Superfund Research Program
Elucidating Mechanisms of Heavy Metal-Induced Toxicity and Disease
Project Leader: Rebecca C. Fry
Grant Number: P42ES005948
Funding Period: 2011-2018
- Project Summary
Project Summary (2011-2018)
Cadmium is a toxic heavy metal of considerable environmental concern. It is ranked within the top 20 most toxic substances by the Agency for Toxic Substances and Disease Registry (ATSDR) and is a priority contaminant identified at more than one third of all Superfund Sites. In addition to diseases linked to adult exposure to cadmium, prenatal exposure has been associated with poor birth outcomes including low birth weight. Besides the immediate postnatal concerns, low birth weight is also associated with increased risk for chronic diseases later in life, such as diabetes, hypertension, and cardiovascular disease. While poor birth outcomes have been associated with environmental exposure to cadmium and other metals, the underlying biological mechanisms have not yet been identified.
Based on Dr. Swenberg’s preliminary findings and the research group’s interest in understanding how metal exposure influences pregnancy outcome in the United States, they are examining gene-environmental interactions that influence cadmium-induced signaling of the NF-κB pathway, and are determining the association of pathway modulation with birthweight. They hypothesize that maternal cadmium exposure alters the NF-κB signaling pathway in the newborn, that this modulation is associated with newborn birth weight, and that gene-environment interactions influence cadmium-induced modulation of the NF-κB signaling pathway. This study uses tightly linked in vitro and in vivo approaches to test the researchers’ hypothesis. The impact of fetal genotype of NF-κB on newborn birth weight and interaction effects between fetal genotypes and cadmium exposure is being determined. The modulation of the expression levels of the NF-κB pathway in newborns and association with maternal cadmium exposure is being determined. The role of DNA methylation in controlling the gene expression alterations is being established. To investigate further gene-environment interactions that influence cadmium-induced effects on NF-κB pathway signaling, the researchers are using a panel of cell lines derived from a genetically diverse human population to assess cellular responses to cadmium. These cell lines will establish in vitro links between inter-individual differences in NF-κB pathway/inflammation signaling upon exposure to cadmium.