Growing evidence suggests that the toxic effects of certain chemicals on mitochondrial function can be highly persistent. This is critical because mitochondrial function influences organismal phenotypes related to chronic diseases such as metabolic diseases, cancers, neurodegenerative diseases, and reproductive disorders. Therefore, exposures affecting mitochondria could contribute to these conditions. The likelihood of persistent effects may be especially great for exposures of germ cells and gametes, because mitochondria undergo biogenesis and major functional changes during germline proliferation and gamete production. Furthermore, epigenetic patterns that can have long-term effects on cellular function are reprogrammed in the same time frame. We will test the hypothesis that pollutant exposures targeting mitochondria in germ cells result in persistent epigenetic changes that escape embryonic reprogramming and alter regulation of pathways governing mitochondrial metabolism in offspring. We will test six important mitochondrial toxicants: arsenic, rotenone, methyl mercury, pyraclostrobin, chlorfenapyr, and the organophosphate flame retardant triphenyl phosphate. We will also test whether dietary restriction, which improves mitochondrial function, and caloric overload, which has the opposite effect, will alter these outcomes. If so, this would both reinforce our mechanistic understanding of the toxic effects of these chemicals, and provide a possible therapeutic approach. This work will be carried out in the nematode Caenorhabditis elegans to take advantage of very well-developed mitochondrial and epigenetic genetic tools, a rapid lifespan, and, most critically, the availability of genetic and other tools that will allow us to mechanistically test the causality of observed epigenetic and transcriptomic changes. Ultimately, this knowledge will improve our ability to reduce the deleterious mitochondrial impacts of preconception exposures both by prevention (i.e., reduced exposures) and treatment (i.e., pharmacological and lifestyle interventions to alter mitochondrial function).

Public Health Relevance

Altered mitochondrial function is implicated in a wide range of chronic diseases, including metabolic diseases, cancers, neurodegenerative diseases, and reproductive disorders. We will test whether exposure to environmental chemicals that target mitochondria, prior to conception, will lead to altered mitochondrial function in offspring. We will also test the mechanisms by which preconception exposures alter the health of offspring.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES028218-03
Application #
9762106
Study Section
Special Emphasis Panel (ZES1)
Program Officer
Schug, Thaddeus
Project Start
2017-09-15
Project End
2022-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Earth Sciences/Resources
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Weinhouse, Caren; Truong, Lisa; Meyer, Joel N et al. (2018) Caenorhabditis elegans as an emerging model system in environmental epigenetics. Environ Mol Mutagen 59:560-575
Sanders, Laurie H; Rouanet, Jeremy P; Howlett, Evan H et al. (2018) Newly Revised Quantitative PCR-Based Assay for Mitochondrial and Nuclear DNA Damage. Curr Protoc Toxicol 76:e50
Meyer, Joel N; Hartman, Jessica H; Mello, Danielle F (2018) Mitochondrial Toxicity. Toxicol Sci 162:15-23
Hartman, Jessica H; Smith, Latasha L; Gordon, Kacy L et al. (2018) Swimming Exercise and Transient Food Deprivation in Caenorhabditis elegans Promote Mitochondrial Maintenance and Protect Against Chemical-Induced Mitotoxicity. Sci Rep 8:8359