A Practical Approach, Second Edition=Ronald D. Ho.pdf

104 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONof rats found that late gestational blockade of opioid receptors by administration of naltrexoneprevented reduction in male anogenital distance and altered certain behavioral outcomes in offspringof light and noise-stressed dams. 121 Further, the stress-induced reductions in pain induced byrestraint and other stressors can be blocked by opioid antagonists. 122 These data suggest that opioidreceptors may be involved in at least some maternally mediated effects of stress.At least one potential maternally mediated factor has apparently not been discussed in theabove-mentioned reviews. That is the possibility of inducing abnormal maternal biotransformationat high — often maternally toxic — doses of chemical agents that are typically metabolized to lesstoxic forms by the mother. Such high exposures may overwhelm the normal maternal biotransformingabilities and lead to metabolism by normally minor pathways, some of which may producehazardous metabolites. If such metabolites are produced in significant quantities, some may havethe potential to harm the conceptus. Further, maternal stress can inhibit normal xenobioticbiotransformation 123 and might result in exposure of the conceptus to higher levels of toxicantsthan would otherwise be the case.III. ASSESSMENT OF MATERNAL STRESS OR TOXICITYMultiple biochemical, physiological, and behavioral changes are engendered by stress and wouldappear to provide the toxicologist or teratologist with a variety of endpoints suitable for assessingmaternal stress. In studies specifically designed to evaluate the impact of stress on development,there is no doubt that both systemic and neurogenic stressors, 42 when applied to pregnant animalsin an experimental setting, will alter developmental outcome (see Chernoff et al., 2,59,60,62,124 Joffe, 125Hood, 4,35 and Weinstock et al., 126 for studies relevant to this issue). These studies, as well as studiesinvestigating the impact of stress in the adult, utilize a variety of methods to measure the manychanges associated with exposure to a stressor. In the following section, we briefly catalog a varietyof methods for assessing stress. However, the reader should be aware that their implementation ina standard teratology study may be quite difficult. It is one thing to determine the consequencesof an operationally defined stressor; it is quite another to determine if stress plays a role in aparticular developmental outcome. As Chernoff et al. 62 found in their investigation of overt maternaltoxicity and adverse developmental effects, the relationship between maternal toxicity, maternalstress, and developmental outcomes is not easy to define. One should, however, be aware of howvarious manipulations can act as neurogenic stressors (e.g., nose-only inhalation exposure procedures)and the impact these manipulations may have on development.A. Biochemical Measures1. Measures Related to the Stress CascadeThe biochemical indicators that are nearly synonymous with stress are those associated with thestress cascade; namely glucocorticoids (corticosterone in rodents and cortisol in primates, guineapigs, and hamsters). Selye 127 in his landmark studies first emphasized the use of this adrenal corticalproduct as a marker for stress. The levels of glucocorticoids in blood and their metabolites in urineare used much more often to gauge stress than are the levels of either ACTH or CRF. In mostexperimental studies that utilize circulating glucocorticoid levels as a stress marker, their elevationin blood is accepted as prima facie evidence that other components of the stress cascade have beenactivated. That is, CRF has been released from the hypothalamus into the hypophyseal portal vesselsleading to the pituitary gland. Subsequent release of ACTH from the corticotropes in this structureresults in the eventual stimulation of the adrenal cortex and release of glucocorticoids into thegeneral circulation. Generally, ACTH and CRF are evaluated after elevated glucocorticoid levels© 2006 by Taylor & Francis Group, LLC