Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 238-246 |
| Number of pages | 9 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 177 |
| Issue number | 3 |
| DOIs | |
| State | Published - Dec 15 2001 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Pharmacology
- Toxicology
Cite this
Arsenic-induced congenital malformations in genetically susceptible folate binding protein-2 knockout mice. / Wlodarczyk, Bogdan; Spiegelstein, Ofer; Gelineau-van Waes, Janee; Vorce, Roseann L.; Lu, Xiufen; Le, Chris X.; Finnell, Richard H.
In: Toxicology and Applied Pharmacology, Vol. 177, No. 3, 15.12.2001, p. 238-246.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Arsenic-induced congenital malformations in genetically susceptible folate binding protein-2 knockout mice
AU - Wlodarczyk, Bogdan
AU - Spiegelstein, Ofer
AU - Gelineau-van Waes, Janee
AU - Vorce, Roseann L.
AU - Lu, Xiufen
AU - Le, Chris X.
AU - Finnell, Richard H.
PY - 2001/12/15
Y1 - 2001/12/15
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=0035894337&partnerID=8YFLogxK
U2 - 10.1006/taap.2001.9303
DO - 10.1006/taap.2001.9303
M3 - Article
C2 - 11749123
AN - SCOPUS:0035894337
VL - 177
SP - 238
EP - 246
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 3
ER -