Mthfr gene ablation enhances susceptibility to arsenic prenatal toxicity

Toxicol Appl Pharmacol. 2014 Feb 15;275(1):22-7. doi: 10.1016/j.taap.2013.12.014. Epub 2013 Dec 30.


Background: In utero exposure to arsenic is known to adversely affect reproductive outcomes. Evidence of arsenic teratogenicity varies widely and depends on individual genotypic differences in sensitivity to As. In this study, we investigated the potential interaction between 5,10-methylenetetrahydrofolate reductase (Mthfr) genotype and arsenic embryotoxicity using the Mthfr knockout mouse model.

Methods: Pregnant dams were treated with sodium arsenate, and reproductive outcomes including: implantation, resorption, congenital malformation and fetal birth weight were recorded at E18.5.

Results: When the dams in Mthfr(+/-)×Mthfr(+/-) matings were treated with 7.2 mg/kg As, the resorption rate increased to 43.4%, from a background frequency of 7.2%. The As treatment also induced external malformations (40.9%) and significantly lowered the average fetal birth weight among fetuses, without any obvious toxic effect on the dam. When comparing the pregnancy outcomes resulting from different mating scenarios (Mthfr(+/+)×Mthfr(+/-), Mthfr(+/-)×Mthfr(+/-) and Mthfr(-/-)×(Mthfr+/-)) and arsenic exposure; the resorption rate showed a linear relationship with the number of null alleles (0, 1 or 2) in the Mthfr dams. Fetuses from nullizygous dams had the highest rate of external malformations (43%) and lowest average birth weight. When comparing the outcomes of reciprocal matings (nullizygote×wild-type versus wild-type×nullizygote) after As treatment, the null dams showed significantly higher rates of resorptions and malformations, along with lower fetal birth weights.

Conclusions: Maternal genotype contributes to the sensitivity of As embryotoxicity in the Mthfr mouse model. The fetal genotype, however, does not appear to affect the reproductive outcome after in utero As exposure.

Keywords: 5,10-Methylenetetrahydrofolate reductase (MTHFR); Embryotoxicity; Gene–environment interaction; Mthfr knockout mice; Sodium arsenate; Teratogenicity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arsenates / administration & dosage
  • Arsenates / toxicity*
  • Arsenic Poisoning / embryology
  • Arsenic Poisoning / genetics*
  • Arsenic Poisoning / metabolism
  • Arsenic Poisoning / physiopathology
  • Congenital Abnormalities / etiology
  • Crosses, Genetic
  • Dose-Response Relationship, Drug
  • Embryo Implantation / drug effects
  • Embryo Loss / etiology
  • Female
  • Fetal Growth Retardation / etiology
  • Fetal Resorption / etiology
  • Genetic Predisposition to Disease
  • Heterozygote
  • Homozygote
  • Maternal Exposure / adverse effects*
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Methylenetetrahydrofolate Reductase (NADPH2) / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Teratogens / toxicity*


  • Arsenates
  • Teratogens
  • sodium arsenate
  • Methylenetetrahydrofolate Reductase (NADPH2)