PMID- 12854658 OWN - NLM STAT- MEDLINE DCOM- 20040114 LR - 20161124 IS - 1542-0752 (Print) IS - 1542-0752 (Linking) VI - 67 IP - 4 DP - 2003 Apr TI - Effect of arsenite, maternal age, and embryonic sex on spina bifida, exencephaly, and resorption rates in the splotch mouse. PG - 231-9 AB - BACKGROUND: This study examines interactions of a mutation in Pax3, 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 both Pax3 and sex. RESULTS: Arsenite treatment was a significant contributor to both exencephaly and spina bifida. Advanced maternal age resulted in a high exencephaly rate in Sp/Sp female 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 mutant Pax3 alleles 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 in Sp/Sp embryos 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. FAU - Martin, Lisa J AU - Martin LJ AD - Department of Environmental Health Sciences, Interdepartmental Program in Molecular Toxicology, UCLA School of Public Health, Los Angeles, California 90095-1772, USA. FAU - Machado, Antonio F AU - Machado AF FAU - Loza, M Angelica AU - Loza MA FAU - Mao, Gloria E AU - Mao GE FAU - Lee, Grace S AU - Lee GS FAU - Hovland, David N Jr AU - Hovland DN Jr FAU - Cantor, Rita M AU - Cantor RM FAU - Collins, Michael D AU - Collins MD LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Birth Defects Res A Clin Mol Teratol JT - Birth defects research. Part A, Clinical and molecular teratology JID - 101155107 RN - 0 (Arsenites) RN - 0 (DNA-Binding Proteins) RN - 0 (PAX3 Transcription Factor) RN - 0 (Paired Box Transcription Factors) RN - 0 (Sodium Compounds) RN - 0 (Transcription Factors) RN - 138016-91-8 (Pax3 protein, mouse) RN - 48OVY2OC72 (sodium arsenite) SB - IM MH - Abnormalities, Drug-Induced/*etiology/genetics MH - Age Factors MH - Animals MH - Arsenites/*toxicity MH - DNA-Binding Proteins/metabolism MH - Dose-Response Relationship, Drug MH - Embryonic and Fetal Development/*drug effects/genetics MH - Female MH - Fetal Resorption/*chemically induced/genetics MH - Genotype MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Mutant Strains MH - Neural Tube Defects/*chemically induced/genetics MH - PAX3 Transcription Factor MH - Paired Box Transcription Factors MH - Pregnancy MH - Sex Factors MH - Sodium Compounds/*toxicity MH - Spinal Dysraphism/*chemically induced/genetics MH - *Transcription Factors EDAT- 2003/07/12 05:00 MHDA- 2004/01/15 05:00 CRDT- 2003/07/12 05:00 PHST- 2003/07/12 05:00 [pubmed] PHST- 2004/01/15 05:00 [medline] PHST- 2003/07/12 05:00 [entrez] AID - 10.1002/bdra.10006 [doi] PST - ppublish SO - Birth Defects Res A Clin Mol Teratol. 2003 Apr;67(4):231-9. doi: 10.1002/bdra.10006.