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<p>Early life exposure to mitochondrial toxicants, including paraquat, rotenone, and
manganese, has been hypothesized to promote early onset of genetic mitochondrial disorders
as well as common degenerative diseases such as Parkinson's Disease and Alzheimer's
Disease. This dissertation aimed to investigate the biochemical and physiological
effects of early life exposure to mitochondrial genotoxicants during development in
the whole organism model<i>C. elegans</i>. In the first experiment, a panel of model
mammalian neurotoxicants and heavy metal ions was screened for mitochondrial genotoxicity
by measuring mitochondrial DNA (mtDNA) copy number and damage in <i>C. elegans</i>.
Exposures to paraquat, cumene hydroperoxide, rotenone, maneb, cadmium (II) chloride,
and manganese (II) chloride have no significant effect on the mtDNA : nuclear DNA
(nuDNA) ratio; only exposure to paraquat resulted in higher mtDNA than nuDNA damage
level.In the second experiment, a laboratory method was developed to generate persistent
mtDNA damage in larval <i>C. elegans</i> using serial ultraviolent C (UVC) exposures.
While the mitochondrial DNA damage persisted from L1 to L4 stage, there was no difference
between mitochondrial copy number of the control and UVC treated worms. The UVC treatment
significantly inhibited both ATP level and oxygen consumption 24 and 48 hr after the
exposure, while the mitochondrial mRNA expression was inhibited 3 hr after the exposure.
The <i>pink-1</i> mutation, a mitochondrial serine/threonine-protein kinase involved
in the mitophagy process, appeared to limit the growth inhibitory effect of UVC treatment
and increase the mitochondrial DNA content of the organism. In the third experiment,larval
<i>C. elegans</i> was exposed to UVC and paraquat and examined using differential
interference contrast and fluorescence confocal microscopy. Both resulted in detectable,
dose-dependent lesions in dopaminergic CEP neurons in adult <i>C. elegans</i>. Neither
significant lesions in the GABAergic dorsal nerve cord nor any sign of pharyngeal
necrosis were detected. This work demonstrated a mechanism in which early life exposure
to mitochondrial genotoxicants could result in both biochemical and physiological
changes in later stages of life, thereby highlighting the potential health hazard
of time-delayed effects of these chemicals in the environment.</p>
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