Does exposure to mitochondrial toxicants during germ cell development result in lifelong alterations in mitochondrial function mediated by epigenetic changes?

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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).