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Speaker Explores Gene-Environment Interactions

By Dixie-Ann Sawin
October 2009

Leikauf speaking to the audience.
Leikauf told the audience that the field is "ripe" with associations that link both genetics and environmental factors to the lung's response to hazardous chemicals. (Photo courtesy of Steve McCaw)

Pat Mastin, Ph.D. [Right], and Caroline Dilworth, Ph.D.
NIEHS Acting Deputy Director of DERT Pat Mastin, Ph.D., right, was one of several people from throughout the Institute who had questions for Leikauf. Seated beside Mastin was Caroline Dilworth, Ph.D., center, a health science administrator with DERT. (Photo courtesy of Steve McCaw)

Leikauf responding to a question from NIEHS Deputy Scientific Director Bill Schrader, Ph.D.
Leikauf responded to a question from NIEHS Deputy Scientific Director Bill Schrader, Ph.D., as host Sri Nadadur, right, looks on. In addition to Schrader and Mastin, NIEHS leadership at the meeting included NIEHS Acting Deputy Director Steve Kleeberger, Ph.D. (Photo courtesy of Steve McCaw)

On September 17, Professor George Leikauf, Ph.D., of the University of Pittsburgh, presented the first in a series of talks in the Keystone Seminar Series hosted by the Division of Extramural Research and Training (DERT). Hosted by Health Science Administrators Sri Nadadur, Ph.D., and Liz Maull, Ph.D., Leikauf's lecture, "Gene-Environment Interactions: Utility and Uncertainty," surveyed his recent research supported by a five-year grant from the NIEHS under the NIH Countermeasures Against Chemical Threats (CounterACT) Research Network for "Functional Genomics of Chemical-Induced Acute Lung Injury." (http://tools.niehs.nih.gov/portfolio/sc/detail.cfm?appl_id=7662563)

Leikauf is searching for more effective ways to treat survivors of a possible terrorist act involving chemical agents. With a widely applicable, survival-based approach, he is assessing the effects of chemical-induced acute lung injury (CIALI) on gene pathways. CIALI has a complex etiology and a poor prognosis. Current therapies are by and large palliative and of limited efficacy.

Leikauf hopes to identify genetic determinants and molecular mechanisms involved in CIALI from exposure to five leading hazardous chemicals - chlorine, phosgene, sulfuric acid, ammonia and acrolein. He also plans to develop a preliminary chemical-specific database based on the selective signatures of these chemicals.

He began his talk with a broad overview of genes and environment interactions and the impact of these parameters on human variability. When considering any human population, Leikauf noted that there is always concern about the uncertainty factor incorporated into any risk assessment to account for inter-individual variability, including age, weight, sex, physical condition, medications, nutrition, and last but not least, genetic heritability and environmental factors.

Genetic heritability and environmental factors should be seen as two interacting components that result in a specific event, Leikauf insisted. As an example, he pointed to mortality trends that relate to solely genetic diseases compared to complex diseases. From the global perspective, purely genetic diseases account for approximately 5000 deaths per year, while almost 1.5 million deaths per year are caused by complex diseases, such as heart disease, cancer and cardiovascular diseases.

There is an environmental component to most "genetic" diseases, Leikauf maintained, and a genetic component involved in most "environmental" disease. "There isn't any barrier to environmental health," he said.

The question then becomes, how can one apply gene and environmental interactions to daily situations? Understanding how genetic pathways are altered in response to environmental toxicants may improve genetic risk assessment. Nonetheless, there are caveats. For instance, there is no one enzyme that metabolizes a single chemical, and there is an "array of genetic variation" among the population that cumulatively contributes to the variability in the risk assessment.

Two of the chemicals that Leikauf addressed in his talk are acrolein and chlorine. Acrolein is a 3-carbon aldehyde formed during combustion and is an irritant even at doses as low as 0.06 ppm. Leikauf has developed a mouse model for studying acrolein exposure that exhibits increased levels of pro-inflammatory cytokines, such as IL-6 and TNFα, and decreased neutrophil infiltration.

His approach includes genome-wide and single-nucleotide polymorphism analyses to identify candidate genes and biochemical pathways. For acrolein, he identified several possible candidates and concluded that acrolein exposure is not associated with changes at the transcriptional level, but instead affects protein function. For chlorine, he found associations with a different complex of genes, but these can be viewed as members of the same pathway.

Leikauf's overall aim is to combine the data from acrolein and chlorine, ultimately including the three other chemicals that he plans to test, and scrutinize for proteins of interest involved in common, exposure-related cell survival pathways - leading to the development of new and improved "medical countermeasures" to quickly and effectively treat conditions caused by the chemical agents of terrorism or accidents due to natural disasters and transportation, leakage or storage of these chemicals.

(Dixie-Ann Sawin, Ph.D., is a post-doctoral research fellow in the NIEHS Laboratory of Neurobiology Neurotoxicology Group on detail as a writer for the Environmental Factor.)



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