Project Summary (2017-2022)

The Duke University Superfund Research Program (SRP) Center examines the problem of early life exposure to hazardous chemicals and later life consequences. Growing evidence suggests that the toxic effects of certain chemicals on mitochondrial function can be highly persistent, and that some individuals may be more sensitive due to genetic differences. Mitochondria undergo biogenesis and major functional changes during early development and cellular differentiation, periods during which epigenetic reprogramming also occurs.

The Duke SRP Center researchers are testing the hypothesis that mitochondrial toxicity during vulnerable, plastic windows of mitochondrial and epigenetic programming results in persistent mitochondrial dysfunction, persistent changes in epigenetic patterning, and that these changes are mechanistically linked. The researchers assess the persistence of both mitochondrial and epigenetic changes throughout life, and through three subsequent generations, to test whether effects are persistent even in the absence of direct chemical exposure. The researchers acknowledge and will test the possibility that persistent mitochondrial effects are not mediated by epigenetic changes, and that epigenetic changes may occur but not have effects on mitochondrial function. Finally, they also test the hypothesis that existing mitochondrial dysfunction will be exacerbated in organisms with genetic backgrounds selected for relevance to human mitochondrial disease, in which mitochondrial homeostatic processes are reduced.

Innovative aspects of this project include:

1. Examination of epigenetic and transcriptional changes linked to mitochondrial disruption during potentially sensitive windows of time early in development and during cellular differentiation;
2. Analysis of less-studied histone modifications in conjunction with better-studied cytosine methylation;
3. Systematic examination of the effects of deficiencies in genetic pathways that modulate mitochondrial toxicity; and
4. Development of high-throughput, rapid, in vivo, and in vitro systems for testing persistent and transgenerational effects.