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

MATERNALLY MEDIATED EFFECTS ON DEVELOPMENT 95Figure 4.1 Schematic of the stress cascade. (Adapted from Colby, H.D., J. Am. Coll. Toxicol., 7, 45, 1988.)with increased maternal plasma corticosterone levels, 14,19 and resulted in an increased incidence ofcleft palate. Additional early studies suggested that maternal restraint stress in the rat couldpotentiate the effects of chemical teratogens. 20,21Although investigations of the role of maternal effects in causing growth retardation, death,behavioral effects, biochemical alterations, or dysmorphogenesis in the embryo and fetus continuedinto the 1980s, 22–30 the major impetus for further research came as a consequence of publicationsby Khera. 31–34 Khera reviewed published studies and proposed that a number of effects on theoffspring of mice, rats, and rabbits occurred merely as a consequence of maternal toxicity. Suchputative maternally mediated fetal effects included decreased body weights, certain malformationsand variations, and resorptions. Additional discussion of the significance of maternally mediatedeffects can be found in reviews by Hood, 4,35 Chernoff and colleagues, 2 and Daston. 1C. Causes of Maternal StressIn the broadest sense “stress” is any change in the organism’s environment that disturbs homeostasis.The resulting series of neural and endocrine adaptations is commonly referred to as the “stressresponse” or “stress-cascade” (Figure 4.1). Operationally defined, a “stressor” is any manipulationcapable of disturbing homeostasis. Many of the procedures utilized in the collection of data intoxicology, and teratology is no exception, would qualify as stressors under this definition (Table4.1). Thus, stress can be considered an adaptive mechanism that has evolved to protect the organismin times of crisis. 36The mammalian response to stress is a basic regulatory mechanism carried out in part by thelimbic-hypothalamo-pituitary-adrenal (LHPA) axis. 36 Release of catecholamines from the adrenalmedulla and the sympathetic nervous system; adrenocorticotropin (ACTH) from the anterior portionof the pituitary gland; corticotropin releasing factor (CRF) and arginine vasopressin (AVP) fromthe hypothalamus; and glucocorticoids from the adrenal cortex are all key components of thisaction. The stress cascade is considered an example of a classic negative feedback loop. Whenglucocorticoids, the terminal element in the cascade, reach a sufficiently high level in the circulation,they inhibit the release of the initiating components of the cascade, CRF and ACTH.© 2006 by Taylor & Francis Group, LLC