Enhancement of the teratogenicity of all-trans-retinoic acid by maternal restraint stress in mice as a function of treatment timing.

Abstract

In CD-1 mice, maternal restraint stress was combined with all-trans-retinoic acid (tRA) given during the restraint period (9:00 a.m. to 9:00 p.m.) to determine in what manner and to what degree teratogenesis might be affected by treatment timing within the stress period and to determine the optimum timing for stress-enhanced production of fetal defects. Eleven groups were treated on gestation day 9 (copulation plug = day 1): group 1, vehicle (corn oil) control (C); group 2, food/water deprived (FWD); group 3, restraint only (R); group 4, tRA plus food/water deprivation (tRA+FWD); groups 5 and 6, tRA at 0 or 4 hr after 9:00 a.m., i.e., tRA(0) and tRA(4), respectively; and groups 7-11, restraint plus tRA at 0, 2, 4, 8, or 12 hr after 9:00 a.m., (i.e., R+tRA(0), R+tRA(2), R+tRA(4), R+tRA(8), and R+tRA(12), respectively). The tRA dose was 20 mg/kg, PO; mice were restrained in the supine position. FWD mice were deprived for the same 12 hr as the restrained mice. All stated differences were significant (P < or = 0.05), based on litter incidences. The incidences of short tails (65%), fused ribs (62%), and fused vertebrae (37%) were elevated in the R+tRA(4) group in comparison with all others, and there appeared to be more exencephalies in R+tRA(2) litters than in any others. The incidence of supernumerary ribs was elevated in the R group in comparison with C and FWD; it was further elevated by tRA at all treatment times.(ABSTRACT TRUNCATED AT 250 WORDS)