Thesis

Effect of organochlorine pesticides on deregulation of cellular metabolism in mammary cells

Considerable evidence links cumulative and sustained exposure to estrogens to breast tumor proliferation. Chemicals with estrogenic activity can bind to the estrogen receptor (ER) to affect downstream signaling of estrogen-responsive genes. Organochlorines (OC) are a class of chemical pesticides that can act as xenoestrogens to disrupt normal endocrine function. Methoxychlor and Toxaphene are two OC pesticides that have been widely used in California. However, the complete molecular mechanisms that connect OC pesticide exposure and breast cancer are still unclear. Experiments show that some members of the orphan nuclear receptor Estrogen Related Receptor (ERR) family interact with the OC pesticides and hypoxia inducible factors to modulate mitochondrial stress response. Mitochondrial DNA transcription is altered by estrogenic and stress signals. The mTOR pathway integrates different cellular stress signals to regulate glucose metabolism, insulin signaling, apoptosis, and cellular detoxification, all processes controlled by the mitochondria. This project investigates how organochlorine pesticides may increase intracellular oxidative damage that changes mitochondrial energy use to favor a cancerous phenotype, and do those changes differ based on Estrogen Receptor (ER) status. To explore this problem I use ER+ and ER- cell lines to evaluate the expression of proteins, and their mRNA, involved in pesticide binding (ERR?, ERR?, and ERR?), oxidative stress (PGC-1?, HIF-1?, -1?, -2?), and mitochondrial function (mTOR, SIRT1, FOXO1).

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