Arsenic-induced congenital malformations in genetically susceptible folate binding protein-2 knockout mice.
Arsenic is a well-known carcinogen, which has been suspected of being a human teratogen, although there is currently insufficient and inadequate supportive data to make any definitive judgments. In addition, the significance of individual genetic differences on pregnancy outcomes following in utero exposure to arsenic is currently unknown. In order to better understand the role of folate transport mechanisms in arsenic-induced neural tube defects, we examined the effect of in utero exposure to sodium arsenate in a genetically altered murine model in which the folate binding protein 2 (Folbp2) gene has been inactivated by homologous recombination. In utero sodium arsenate exposure induced exencephaly in 40.6% of Folbp2(-/-) embryos compared with 24.0% in control Folbp2(+/+) embryos. The differences in response frequencies were further exacerbated when the dams were fed a folate-deficient diet. Under these conditions, exencephaly was observed in 64.0% of Folbp2(-/-) embryos compared with 25.7% in control Folbp2(+/+) embryos. Analysis of arsenic metabolites excreted in the urine following sodium arsenate injection to Folbp2(-/-) and Folbp2(+/+) mice indicated that there were no significant differences in arsenic metabolism between the two groups. Thus, the increased susceptibility of Folbp2(-/-) mice to arsenate-induced teratogenicity may not be due to differences in biomethylation and exposure. In conclusion, the data suggest that impaired folate transport in the developing mouse embryo increases the risk for developmental defects following in utero exposure to sodium arsenate and that these differences are not due to differences in metabolism of arsenic.
Wlodarczyk
B
B
Center for Human Molecular Genetics, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Spiegelstein
O
O
Gelineau-van Waes
J
J
Vorce
R L
RL
Lu
X
X
Le
C X
CX
Finnell
R H
RH
D000818:Animals; D001149:Arsenates / Q000378:metabolism / Q000633:toxicity*; D001152:Arsenicals / Q000652:urine; D018053:Arsenites / Q000652:urine; D002101:Cacodylic Acid / Q000652:urine; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D058973:Folate Receptors, GPI-Anchored; D005494:Folic Acid Deficiency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011956:Receptors, Cell Surface; D013723:Teratogens / Q000378:metabolism / Q000633:toxicity*
D001149:Arsenates; D001152:Arsenicals; D018053:Arsenites; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; D013723:Teratogens; D006710:Homocysteine; C052920:trimethylarsine oxide; C009277:sodium arsenate; D002101:Cacodylic Acid; C020300:monomethylarsonic acid; C015001:arsenite