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

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Abstract
In CD-1 mice, maternal restraint stress was combined with all-trans-retinoic acid (†RA) 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, †RA plus food/water deprivation (†RA+FWD); groups 5 and 6, †RA at 0 or 4 hr after 9:00 a.m., i.e., †RA(0) and †RA(4), respectively; and groups 7-11, restraint plus †RA at 0, 2, 4, 8, or 12 hr after 9:00 a.m., (i.e., R+†RA(0), R+†RA(2), R+†RA(4), R+†RA(8), and R+†RA(12), respectively). The †RA 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⩽0.05), based on litter incidences. The incidences of short tails (65%), fused ribs (62%), and fused vertebrae (37%) were elevated in the R+†RA(4) group in comparison with all others, and there appeared to be more exencephalies in R+†RA(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 †RA at all treatment times. Fetuses from the R+†RA(4) group weighed less than those from all other †RA-exposed groups; the differences were nonsignificant except for the comparison with †RA+FWD. These results show that timing of teratogen exposure relative to maternal stress can significantly influence the magnitude of effects on the offspring and that this influence is not merely due to the changing developmental susceptibility of the conceptus.