EXPOSURE TO CIGARETTE SMOKE AND ITS IMPACT ON THE OVARIAN FOLLICLE POPULATION: MECHANISMS OF FOLLICLE LOSS

Abstract

<p>Cigarette smoking is a lifestyle behaviour associated with adverse reproductive health effects including premature exhaustion of the follicle population and premature menopause; however, the mechanisms mediating its effects on follicle loss are largely unexplored. Therefore, this thesis was undertaken to examine the effect of cigarette smoke (CS), at concentrations representative of human exposure, on follicle loss in mouse ovaries and determine the underlying mechanisms mediating their loss. CS contains over 4,000 chemicals, many of which result in reactive oxygen species (ROS) generation, which can cause cell death. In the first study, we hypothesized that follicles exposed to CS would be lost via apoptosis in a selective stage-dependent manner. Although apoptosis is a cell death pathway through which follicles are thought to die, the studies herein found no changes in apoptosis, despite increased follicle loss. Given these findings, we hypothesized that an alternative cell death mechanism was responsible. At the time, the relevance of autophagy, a novel ovarian cell death pathway, to granulosa cell death and toxicant-induced changes in ovarian function were unknown. We further demonstrated increased oxidative stress, decreased antioxidant expression, and autophagy in treated ovaries. Finally, we tested the hypothesis that CS exposure results in dysregulation of mitochondrial repair mechanisms, leading to follicle loss via autophagy-mediated granulosa cell death. We demonstrated that CS exposure activates autophagy and alters mitochondrial dynamics. Taken together, these studies provide evidence that CS causes significant follicle loss, decreases the cell’s ability to cope with ROS disrupting mitochondrial repair mechanisms, leading to autophagy-mediated follicle loss.</p>