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

To ascertain the relative contributions of,genotypes of conceptus and dam t o developmental toxicity occasioned by valproic acid (VPA), crosses were es tablished between resistant C57BL/6JBk (C, C57) and susceptible SWV/Bk (S, SWV) strains of mice. These included matings of pure lines, reciprocal outc rosses, and reciprocal backcrosses with Fl hybrids. At 8 d:12 h +/- 5 h, fo r each mating, 0, 500, or 600 mg/kg aqueous VPA was injected ip. Fetuses we re examined on gestation day (gd) Is for exencephaly (the paradigmatic anom aly), 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 f unction of the uterine environment produced by the maternal genotype. This inference is confirmed in backcrosses where F1-dams x S-sires and F1-dams X C-sires produced identical outcomes, and S-dams x F1-sires produced much h igher frequencies of exencephaly than C-dams X F1-sires. For prenatal mortality, the genotypes of both dam and conceptus appear to b e important determinants. Fetal contribution is inferred from the observati ons that S-dam X S-sire matings produced a much higher frequency of mortali ty than S-dams X C-sires, and C-dams X C-sires produced higher mortality th an C-dams X S-sires. Therefore, heterozygosity of the conceptus was protect ive. Among backcrosses, fetal determination of sensitivity to mortality is also seen by the observation that F1-dams X C-sires produces the same fetal mortality as C-dams x F1-sires. The contribution of uterine environment is seen in the observation that matings of S-dams X C-sires resulted in highe r fetal mortality than did those with C-dams X S-sires. Therefore, identica l conceptuses in different dams showed different levels of fetal loss. Thus exencephaly response appears to be largely controlled by genes active in t he 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 pur e-line dams make a contribution to prenatal mortality not seen in C57 or Fl dams. Mean litter size among VPA-exposed litters showed high variability in pure lines and outcrosses. In backcrosses, Fl dams produced larger litters than pure line dams, arguing for heterosis as a contributor to this parameter. R eduction in litter size occasioned by VPA exposure was great in pure line d ams and nonexistent in Fl dams. The SWV dams crossed with Fl sires were the only group among the backcrosses to show reduction of litter size, providi ng further confirmation of the increased sensitivity of pure-line (i.e., ho mozygous) SWV dams to VPA exposure. Fetal weight seems to be a function of uterine environment because female S WV produced conceptuses with lower fetal weight in all crosses, and produce d a greater reduction in fetal weight attributable to VPA exposure than C57 or Fl dams. Fetal weight did not correlate closely with litter size, sugge sting that a lower fetal weight may be a strain characteristic, as are exen cephaly induction and prenatal mortality in response to VPA. Differences in sensitivity to VPA insult are seen for all parameters investigated with SW V dams being the most sensitive, but mechanisms seem to differ for a number of the endpoints. (C) 1999 Elsevier Science Inc. All rights reserved.