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

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 1999-09, Vol.13 (5), p.353-360
• Main Author: Beck, Sidney L
• Format: Article
• Language: English
• Subjects: Abnormalities, Drug-Induced - genetics; Animals; Anticonvulsants - toxicity; Biological and medical sciences; Body Weight - drug effects; Body Weight - genetics; Crosses, Genetic; Drug toxicity and drugs side effects treatment; Embryonic and Fetal Development - drug effects; Embryonic and Fetal Development - genetics; Female; Fetal Death - chemically induced; Fetal Death - genetics; Fetal Weight - drug effects; Fetal Weight - genetics; Genetic Predisposition to Disease; Genotype; Litter Size - drug effects; Litter Size - genetics; Male; Medical sciences; Mice; Mice, Inbred C57BL; Miscellaneous (drug allergy, mutagens, teratogens...); Neural Tube Defects - chemically induced; Neural Tube Defects - genetics; Pharmacology. Drug treatments; Pregnancy; Species Specificity; Valproic Acid - toxicity
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/S0890-6238(99)00038-6

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