Semester

Fall

Date of Graduation

2021

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Exercise Physiology

Committee Chair

John Hollander

Committee Member

Paul Chantler

Committee Member

Roberta Leonardi

Committee Member

Timothy Nurkiewicz

Committee Member

I. Mark Olfert

Abstract

Introduction: Nano-titanium dioxide (TiO2), a prominently utilized engineered nanomaterial (ENM), is being employed for its physiochemical properties in several fields including the food industry, manufacturing, and biomedicine. As the prevalence of this ENM, and other particulate matter grows, so does the concern for antagonistic consequences on long-term heart function in vulnerable populations, which until now have not been investigated. Due to the reliance of the heart on the ATP generating capacity of mitochondria for contraction, understanding the role of mitochondrial bioenergetics and structure is pivotal in understanding the repercussions of particulate matter exposure during gestation. As the mass population in cities, where particulate matter exposure is highest, do not have many options for mitigating their exposure, it is of utmost importance that strategies are developed that limit the detriments associated with xenobiotic exposure. Understanding the mechanisms, both epigenetic and epitranscriptomic, that regulate mitochondrial and cardiac function under these circumstances will allow for a better understanding of potential therapeutic or preventative strategies and mitigate the disease burden related to particulate matter exposure each year. The purpose of this compilation of work is to identify the mechanisms contributing to the acute and chronic pathological effects of ENM inhalation exposure during gestation as a prerequisite to developing strategies to reduce risks to public health.

Methods and Results: Using an inhalation exposure paradigm that mimics the lung burden seen in an occupational setting, we first examined the effects of maternal nano-TiO2 inhalation exposure during gestation on the cardiac function of wild type offspring at the fetal (acute) and adult (chronic) stage using both conventional and speckle tracking stress-strain echocardiographic assessments. Cardiac contractile function was decreased in both the fetal (gestational day 15 (GD 15)) and the adult (11 weeks) offspring. Assessment of mitochondrial bioenergetic and electron transport chain (ETC) complex activities revealed a decreased oxygen consumption rate in offspring and decreased ETC Complex IV at both the fetal and adult stage following maternal ENM inhalation exposure during gestation. Furthermore ELISA-based assessment of 5-methylcytosine (5mC methylation) and Dnmt expression pointed to the involvement of epigenetic mechanisms in altered mitochondrial and cardiac function. Implementation of a novel breeding strategy, using a transgenic mouse model that overexpresses mitochondrial phospholipid hydroperoxide glutathione peroxidase (mPHGPx), an antioxidant enzyme, determined that enhanced antioxidant expression in the maternal environment can mitigate the effects of gestational nano-TiO2 inhalation exposure on fetal and adult offspring cardiac and mitochondrial function. N6-methyladenosine (m6A) was implicated as a modulator of altered mPHGPx activity following maternal ENM exposure in adult offspring, suggesting that epitranscriptomics also has a regulatory role in the adverse effects of particulate matter exposure.

Conclusions: The work presented in this presentation demonstrates the ability for ENM inhalation exposure during gestation to alter cardiac function through a mechanism that involves altering mitochondrial function and elevating ROS levels. These studies also provide evidence that there is likely overlap and interplay between epitranscriptomic and epigenetic mechanisms that contribute to changes in the mitochondrial proteome that reduces the ability of the mitochondrion to regulate stress in the form of ROS and leads to dysfunction. Limiting ROS levels through mitochondrially-targeted antioxidant defense enhancement provides a potential preventative route that may allow for the evasion of the adverse cardiac outcomes in offspring that are gestationally exposed to xenobiotics.

Download

Share

COinS