Effect of arsenite, maternal age, and embryonic sex on spina bifida, exencephaly, and resorption rates in the splotch mouse.
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.
Martin
Lisa J
LJ
Department of Environmental Health Sciences, Interdepartmental Program in Molecular Toxicology, UCLA School of Public Health, Los Angeles, California 90095-1772, USA.
Machado
Antonio F
AF
Loza
M Angelica
MA
Mao
Gloria E
GE
Lee
Grace S
GS
Hovland
David N
DN
Cantor
Rita M
RM
Collins
Michael D
MD
D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000235:genetics; D000367:Age Factors; D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced* / Q000235:genetics; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000235:genetics; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011247:Pregnancy; D012737:Sex Factors; D017670:Sodium Compounds / Q000633:toxicity*; D016135:Spinal Dysraphism / Q000139:chemically induced* / Q000235:genetics; D014157:Transcription Factors
D018053:Arsenites; D004268:DNA-Binding Proteins; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D017670:Sodium Compounds; D014157:Transcription Factors; C068686:Pax3 protein, mouse; C017947:sodium arsenite