Does genomic imprinting contribute to valproic acid teratogenicity?

Reciprocal outcrosses and backcrosses were made between strains of mice wit h different susceptibilities to valproic acid (VPA) teratogenicity. Relativ ely resistant C57BL/6J (C) and more susceptible SWV (S) strains of mice pro duced Fl hybrids in which the female parent was C and the male parent was S (CS-F1) as well as the reciprocal with S dams and C sires (SC-FI). Each wa s backcrossed to each strain, producing 8 types of backcross matings: CS X C, SC X C, CS X S, SC X S; C X CS, C X SC, S X CS, S X SC (for all matings dams are listed first). At 8d:12 +/- 5h of gestation, a teratogenic dose, 6 00 mg/kg, of aqueous VPA was injected ip into the dams. Fetuses: were exami ned on gestation day (gd) 18 for abnormality, mortality, litter size, and w eight. Genomic imprinting (imprinting) is a phenomenon at least in part involving hyper- or hypomethylation of bases: in DNA, which is believed to determine whether or not the imprinted gene will be expressed. Imprinting has been re ported to occur differentially in the male and female for a number of gene loci. Thus, in crosses between strains with differing susceptibility to VPA , if imprinting is occurring, the susceptibility of a fetus might be predic ted to be disproportionately influenced by susceptibility of its grandparen ts. Significant differences in frequency (%) of occurrence of exencephaly in pr ogeny of all backcrosses with F1 dams consistent with those expected for im printing were found in the present study (CS-F1 X C = 21.8 +/- 3.9%, SC-F1 X C = 10.8 +/- 3.2%. P < 0.03; CS-FIX S = 14.8 +/- 3.1%, SC-F1 X S = 6.3 +/ - 2.3%, P < 0.03). SWV darns revealed the same pattern (S X SC-F1 = 50.0 +/ - 8.3%, S X CS-F1 = 37.1 +/- 4.7%, P < 0.04). Differences in prenatal mortality also consistent with genomic imprinting o ccurred in backcrosses: with pure-line SWV dams (S X SC = 64.4 +/- 8.0%, S X CS = 30.5 +/- 4.5%, P < 0.001). Fetal weight was reduced in a manner cons istent with imprinting in backcrosses involving SWV (S X SC = 0.50 +/- 0.18 g, S X CS = 0.96 +/- 0.05, P < 0.01). Three of four of the parameters inve stigated showed differences in some of the backcrosses of reciprocal F1's c onsistent with those expected if genomic imprinting were occurring. (C) 200 1 Elsevier Science Inc. All rights reserved.