissue architecture and function. Iodine may also have important antioxidant functions in breast tissue and other tissues that concentrate iodine via the sodium iodide symporter. (Altern Med Rev 2008;13(2):116-127)

/pdf/iodine-deficiency-and-therapeutic-considerations-1xwx2a6gxe.pdf

Iodine: deficiency and therapeutic considerations

Basal activity of the rat hypothalamic-pituitary-adrenal (HPA) axis is highly dynamic and displays both circadian and ultradian rhythmicity in corticosterone secretion. This study investigated the relationship between basal corticosterone pulsatility and the corticosterone response to noise during the early light phase when there are no endogenous corticosterone pulses and during the early dark phase when there are hourly pulses of corticosterone. An automated blood sampling system was used to collect blood in conscious male rats at 5-min intervals before, during and after exposure to 10-min periods of white noise (104 dB). Behavioural responses to noise were also monitored during these periods. During the early light phase (morning), there was a consistent corticosteroid response to noise with corticosterone concentrations rising rapidly and reaching peak values 10-15 min after the noise had ceased, following which circulating concentrations declined at a rate comparable to the hormones half-life. A second noise stress, 80 min later, resulted in adaptation of the corticosterone response. During the early dark phase (evening), the corticosterone response to the noise was similar to that seen in the morning, although there was no adaptation to a second stimulus. During the evening, the inhibition of endogenous HPA activity after the sound was limited to 40 min following stress.

Diurnal variation in the responsiveness of the hypothalamic-pituitary-adrenal axis of the male rat to noise stress.

Many millions of people throughout the world are at risk of developing iodine deficiency-associated disorders The underlying effects of iodine deficiency on neuroendocrine function are poorly defined We have studied stress-induced and diurnal variation in corticosterone secretion in female rats rendered chronically hypothyroid by feeding them an iodine-free diet for 6 months Corticosterone secretory responses in iodine deficient animals were compared to those seen in animals rendered hypothyroid with propylthiouracil and untreated controls By using a well-validated, automated blood sampling system to collect small samples of blood over the complete daily cycle in unrestrained animals, we have demonstrated for the first time that the normal diurnal rhythm of corticosterone secretion is lost in chronic iodine deficiency and that the corticosterone secretory response to the psychological stress of 10 min exposure to white noise is attenuated Despite restoration of circulating triiodothyronine and thyrotropin releasing hormone- and thyroid stimulating hormone beta-transcript prevalence in the hypothalamus and pituitary, respectively, 1 month after restoration of normal iodine-containing diet both the diurnal variation in corticosterone levels and the corticosterone secretory response to the noise stress remained reduced in amplitude compared to control animals Thus, chronic hypothyroidism induced by iodine deficiency significantly attenuates hypothalamo-pituitary-adrenal axis activity, an effect that persists after functional recovery of the thyroid axis

HL Lunness

Papers

Chronic iodine deprivation attenuates stress-induced and diurnal variation in corticosterone secretion in female Wistar rats.