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 congenital malformations, primarily neural tube defects, in laboratory animals, and it may contribute to human birth defects. The acute doses of arsenicals required to elicit teratogenesis in outbred strains of mice, however, are orders of magnitude higher than those to which humans are exposed environmentally. In order to examine interactions between arsenite administration during neurulation and murine genotype, the present study compares two inbred mouse strains, establishes a teratogenic dose of arsenite, and evaluates the effect of the splotch mutation on arsenic-induced teratogenesis. SWV/Fnn or C57BL/6J females were injected intraperitoneally 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 the C57BL/6J strain, and the effect of the splotch mutation, introduced via the male (C57BL16J Sp/(+)), was assessed. Fetuses were examined for external, visceral, and skeletal malformations. Fetuses from crosses of C57BL16J females with C57BL16J Sp/(+) males were genotyped by PCR. Ten-mg/kg sodium arsenite was teratogenic in nearly 50% of C57BL16J fetuses, and the C57BL/6J strain was significantly more sensitive to arsenite-induced embryo-lethality and teratogenicity than the SWV/Fnn strain. The spectrum of malformations produced was dependent on the gestational time point of arsenite administration. Introduction of the splotch allele significantly increased neural tube defects and other specific malformations. This result demonstrates that a mutation in a single gene can increase sensitivity to arsenic-induced birth defects. This murine study examines the interaction between arsenite-induced teratogenicity and genotype.