Nutritional modulation of fetal susceptibility to iAs-associated gene expression underlying oxidative stress and inflammation in cord blood

Abstract

BACKGROUND AND AIM: iAs contamination of drinking water has been identified in 70 countries at levels exceeding the World Health Organization limit of 10 ppb. The fetus is particularly vulnerable to exposure due to dynamic changes in gene expression that must be tightly regulated to promote fetal growth. iAs crosses the placental barrier and is associated with lower birth weight and transcriptomic alterations underlying oxidative stress, inflammation, and other growth-related signaling pathways in fetal cells. Fortunately, iAs metabolism is influenced by modifiable factors that may also protect the developing fetus. Specifically, as part of metabolism, iAs is sequentially methylated in a process facilitated by the one-carbon metabolism (OCM) pathway, with incomplete methylation (e.g., higher %MMAs) a risk factor for iAs-related health outcomes including lower birth weight. Among adults, OCM factors (e.g., folate, B12, homocysteine) influence iAs metabolism and the risk of iAs-associated diseases. METHODS: We explore maternal serum concentrations of OCM factors as modifiers of iAs-associated changes in gene expression in cord blood using data from the Biomarkers of Exposure to ARsenic (BEAR) cohort (overall N=200; subcohort N=38). Genome-wide expression levels were quantified using microarray technology. Drinking water, maternal urine, and infant cord serum arsenicals were previously measured using HG-AAS and ICP-MS. RESULTS:To test our hypothesis, genes underlying oxidative stress and inflammation will be selected a priori and evaluated in relation to iAs exposure using linear regression modeling. Genes differentially expressed (p 0.05) in relation to iAs exposure will be evaluated further for effect measure modification. Specifically, effect measure modification on the additive scale will be assessed using a likelihood ratio test (LRT) of nested linear regression models (e.g., model0=interaction, model1=main effects). CONCLUSIONS:Given widespread contamination of drinking water by iAs, the work has global implications and could present maternal diet as a preventative intervention for fetal susceptibility to iAs-associated decreases in birth weight. KEYWORDS: arsenic, gene expression, birth weight, intervention