자료유형  

 학위논문

Control Number  

0017164097

International Standard Book Number  

9798384098898

Dewey Decimal Classification Number  

613

Main Entry-Personal Name  

McLarnan, Sarah M.

Publication, Distribution, etc. (Imprint  

[S.l.] : Columbia University., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

231 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-03, Section: B.

General Note  

Advisor: Pearson, Brandon L.;Herbstman, Julie B.

Dissertation Note  

Thesis (Ph.D.)--Columbia University, 2024.

Summary, Etc.  

요약The prenatal period of development is uniquely susceptible to lasting harmful health effects from exposure to environmental toxicants. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants which have a wide variety of associated health effects, including impaired neurodevelopment when exposure occurs in-utero. While a handful of mechanisms have been implicated in PAH neurodevelopmental toxicity, none fully resolve the intricate biological processes that contribute to these outcomes. Mitochondria are increasingly being studied as sensitive targets of many environmental toxicants including PAHs. Despite the known mitochondrial sensitivity to PAHs, and the role of mitochondrial functions in neurodevelopment, little research has been done to evaluate mitochondrial dysfunction as mechanism of PAH neurodevelopmental toxicity.The work of this dissertation seeks to investigate a number of questions on this topic using a wide variety of techniques. We study exposure sources of individual PAHs, the relationship between prenatal PAH exposure constituents and mitochondrial functional outcomes and mitochondrial DNA copy number (mtDNAcn) in multiple biospecimens, including windows of exposure. We employ both epidemiological and experimental techniques, leveraging the advantages of one approach against the weakness of another to draw robust conclusions.Chapter 2 begins by comprehensively studying the demographic and behavioral variables predictive of personal PAH exposure. We combined a significant amount of personal exposure data collected using silicone wristbands with prenatal questionnaires to identify variables most predictive of both exposure to individual PAH compounds and total exposure. This work revealed complex relationships between multiple parameters in the prediction of each individual PAH. We found demographic and socioeconomic variables to be the most common predictors of exposure, followed by behavior variables. This work provides the foundation to identify pathways to reduce exposure and protecting the most vulnerable populations.In chapter 3, we describe two epidemiological studies conducted in Northern Manhattan birth cohorts. The first study uses data from the Columbia Center for Children's Environmental Health (CCCEH) Fair Start cohort. We measured mitochondrial DNA copy number (mtDNAcn) in umbilical cord tissue, a novel biospecimen with unique utility due to its ease of acquisition and homogenous cellular composition. We measured individual exposure to 63 PAH compounds using silicone wristband samplers and analyze this data using both individual models and quantile G computation to estimate the overall mixture effect. We identified three compounds associated with mtDNAcn in individual models, and a positive association between the mixture of 19 compounds and mtDNAcn.In the second study we expanded upon previous analyses in the CCCEH Mothers and Newborns cohort which had demonstrated an association between summed-total prenatal exposure to 8 carcinogenic PAHs and scores on the Bayley Scale of Infant Development-II at age 3. We used measures of mtDNAcn in umbilical cord blood to evaluate the role of mitochondrial toxicity in PAH neurodevelopment and improved upon prior studies by including adjustment for cell type composition. We utilized both traditional linear model approaches as well as quantile G computation to evaluate the mixture both as a sum-total and using newly developed mixture methods. We determined that while prenatal PAH exposure was negatively associated with umbilical cord blood mtDNAcn using mixtures methods mtDNAcn was not associated with neurodevelopment. The bidirectional effect of prenatal PAH exposure on mtDNAcn between these two studies reveals the complexity of mtDNAcn as a biomarker and the need for more direct measures of mitochondrial functions in the study of PAH neurodevelopmental toxicity.Chapter 4 seeks to complement the epidemiological research with an experimental system. Using mouse preimplantation embryos, we measured the effect of exposure to an environmentally relevant mixture of PAHs on morphological development, superoxide production, mitochondria membrane potential, and mtDNAcn. We found exposure to low levels of a PAH mixture from days 2.5-3.5 post fertilization caused a significant decrease in healthy embryo morphology and a reduction in mtDNAcn. PAH exposure increased mitochondrial membrane potential under several dosing regimens while the effect on superoxide levels was variable and potentially mediated by changes in mitochondrial mass. As a whole these results indicate mitochondrial dysfunction as a result of low-level PAH exposure during the earliest periods of development with a window of heightened susceptibility immediately prior to implantation.In chapter 5 we evaluate the relative mitochondrial potency of the 8 commonly studied carcinogenic PAHs and an environmental relevant mixture of those 8 compounds. Using human umbilical cord mesenchymal stem cells, we specifically study these effects in the context of prenatal development. Superoxide production, mitochondrial membrane potential, mitochondrial mass, cell death and mtDNAcn was quantified at 9 doses for each exposure. This data was used to fit dose response curves and determine relative potency of each exposure/outcome endpoint. We identified benzo[k]fluoranthene and chrysene among the most toxic compounds analyzed and noted differences between relative mitochondrial toxicity and carcinogenicity of these constituents emphasizing the need for continued research into the non-cancer endpoints of PAH exposure.With the intentional comparable exposures and outcomes utilized in these studies comes the opportunity to make connections and draw conclusions across chapters to arrive at four major conclusion: (1) Demographic variables, not behavior, are most predictive of exposure to many PAH compounds (2) prenatal PAH exposure affects multiple measures of mitochondrial functions, (3) there is variability in the susceptibility during early development, and (4) the developmental mitochondrial toxicity of previously studied PAH compounds does not follow the same patterns of relative potency seen in carcinogenesis. This work provides significant insight into the impact of prenatal PAH exposure on mitochondrial functions while highlighting critical areas for further research. More studies are needed to fully understand the mechanisms and long-term effects of PAH exposure on early development, as well as to identify effective interventions to mitigate these risks.

Subject Added Entry-Topical Term  

Environmental health.

Subject Added Entry-Topical Term  

Developmental biology.

Subject Added Entry-Topical Term  

Toxicology.

Subject Added Entry-Topical Term  

Neurosciences.

Subject Added Entry-Topical Term  

Health sciences.

Index Term-Uncontrolled  

Mitochondria

Index Term-Uncontrolled  

Neurodevelopment

Index Term-Uncontrolled  

Polycyclic aromatic hydrocarbons

Index Term-Uncontrolled  

Neurodevelopmental toxicity

Index Term-Uncontrolled  

Mitochondrial DNA copy number

Added Entry-Corporate Name  

Columbia University Environmental Health Sciences

Host Item Entry  

Dissertations Abstracts International. 86-03B.

Electronic Location and Access  

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Control Number  

joongbu:657534