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Persistent Effects of Polycyclic Aromatic Hydrocarbon Exposure Across Generations: a Bioenergetic and Mitochondrial Perspective

dc.contributor.advisor Di Giulio, Richard T. Kozal, Jordan Sierra 2018-05-31T21:14:42Z 2020-04-26T08:17:10Z 2018
dc.description.abstract <p>Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BaP) are ubiquitous environmental contaminants. PAHs are toxicologically important for both humans and wildlife in large part due to their mutagenic, carcinogenic, and teratogenic properties. While the effects of adult and developmental exposures to PAHs are relatively well characterized, the potential for PAHs to have effects across generations is an emerging concern in the field of environmental health. In epidemiological studies, prenatal exposure to PAHs is associated with adverse birth outcomes as well as later life metabolic, neurological, and reproductive disorders— which have become global human health epidemics. These findings have been validated in animal models, with reduced survivorship, increased morphological deformities, and alterations in behavior, physiology, and disease risk in multiple subsequent generations. However, the mechanisms underlying the multigenerational effects of PAHs are poorly understood. This dissertation focuses on mitochondrial contributions to the maternal and cross-generational toxicity of PAHs. </p><p>Mitochondria are essential to the development, health, survival, and reproduction of all aerobic organisms. The importance of maintaining mitochondrial function for health is supported by the prevalence of mitochondrial diseases, which clinically manifest in at least 1 in 4,300 people. Mitochondrial diseases often present with metabolic, neurological, and reproductive consequences, similar to those associated with prenatal PAH exposures. Mitochondrial DNA (mtDNA) is maternally inherited and undergoes bottlenecks (i.e. reductions in mtDNA copy number per cell) during oogenesis and early embryonic development, creating potential for maternal and cross-generational inheritance of mitochondrial diseases. Inheritance of mitochondrial dysfunction across generations has been established for genetic, pharmacological, and dietary etiologies. Notably, mitochondria are important targets of environmental contaminants such as PAHs, which affect bioenergetics at multiple levels of biological organization. However, the potential for environmental toxicant-induced mitochondrial dysfunction to have persistent effects across multiple generations is still largely uncharacterized. This is the knowledge gap we address in this dissertation.</p><p>To this end, we evaluate the persistent bioenergetic effects of BaP – a model PAH and known mitochondrial toxicant – in F1 (maternally exposed) and F2 (cross-generationally exposed or germline exposed) generations following a chronic maternal (F0) dietary exposure using the model teleost Danio rerio. Maternally exposed F1 embryos exhibit reduced mitochondrial DNA integrity, reduced mitochondrial function and efficiency, and impaired antioxidant defense systems during development, largely in the absence of effects in exposed F0 females. Metabolic shifts during development create potential for disease pathologies and reduced organismal fitness later in life. In F1 adults, mitochondrial dysfunction presents in cardiac tissue with reductions in mitochondrial reserve capacity. Cardiac function and plasticity are key determinants of fitness in the environment, and impaired function confers disease risk in humans. Maternally BaP exposed F1 fish also exhibit altered locomotor activity throughout life and reduced fear/anxiety behaviors as adults. </p><p>PAH-induced changes in mitochondrial function and metabolic plasticity persist in the F2 embryos, two generations removed from the original BaP exposure, suggesting cross-generational reductions in fitness may follow a single exposure event. Metabolic consequences occur in F2 embryos at F0 exposure levels that do not cause significant dysfunction in the F1 generation, with important implications for evaluating the risk associated with the persistent effects of pollution (e.g. lasting impacts of oil spill events) in the environment.</p><p>The ability to adjust metabolism is crucial for organisms to effectively respond to a variety of natural and anthropogenic stressors, suggesting that organisms with alterations in fundamental bioenergetic processes may be more sensitive to secondary stressors. Herein we demonstrate that F2 organisms with a cross-generational history of exposure exhibit altered metabolic response to thermal stress, reduced thermal tolerance, and fitness tradeoffs. Cross-generational exposure to BaP potentiates metabolic effects under thermal stress even in the absence of effects at baseline temperature. Taken together, these data suggest that exposure to PAHs such as BaP affects mitochondrial function, organismal physiology, behavior, and secondary stress response capacity across generations, creating potential for downstream population and ecosystem level effects.</p>
dc.subject Toxicology
dc.subject Environmental health
dc.subject Environmental science
dc.subject benzo(a)pyrene
dc.subject metabolic plasticity
dc.subject mitochondria
dc.subject multigenerational
dc.subject polycyclic aromatic hydrocarbon
dc.subject secondary stressors
dc.title Persistent Effects of Polycyclic Aromatic Hydrocarbon Exposure Across Generations: a Bioenergetic and Mitochondrial Perspective
dc.type Dissertation
dc.department Environment
duke.embargo.months 23

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