Toxicological Sciences, Vol 51, 98-107, Copyright © 1999 by Society of Toxicology
AF Machado, DN Hovland Jr, S Pilafas and MD Collins
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 (C57BL/6J Sp/+), was assessed. Fetuses were examined for external,
visceral, and skeletal malformations. Fetuses from crosses of C57BL/6J
females with C57BL/6J Sp/+ males were genotyped by PCR. Ten-mg/kg sodium
arsenite was teratogenic in nearly 50% of C57BL/6J 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.
ARTICLES
Teratogenic response to arsenite during neurulation: relative sensitivities of C57BL/6J and SWV/Fnn mice and impact of the splotch allele
Department of Environmental Health Sciences, UCLA School of Public Health, Los Angeles, California 90095, USA.
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