Wednesday, April 24, 2024
4/24/2024
¿ DESCRIPTION (provided by applicant): Maternal homeostasis and the fetal milieu are highly susceptible to a variety of external or environmental exposures during gestation (e.g. malnutrition, toxicant exposure). Any dysfunction within the coordinated exchange of nutrients and waste during gestation could create a hostile gestational environment (HGE), leading to devastating fetal consequences. It has been hypothesized that fetal development within a HGE could be an underappreciated etiology for adult disease and/or sensitivity. Mitochondrial inefficiency has been theorized as one mechanistic link between development within a HGE and the development of adult disease. The continued development of engineered nanomaterials (ENM) (<100 nm in one dimension) coupled with their increasing use in biomedical and commercial products have given rise to concerns over potential exposure and resulting human health effects. Recent evidence from this laboratory suggests that inhalation of titanium dioxide nanoparticles (TiO2) by pregnant rats can lead to the development of a HGE, impairing maternal and fetal microvascular function. Existing evidence from this laboratory indicates that inhaled ENM (multi-walled carbon nanotubes (MWCNT), TiO2, and CeO2) can impair coronary microvascular function in healthy male rats associated with decreased nitric oxide (NO) bioavailability. Further, recent preliminary findings from the Candidate provide evidence of mitochondrial inefficiencies and fetal microvascular dysfunction that persist systemically into adulthood. The present study proposes exposing pregnant rats to MWCNT via inhalation in order to: (1) identify mitochondrial health as a high throughput predictive screening test, (2) ascertain the toxicokinetic "critical windows" of exposure associated with adverse effects of gestational ENM exposure, (3) determine if significant maternal, fetal, and adult progeny systemic microvascular dysfunction arises from the creation of HGE stemming from MWCNT exposure, and (4) provide the necessary skills in mitochondrial functional assessment and career-mentoring for an independent and productive research career. The working hypothesis is that MWCNT exposure creates a hostile gestational environment leading to the development of fetal mitochondrial insufficiencies in an attempt to adapt to the unfavorable intrauterine milieu. This study is innovative because it challenges the long-standing status quo of nanotechnology with the use of pregnant rats to determine the mechanistic microvascular alterations of ENM exposure to current and future generations. This study is forward thinking as it establishes the conceptual framework that predisposition to adult disease (or fetal programming) could be due to in utero nanomaterial exposure. This study is significant because it will yield important toxicokinetic and mechanistic data, permitting the development of evidence-based strategies and regulatory policy for the safe production and prudent use of ENM in consumer products, especially relevant to women of childbearing years; overall, allowing the true potential of nanotechnology to be fully realized.
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