Evaluation of Choline Metabolic Genes in the Liver of the Dam as Candidates for Mediating Choline's Efficacy in Mitigating Ethanol-Induced Cell Death in the Neural Tube: A Preliminary Analysis.

Background/

Objectives

Emerging evidence has suggested that choline is an effective treatment for at least some of the neurobehavioral deficits associated with Fetal Alcohol Spectrum Disorders (FASD). However, the mechanism of how choline works to ameliorate ethanol's teratogenic effects, and whether it acts directly on the fetus or indirectly by altering the uterine environment, remains unknown. Previous work from our lab demonstrated that 4 BXD mouse strains that show high levels of ethanol-induced cell death on embryonic day 9.5 (E9.5) have differential responses to choline supplementation. This differential response in mouse strains highlights a need to further understand the role of genetics in choline metabolism. Because the liver is the central organ for choline metabolism, and the embryonic liver of mice is not functional this early in gestation, we focused on choline metabolism in the liver of the dam.

Methods

Using a bioinformatics approach, the goals were to assess whether (1) genetic differences in liver choline metabolism in the dam could affect ethanol-induced cell death in a genotype-specific manner and (2) any of these candidate genes in the liver of the dam could be linked to differential response to choline amongst the strains. By performing a literature review, haplotype analysis among the 4 BXD strains, and liver protein expression analysis among 3 strains, we show that there are genetic differences in choline metabolic genes that are consistent with the hypothesis that maternal choline metabolism could mediate differential sensitivity.

Results

While we identified two genes as promising candidates for the variable responses to choline supplementation among the four previously identified BXD strains choline/ethanolamine phosphotransferase 1 (cept1) and choline transporter gene solute carrier family 44 member 1 (slc44a1), the wealth of data on slc44a1 makes it the stronger candidate and suggests that it should be further explored.

Conclusions

Genetic differences in maternal choline metabolism are present and may underlie variable therapeutic responses to choline, warranting a hypothesis that requires further investigation across animal models and human populations.