Teratogenic response to arsenite during neurulation: relative sensitivities of C57BL/6J and SWV/Fnn mice and impact of the splotch allele

Arsenic is an environmental contaminant that induces congenitalmalformations, primarily neural tube defects, in laboratory animals, and itmay contribute to human birth defects. The acute doses of arsenicalsrequired to elicit teratogenesis in outbred strains of mice, however, areorders of magnitude higher than those to which humans are exposedenvironmentally. In order to examine interactions between arseniteadministration during neurulation and murine genotype, the present studycompares two inbred mouse strains, establishes a teratogenic dose ofarsenite, and evaluates the effect of the splotch mutation onarsenic-induced teratogenesis. SWV/Fnn or C57BL/6J females were injectedintraperitoneally with sodium arsenite (10 mg/kg) on days 6.5, 7.0, 7.5,8.0, 8.5, or 9.0 of gestation. A dose-response study was carried out in theC57BL/6J strain, and the effect of the splotch mutation, introduced via themale (C57BL/6J Sp/+), was assessed. Fetuses were examined for external,visceral, and skeletal malformations. Fetuses from crosses of C57BL/6Jfemales with C57BL/6J Sp/+ males were genotyped by PCR. Ten-mg/kg sodiumarsenite was teratogenic in nearly 50% of C57BL/6J fetuses, and theC57BL/6J strain was significantly more sensitive to arsenite-inducedembryo-lethality and teratogenicity than the SWV/Fnn strain. The spectrumof malformations produced was dependent on the gestational time point ofarsenite administration. Introduction of the splotch allele significantlyincreased neural tube defects and other specific malformations. This resultdemonstrates that a mutation in a single gene can increase sensitivity toarsenic-induced birth defects. This murine study examines the interactionbetween arsenite-induced teratogenicity and genotype.