Endocrine disrupting chemicals (EDCs) interfere with mammalian hormones, and can cause myriad adverse health effects, including developmental effects, neurological effects, reproductive effects, and cancer. One way that EDCs cause disease is by causing epigenomic modifications that change how genes are regulated in specific cells and tissues. It is often not feasible to sample brain tissue in humans, but other tissues lik blood and skin can be readily sampled. This raises the question of whether epigenomic profiles associated with EDC exposure in blood and skin are good surrogates for exposure in brain. The proposed research will test this directly using mice and mouse cells exposed to 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD, or dioxin). TCDD is an EDC that affects multiple tissue systems and has adverse neurodevelopmental effects. Mice will be exposed to TCDD during adolescence, a critical time for brain development. The project's objective is to understand how TCDD exposure alters epigenomic profiles in three specific brain regions (cortex, hypothalamus, and hippocampus), peripheral blood leukocytes, and skin. Comparing these samples will reveal robust epigenomic signatures of TCDD exposure. Importantly, the study will use the genetically diverse mouse Collaborative Cross reference population to better reflect human populations. Some individuals may be more susceptible to TCDD exposure than others, and this experimental design will capture that variation. In parallel, mouse primary cells will be exposed to TCDD in vitro to determine if cell-based systems can accurately reflect the epigenomic modifications seen in tissues. If so, cell-based systems will have many applications for research and for screening potentially hazardous chemicals. The results will be integrated with available public data sources to better understand how mouse epigenomic profiles can be used to predict TCDD effects in humans, and in other affected tissues in mouse and humans.

Public Health Relevance

Establishing how environmental chemical exposures may impact human health is extraordinarily difficult, particularly in inaccessible tissues like the bran. Moreover, existing strategies fail to account for genetic variability among individuals, and determining who is most susceptible remains a significant obstacle in the field. This study will measure the specific molecular effects of a highly toxic chemical, TCDD (dioxin), in a population of genetically diverse mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01ES026717-02
Application #
9277472
Study Section
Special Emphasis Panel (ZES1-LWJ-J (TG))
Program Officer
Tyson, Frederick L
Project Start
2016-06-01
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
$589,123
Indirect Cost
$130,476
Name
North Carolina State University Raleigh
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Venkatratnam, Abhishek; House, John S; Konganti, Kranti et al. (2018) Population-based dose-response analysis of liver transcriptional response to trichloroethylene in mouse. Mamm Genome 29:168-181
Wang, Ting; Pehrsson, Erica C; Purushotham, Deepak et al. (2018) The NIEHS TaRGET II Consortium and environmental epigenomics. Nat Biotechnol 36:225-227