Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies

Ofer Spiegelstein; Amy Gould; Bogdan Wlodarczyk; Marlene Tsie; Xiufen Lu; Chris Le; Aron Troen; Jacob Selhub; Jorge A. Piedrahita; J. Michael Salbaum; Claudia Kappen; Stepan Melnyk; Jill James; Richard H. Finnell

doi:10.1016/j.taap.2004.07.006

Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies

Ofer Spiegelstein, Amy Gould, Bogdan Wlodarczyk, Marlene Tsie, Xiufen Lu, Chris Le, Aron Troen, Jacob Selhub, Jorge A. Piedrahita, J. Michael Salbaum, Claudia Kappen, Stepan Melnyk, Jill James, Richard H. Finnell^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Previous studies have demonstrated that mice lacking a functional folate binding protein 2 gene (Folbp2^-/-) were significantly more sensitive to in utero arsenic exposure than were the wild-type mice similarly exposed. When these mice were fed a folate-deficient diet, the embryotoxic effect of arsenate was further exacerbated. Contrary to expectations, studies on 24-h urinary speciation of sodium arsenate did not demonstrate any significant difference in arsenic biotransformation between Folbp2^-/- and Folbp2^+/+ mice. To better understand the influence of folate pathway genes on arsenic embryotoxicity, the present investigation utilized transgenic mice with disrupted folate binding protein 1 (Folbp1) and reduced folate carrier (RFC) genes. Because complete inactivation of Folbp1 and RFC genes results in embryonic lethality, we used heterozygous animals. Overall, no RFC genotype-related differences in embryonic susceptibility to arsenic exposure were observed. Embryonic lethality and neural tube defect (NTD) frequency in Folbp1 mice was dose-dependent and differed from the RFC mice; however, no genotype-related differences were observed. The RFC heterozygotes tended to have higher plasma levels of S-adenosylhomocysteine (SAH) than did the wild-type controls, although this effect was not robust. It is concluded that genetic modifications at the Folbp1 and RFC loci confers no particular sensitivity to arsenic toxicity compared to wild-type controls, thus disproving the working hypothesis that decreased methylating capacity of the genetically modified mice would put them at increased risk for arsenic-induced reproductive toxicity.

Original language	English
Pages (from-to)	18-26
Number of pages	9
Journal	Toxicology and Applied Pharmacology
Volume	203
Issue number	1
DOIs	https://doi.org/10.1016/j.taap.2004.07.006
State	Published - 15 Feb 2005
Externally published	Yes

Bibliographical note

Funding Information:
This project was supported in part by grants P42ES04917, P30ES09106, and ES11775 from the National Institute of Environmental Health. We also acknowledge the work done at the Mayo Clinic in the generation of the RFC knockout mouse. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH. The authors would like to thank Ms. Michelle Merriweather and Mr. Joe Wicker for their technical assistance with this study; Dr. Laura E. Mitchell from the Center for Environmental and Genetic Medicine at the Institute of Biosciences and Technology for assisting with the statistical analysis.

Keywords

Arsenic
Biotransformation
Detoxification
Folbp1
Neural tube defects
RFC
Teratogenicity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.taap.2004.07.006

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Spiegelstein, O., Gould, A., Wlodarczyk, B., Tsie, M., Lu, X., Le, C., Troen, A., Selhub, J., Piedrahita, J. A., Salbaum, J. M., Kappen, C., Melnyk, S., James, J., & Finnell, R. H. (2005). Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies. Toxicology and Applied Pharmacology, 203(1), 18-26. https://doi.org/10.1016/j.taap.2004.07.006

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title = "Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies",

abstract = "Previous studies have demonstrated that mice lacking a functional folate binding protein 2 gene (Folbp2-/-) were significantly more sensitive to in utero arsenic exposure than were the wild-type mice similarly exposed. When these mice were fed a folate-deficient diet, the embryotoxic effect of arsenate was further exacerbated. Contrary to expectations, studies on 24-h urinary speciation of sodium arsenate did not demonstrate any significant difference in arsenic biotransformation between Folbp2-/- and Folbp2+/+ mice. To better understand the influence of folate pathway genes on arsenic embryotoxicity, the present investigation utilized transgenic mice with disrupted folate binding protein 1 (Folbp1) and reduced folate carrier (RFC) genes. Because complete inactivation of Folbp1 and RFC genes results in embryonic lethality, we used heterozygous animals. Overall, no RFC genotype-related differences in embryonic susceptibility to arsenic exposure were observed. Embryonic lethality and neural tube defect (NTD) frequency in Folbp1 mice was dose-dependent and differed from the RFC mice; however, no genotype-related differences were observed. The RFC heterozygotes tended to have higher plasma levels of S-adenosylhomocysteine (SAH) than did the wild-type controls, although this effect was not robust. It is concluded that genetic modifications at the Folbp1 and RFC loci confers no particular sensitivity to arsenic toxicity compared to wild-type controls, thus disproving the working hypothesis that decreased methylating capacity of the genetically modified mice would put them at increased risk for arsenic-induced reproductive toxicity.",

keywords = "Arsenic, Biotransformation, Detoxification, Folbp1, Neural tube defects, RFC, Teratogenicity",

author = "Ofer Spiegelstein and Amy Gould and Bogdan Wlodarczyk and Marlene Tsie and Xiufen Lu and Chris Le and Aron Troen and Jacob Selhub and Piedrahita, {Jorge A.} and Salbaum, {J. Michael} and Claudia Kappen and Stepan Melnyk and Jill James and Finnell, {Richard H.}",

note = "Funding Information: This project was supported in part by grants P42ES04917, P30ES09106, and ES11775 from the National Institute of Environmental Health. We also acknowledge the work done at the Mayo Clinic in the generation of the RFC knockout mouse. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH. The authors would like to thank Ms. Michelle Merriweather and Mr. Joe Wicker for their technical assistance with this study; Dr. Laura E. Mitchell from the Center for Environmental and Genetic Medicine at the Institute of Biosciences and Technology for assisting with the statistical analysis.",

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Spiegelstein, O, Gould, A, Wlodarczyk, B, Tsie, M, Lu, X, Le, C, Troen, A, Selhub, J, Piedrahita, JA, Salbaum, JM, Kappen, C, Melnyk, S, James, J & Finnell, RH 2005, 'Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies', Toxicology and Applied Pharmacology, vol. 203, no. 1, pp. 18-26. https://doi.org/10.1016/j.taap.2004.07.006

TY - JOUR

T1 - Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies

AU - Spiegelstein, Ofer

AU - Gould, Amy

AU - Wlodarczyk, Bogdan

AU - Tsie, Marlene

AU - Lu, Xiufen

AU - Le, Chris

AU - Troen, Aron

AU - Selhub, Jacob

AU - Piedrahita, Jorge A.

AU - Salbaum, J. Michael

AU - Kappen, Claudia

AU - Melnyk, Stepan

AU - James, Jill

AU - Finnell, Richard H.

N1 - Funding Information: This project was supported in part by grants P42ES04917, P30ES09106, and ES11775 from the National Institute of Environmental Health. We also acknowledge the work done at the Mayo Clinic in the generation of the RFC knockout mouse. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH. The authors would like to thank Ms. Michelle Merriweather and Mr. Joe Wicker for their technical assistance with this study; Dr. Laura E. Mitchell from the Center for Environmental and Genetic Medicine at the Institute of Biosciences and Technology for assisting with the statistical analysis.

PY - 2005/2/15

Y1 - 2005/2/15

N2 - Previous studies have demonstrated that mice lacking a functional folate binding protein 2 gene (Folbp2-/-) were significantly more sensitive to in utero arsenic exposure than were the wild-type mice similarly exposed. When these mice were fed a folate-deficient diet, the embryotoxic effect of arsenate was further exacerbated. Contrary to expectations, studies on 24-h urinary speciation of sodium arsenate did not demonstrate any significant difference in arsenic biotransformation between Folbp2-/- and Folbp2+/+ mice. To better understand the influence of folate pathway genes on arsenic embryotoxicity, the present investigation utilized transgenic mice with disrupted folate binding protein 1 (Folbp1) and reduced folate carrier (RFC) genes. Because complete inactivation of Folbp1 and RFC genes results in embryonic lethality, we used heterozygous animals. Overall, no RFC genotype-related differences in embryonic susceptibility to arsenic exposure were observed. Embryonic lethality and neural tube defect (NTD) frequency in Folbp1 mice was dose-dependent and differed from the RFC mice; however, no genotype-related differences were observed. The RFC heterozygotes tended to have higher plasma levels of S-adenosylhomocysteine (SAH) than did the wild-type controls, although this effect was not robust. It is concluded that genetic modifications at the Folbp1 and RFC loci confers no particular sensitivity to arsenic toxicity compared to wild-type controls, thus disproving the working hypothesis that decreased methylating capacity of the genetically modified mice would put them at increased risk for arsenic-induced reproductive toxicity.

AB - Previous studies have demonstrated that mice lacking a functional folate binding protein 2 gene (Folbp2-/-) were significantly more sensitive to in utero arsenic exposure than were the wild-type mice similarly exposed. When these mice were fed a folate-deficient diet, the embryotoxic effect of arsenate was further exacerbated. Contrary to expectations, studies on 24-h urinary speciation of sodium arsenate did not demonstrate any significant difference in arsenic biotransformation between Folbp2-/- and Folbp2+/+ mice. To better understand the influence of folate pathway genes on arsenic embryotoxicity, the present investigation utilized transgenic mice with disrupted folate binding protein 1 (Folbp1) and reduced folate carrier (RFC) genes. Because complete inactivation of Folbp1 and RFC genes results in embryonic lethality, we used heterozygous animals. Overall, no RFC genotype-related differences in embryonic susceptibility to arsenic exposure were observed. Embryonic lethality and neural tube defect (NTD) frequency in Folbp1 mice was dose-dependent and differed from the RFC mice; however, no genotype-related differences were observed. The RFC heterozygotes tended to have higher plasma levels of S-adenosylhomocysteine (SAH) than did the wild-type controls, although this effect was not robust. It is concluded that genetic modifications at the Folbp1 and RFC loci confers no particular sensitivity to arsenic toxicity compared to wild-type controls, thus disproving the working hypothesis that decreased methylating capacity of the genetically modified mice would put them at increased risk for arsenic-induced reproductive toxicity.

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KW - Detoxification

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KW - Teratogenicity

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Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies

Abstract

Bibliographical note

Keywords

UN SDGs

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