Effect of arsenite, maternal age, and embryonic sex on spina bifida, exencephaly, and resorption rates in the splotch mouse

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Abstract
BACKGROUND: This study examines interactions of a mutation inPax3, embryonic sex, advanced maternal age, and arsenite exposure in the splotch (Sp) mouse model, with the aim of describing gene‐environment interactions for neural tube defects and embryonic lethality.METHODS: Splotch heterozygous C57BL/6J mice were crossed to produce offspring of three genotypes with a common maternal genotype that were exposed to either sodium arsenite on gestational day (GD) 8.0, or advanced maternal age (dams older than 12 months). Embryos were extracted on GD 12 and genotyped for bothPax3and sex.RESULTS: Arsenite treatment was a significant contributor to both exencephaly and spina bifida. Advanced maternal age resulted in a high exencephaly rate inSp/Spfemale embryos (but not other genotypes) and a high overall resorption rate. Arsenite treatment and advanced maternal age resulted in elevated sex ratios (male:female) for heterozygous and wild‐type embryos. The sex ratio was highest for wild‐type embryos and was lowered as the number of mutantPax3alleles increased. The sex ratio was not significantly different from 1.0 for splotch homozygotes. Control litters had spina bifida rates that were 95% in homozygous, 6% in heterozygous, and 0% in wild‐type embryos.CONCLUSIONS: If arsenite produces exencephaly by inactivating the Pax3 protein, then the fact that the exencephaly rate was increased inSp/Spembryos with no functional Pax3 indicates that arsenite may either induce this defect through additional pathways, or may alter the response via modifier genes. Genetic and environmental factors contributed to the determination of murine sex ratios, with female embryos being more susceptible to loss. Birth Defects Research (Part A) 67:231–239, 2003.