Author ORCID Identifier

https://orcid.org/0000-0002-3863-2172

Semester

Spring

Date of Graduation

2023

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Salik Hussain

Committee Co-Chair

Stanley Hileman

Committee Member

Timothy Nurkiewicz

Committee Member

Eric Kelley

Committee Member

Jonathan Boyd

Abstract

Nano-titanium dioxide (nano-TiO2) is an engineered nanomaterial (ENM), which is widely utilized in diverse products like surface coatings, cosmetics, medical devices, and filters. Inhaled nano-TiO2 has been demonstrated to induce pulmonary inflammation, impair microvascular function, and hinder generational reproductive endpoints. These outcomes indicate why it is important to explore gestation, as it requires timely vascular adaptations to support maternal and fetal health and development. Therefore, the central hypothesis of my dissertation is: maternal nano-TiO2 inhalation exposure will impact maternal microvascular function and fetoplacental hemodynamics and function in a sexually dimorphic manner.

The first purpose of this dissertation was to determine uterine microcirculatory vasoactive responses to cyclooxygenase metabolites prostacyclin (PGI2) and thromboxane (TXA2) after nano-TiO2 inhalation exposure. This aim was carried out across the first and second studies, where vasoactive responses to PGI2 and TXA2 in virgin and pregnant dam uterine radial arterioles were assessed. Nano-TiO2 exposed virgin uterine radial arterioles had a significant decrease in TXA2 induced vasoconstriction at the highest dose compared to sham-controls (-0.337 ± 0.176% vs -3.057 ± 0.600%). However, the pregnant nano-TiO2 exposed uterine radial arterioles had a significantly increased vasoconstriction to the TXA2 mimetic, U46619, compared to sham-control (-41.3 ± 4.3% vs -16.8 ± 3.4%). Maternal nano-TiO2 inhalation exposure decreased nano-TiO2 fetal female pup mass compared to nano-TiO2 fetal males (3.633 ± 0.064 g vs 3.998 ± 0.089 g). Augmented vasoconstriction may lead to decreased placental blood flow and thus compromise maternofetal nutrient-waste exchange.

The second purpose of this dissertation was to assess the impacts of maternal nano-TiO2 inhalation exposure on sexually dimorphic fetoplacental outcomes. This was assessed across the third and fourth studies. Fetoplacental outcomes were assessed via fetal mass, placental mass, placental structural modifications, placental hemodynamics, and fetoplacental redox state. Placental outflow pressure in the presence of the TXA2 mimetic, U46619, was significantly decreased in the nano-TiO2 exposed fetal females compared to sham-control fetal females (3.97 ± 1.30 mm Hg vs 9.10 ± 1.07 mm Hg). The exposed female fetoplacental unit was impacted the most by maternal nano-TiO2 inhalation exposure. The nano-TiO2 exposed female labyrinth zone (LZ) had significantly increased production of TXB2, the stable TXA2 metabolite, compared to exposed male LZ (1186.48 ± 189.92 pg/mg vs 598.39 ± 135.69 pg/mg). Maternal nano-TiO2 inhalation exposure has a greater effect on fetal female pup mass, placental zone mass and area, decreased placental vasoreactivity, and impacts on redox homeostasis and PGI2/TXA2 balance. Overall, the modifications seen in the maternal uterine radial arterioles and within the female placentas are potential adaptations that occur to ensure survival throughout gestation. These adaptations could have lasting impacts on females later in life and cause diseases into adulthood.

Embargo Reason

Publication Pending

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