Superfund Research Program

Genetic Susceptibility to Superfund Chemicals

Project Leader: Martyn T. Smith
Co-Investigator: Luoping Zhang
Grant Number: P42ES004705
Funding Period: 2006-2017

Project-Specific Links

Final Progress Reports

Year:   2016  2010 

People clearly differ in their susceptibility to the toxic effects of Superfund chemicals, and a genetic (familial) component is strongly suspected.

Overall goals
The aim of this project is to identify genes that confer susceptibility to Superfund chemicals through the use of a simple yeast model system that allows rapid identification of these genes. Further studies are then done to confirm the genes in both human cells in a petri dish and eventually in human populations. The investigators are studying Superfund-related chemicals including benzene, arsenic, trichloroethylene (TCE), and flame retardants. An increased understanding of the genetic variability in response to these toxicants will enable more accurate risk assessments for sites contaminated with these compounds.

Important discoveries so far
To date, the investigators have been able to examine thousands of genes in yeast cells for their importance in an individual’s vulnerability to toxic chemicals at Superfund sites, including various metals, arsenic compounds, and benzene and its metabolites. They have discovered several key genes (including NF1, SRXN1, PRDX1) associated with the response to oxidative stress following exposures to benzene and its metabolites. Benzene is an established cause of leukemia and other blood disorders, and oxidative DNA damage may be a potential mechanism to cause the disease.

They also found that yeast deletion mutants lacking the gene MTQ2 were highly resistant to arsenic exposure. The human equivalent of yeast MTQ2 is N-6 adenine-specific DNA methyltransferase 1 (N6AMT1). Enhanced expression of N6AMT1 in human bladder cells significantly increased their resistance to the toxicity of arsenic and its metabolites, and N6AMT1 was shown to methylate arsenic to a non-toxic metabolite. The newly discovered protein N6AMT1 could play a role in susceptibility to arsenic toxicity and carcinogenicity.

Highlight for last year
The most important thing the investigators discovered over the last year was that a recently discovered protein called N6AMT1 can metabolize arsenic compounds and lower toxicity. This is a novel finding. A paper on this is in press at Environmental Health Perspectives.

What the investigators plan to do next
The investigators will extend the studies with the yeast method to several persistent bio-accumulative halogenated toxicants of emerging concern at Superfund sites. Further, they will apply a novel and complementary human cell screening approach to identify additional candidate human susceptibility genes. Together, these studies will provide a comprehensive high-throughput approach to identify important genes and cellular processes involved in susceptibility to Superfund chemicals.