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ARRA Investments in Environmental Exposures Impacting Epigenetics and Mutagenesis


Public Health Burden
Numerous chemical and physical environmental agents affect living systems by altering DNA sequences or by changing how specific genes are expressed. DNA contains instructions for synthesizing proteins and other biological molecules (e.g., RNA) that allow cells to maintain basic functions of life and to respond to external stressors.  Epigenetic processes are a system of controls that are literally superimposed on top of the DNA sequence and direct the turning on and turning off or transcription of DNA sequences.  Cells have special processes to respond to external stress by removing damaged DNA or by altering the number and type of genes that are expressed or transcribed (i.e., allowed to make proteins).  By studying how cells respond and adapt to the environment, investigators can track the process of diseases linked to environmental pollutants, including but not limited to cancer, cardiovascular diseases, autoimmune and respiratory diseases.

Translational research
  • Detailed knowledge of how cells process damage to DNA is critical to understand how organisms maintain genomic stability under constant stress from environmental and internal damaging agents. An ARRA-supported  project is investigating how cellular processes involved in the response to damaged DNA (specialized DNA polymerases) can be manipulated to make tumor cells responsive to chemotherapeutic drugs, particularly in secondary tumors.1
  • Environmental and industrial pollutants, including 1,3 butadiene, damage DNA and cause errors in DNA sequence (mutations) that can lead to cancer in exposed organisms. Scientists will develop a new screening method to rapidly identify mutations in experimental animals and in human populations that will ultimately enable researchers to track the effects of environmental pollutants, like air pollution, on the number and types of mutations that increase risk for numerous diseases, including cancer.2
Basic Science
 
  • Collaborating researchers will investigate the link between maternal exposure to arsenic in drinking water and epigenetic alterations in the placenta that lead to premature birth and underdevelopment.3
  • Researchers will investigate how metals interact with environmental agents such as ultraviolet light and other toxic organic molecules to trigger epigenetic changes that silence tumor suppressor genes and cause cancer.4
  • In addition to single changes in DNA sequence, cells can acquire copy number variations (CNVs), which are large regions of DNA that are copied inappropriately or deleted. CNVs are related to numerous diseases including autism, schizophrenia, epilepsy and cleft palate. Researchers will study how environmental agents may cause CNVs; this will ultimately help in the prevention of environmentally-related diseases.5
  • Low doses of ionizing radiation (such as ultraviolet light) from environmental or man-made sources damage DNA and causes mutations. However, new research has identified additional mechanisms of mutagenesis by radiation, including effects of oxidative damage on the cytoplasm and on mitochondria of cells, the structures responsible for providing the cell with energy. By understanding the mechanism of radiation-induced damage, researchers can identify limits for exposure to radiation that will protect human health.6
  • Altered DNA methylation is a trait of altered epigenetic processes and gene inactivation or silencing. Scientists will use data that links exposure to organophosphate pesticides (OPs), the most commonly used insecticides in the US, to an increase of promoter methylation in several tumor suppressor genes in blood DNA. This project will study whether OP exposure alters gene promoter DNA methylation patterns in humans and in OP-treated cell lines, addressing a critical gap in our knowledge of pesticides and how pesticide exposures may cause cancer.7
  • Researchers are studying the link between one’s DNA methylation levels and environmental factors known to predict chronic disease occurrence. The methylation levels will be compared in twins who have a history of pertinent environmental exposure (such as smoking, alcohol usage, obesity, consumption of folic acid) with relatively unexposed identical co-twins.8
  • The widespread prevalence of persistent organic pollutants such as polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in the environment and their detection in human milk has prompted concern about in utero and early infant exposure to these compounds. Exposure to PCBs and PBDEs in newborn rats results in long-lasting defects in learning, memory, behavior, and seizure susceptibility in adulthood. Human blood and post-mortem brain samples from individuals with autism, mental retardation, and controls will be tested for precise epigenetic changes in three neurodevelopmentally important genes.9
  • Researchers are using cells from largemouth bass and yeast to identify DNA mutations and other changes at the molecular level caused by exposures to pesticides, solvents, and metals.  This research will reveal likely toxicity pathways and identify human susceptibility.10



  1. 3R01ES015818-03S1 -- Mechanism of Eukaryotic Environmental Mutagenesis -- Walker, Graham C (MA)
  2. 3R01ES012689-05S1 -- Adducts as Quantitative Markers of Butadiene Mutagenesis -- Swenberg, James A (NC)
  3. 5P42ES013660-05--Cohortstudy--pregnancyoutcomesforenvironmentallyrelevantexposuresBoekelheideKim(RI)
    5P42ES007373-15--Cohortstudy--pregnancyoutcomesforenvironmentallyrelevantexposuresStantonBruce(NH)
  4. 2P42ES010344-06A2 -- Carcinogenic Metals and Their Interactions With Other Toxicants, Costa, Max (NY)
  5. 1RC1ES018672-01 -- Environmental Risk Factors for Copy Number Variation in Human Chromosomes -- Glover, Thomas W (MI)
  6. 3R01ES012888-05S1 -- Cytoplasmic Damage and Genotoxicity -- Hei, Tom K (NY)
  7. 1RC1ES018461-01 -- DNA methylation alterations in response to pesticides exposure -- Hou, Lifang (IL)
  8. 3R01ES015150-04S1 - DNA methylation differences between identical twins -- Mack, Thomas M (CA)
  9. 3R01ES015171-04S1 - Epigenetic Interaction of MECP2 and Organic Pollutants in Neurodevelopment -- LaSalle, Janine M (CA)
  10. 5R01ES015449-03, -CombiningGenomicDatafromModelOrganismstoProvideInsightintoMOADenslowNancy(FL)
    5P42ES004705-22
    -- Combining Genomic Data from Model Organisms to Provide Insight into MOA, Smith, Martyn (CA)


 
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