Effects of restraint stress in gestation: Implications for rodent developmental toxicology studies

Abstract

Restraint has been used as a procedure to study the effects of stress on gestation outcome in rodents. The effects of restraint could potentially be used as a model for the impact of general stress produced by high doses of toxicants and other interventions. In mice, restraint in the peri-implantation period leads to implantation failure, and restraint at appropriate times in organogenesis produces cleft palate, supernumerary ribs, and resorption. In rats, there is some evidence for an association with restraint for implantation failure, but not for the morphological anomalies. Restraint in late gestation alters adult sexual behavior of male rat offspring, but consequences for their fertility are not known. Intrauterine growth retardation is not commonly associated with gestational restraint. In the few studies where they have been directly compared, different restraint procedures produced graded, qualitatively different, or no effects. Adrenocortical hormones have been implicated as mediating the effect of restraint on cleft palate, but not on supernumerary ribs, implantation failure, or sexual differentiation. Given the variety of restraint procedures and the varying species-dependent consequences, it is not possible to infer a generalizable pattern of developmental effects due to gestational stress from the restraint literature. As an alternative approach, contemporary methods in gene expression and developmental biology could profitably be applied to understanding different patterns of stress-mediated effects of toxicant exposures on intrauterine development. Birth Defects Res B 71:26-36, 2004. r 2004 Wiley-Liss, Inc.

Effect of Maternal Restraint Stress on Fetal Development of ICR Mice

“…In comparison, it is known that restraint in the peri-implantation period leads to implantation failure, and that stress at appropriate times in organogenesis produces cleft palate, costal abnormalities and resorption of fetuses in mice [9,14,21,28,39]. Furthermore, some factors including type and duration of restraint, position and strain of mice, and lights are believed to be closely related to the incidence of maternal and fetal toxicities [15].…”

“…The dams were subjected to restraint stress by 12-h taping of 4 limbs to a plastic board in a supine position [8,21,28,29] under the 300 lux room light (08:00-20:00) for 4 days. The 12-h taping restraint stress was adopted for the present experiments because restraint stress longer than 12 h is generally required for the induction of malformation or resorption of fetuses [15]. During restraint, animals had no access to food and water.…”

“…In general, mice have been found to be more susceptible to stress-or glucocorticoid-induced teratogenesis than rats [9,15]. Furthermore, the presence of glucocorticoid receptors on the embryonic palate was correlated across mouse strains with differential susceptibility to cleft palate induction [40].…”

“…There are, however, species and strain differences in the adrenocortical response to stress and in susceptibilities to glucocorticoid-induced embryo-fetal toxicities [15,17,18,27]. In general, mice have been found to be more susceptible to stress-or glucocorticoid-induced teratogenesis than rats [9,15].…”

“…Many investigators have reported controversial results based on their stress conditions [15], such as gestational period (GD0-20), duration of stress (1.8 min-48 h) and stressors (restraints, electric shock or feed/water deprivation). These results led us to investigate the specific gestational stage susceptibilities of fetuses to maternal stress in mice.…”