37 - Arsenic Causes Neural Tube Defects in Mice by Targeting Folate Metabolism

Poster Board Number: 37
There are separate poster presentation times for odd and even posters.
Odd poster #s – first hour
Even poster #s – second hour

Abstract Body : Background: Neural tube defects (NTDs) are congenital malformations arising from interactions among genetic and environmental factors. Low maternal folate status is a determinant of NTD risk. The Shmt1-/-/+/- mouse model of impaired thymidylate biosynthesis exhibits folic-acid responsive NTDs. Inorganic arsenic is a potent inhibitor of thymidylate biosynthesis and induces DNA damage in a dose-dependent manner in cells.

Objective: The objective of this study was to determine the impact of dietary folic acid on preventing NTDs in wild-type and Shmt1-/- dams exposed to arsenic-contaminated drinking water.

Design: A total of 532 Shmt1-/- and Shmt1+/+ female mice were randomized to either AIN93G or AIN93G lacking folic acid diets for a minimum of eight weeks and then time-mated to males with the matching genotype. From one week before mating and through sacrifice at E12.5, dams were exposed to either 0, 8, or 25 ppm arsenic-contaminated drinking water. A total of 2478 embryos from 532 litters were examined for the presence of NTDs. Arsenic-induced DNA damage was quantified in mouse embryonic fibroblasts (MEFs) as a function of Shmt1 genotype.

Results: Maternal exposure to arsenic increased NTD occurrence in embryos in a dose-dependent manner. Arsenic exposure inhibited de novo thymidylate synthesis and increased DNA damage in mouse embryonic fibroblasts (MEFs) in a dose-dependent manner. Arsenic-induced NTDs were not folic acid-responsive.

Conclusions: Arsenic inhibited folate-dependent de novo thymidylate synthesis at low concentrations and caused NTDs in mice. Arsenic-induced NTDs were not rescued by dietary folic acid. These findings establish arsenic as a causative factor in the etiology of folic acid-resistant NTDs.