Contributions of dam and conceptus to differences in sensitivity to valproic acid among C57 black and SWV mice

Abstract

To ascertain the relative contributions of genotypes of conceptus and dam to developmental toxicity occasioned by valproic acid (VPA), crosses were established between resistant C57BL/6JBk (C, C57) and susceptible SWV/Bk (S, SWV) strains of mice. These included matings of pure lines, reciprocal outcrosses, and reciprocal backcrosses with F1 hybrids. At 8 d:12 h ± 5 h, for each mating, 0, 500, or 600 mg/kg aqueous VPA was injected ip. Fetuses were examined on gestation day (gd) 18 for exencephaly (the paradigmatic anomaly), other abnormalities, mortality, litter size, and fetal weight. At 600 mg/kg, sensitivity to exencephaly induction in all cases was that of the dam, regardless of sire. Thus exencephaly here seems to be largely a function of the uterine environment produced by the maternal genotype. This inference is confirmed in backcrosses where F1-dams × S-sires and F1-dams × C-sires produced identical outcomes, and S-dams × F1-sires produced much higher frequencies of exencephaly than C-dams × F1-sires. For prenatal mortality, the genotypes of both dam and conceptus appear to be important determinants. Fetal contribution is inferred from the observations that S-dam × S-sire matings produced a much higher frequency of mortality than S-dams × C-sires, and C-dams × C-sires produced higher mortality than C-dams × S-sires. Therefore, heterozygosity of the conceptus was protective. Among backcrosses, fetal determination of sensitivity to mortality is also seen by the observation that F1-dams × C-sires produces the same fetal mortality as C-dams × F1-sires. The contribution of uterine environment is seen in the observation that matings of S-dams × C-sires resulted in higher fetal mortality than did those with C-dams × S-sires. Therefore, identical conceptuses in different dams showed different levels of fetal loss. Thus exencephaly response appears to be largely controlled by genes active in the dam, and mortality as a result of a multigenic outcome with contributing genes active in both conceptus and dam. The data also suggest that SWV pure-line dams make a contribution to prenatal mortality not seen in C57 or F1 dams. Mean litter size among VPA-exposed litters showed high variability in pure lines and outcrosses. In backcrosses, F1 dams produced larger litters than pure line dams, arguing for heterosis as a contributor to this parameter. Reduction in litter size occasioned by VPA exposure was great in pure line dams and nonexistent in F1 dams. The SWV dams crossed with F1 sires were the only group among the backcrosses to show reduction of litter size, providing further confirmation of the increased sensitivity of pure-line (i.e., homozygous) SWV dams to VPA exposure. Fetal weight seems to be a function of uterine environment because female SWV produced conceptuses with lower fetal weight in all crosses, and produced a greater reduction in fetal weight attributable to VPA exposure than C57 or F1 dams. Fetal weight did not correlate closely with litter size, suggesting that a lower fetal weight may be a strain characteristic, as are exencephaly induction and prenatal mortality in response to VPA. Differences in sensitivity to VPA insult are seen for all parameters investigated with SWV dams being the most sensitive, but mechanisms seem to differ for a number of the endpoints.