The effects of engineered nanomaterial (ENM) inhalation on the maternal and fetal microcirculations are unknown. It is also unknown if the hostile gestational environment created by maternal ENM inhalation produces progeny with an increased likelihood of adult disease and/or ENM sensitivity. The long term goal is to identify ENM characteristics, exposure conditions and mechanisms of interactions with host tissues that pose minimal cardiovascular risk for the greater benefit of public health. The objective of this application is to determine how maternal ENM exposure influences uterine and fetal health. The rationale is that if nanotechnology is to reach its full potential in reproductive and developmenta health, then ENM toxicity must first be established.
Three specific aims will be completed in rats with ENM inhalation exposure, intravital microscopy, isolated arterioles, transcriptomics and epigenetics.
Aim 1 will identify the mechanisms through which maternal ENM exposures influence uterine microvascular function. The hypothesis is that maternal ENM exposure results in microvascular dysfunction stemming from inflammatory mechanisms such as altered nitric oxide bioavailability, oxidative and nitrosative stress, and enhanced leukocyte-endothelium interactions.
Aim 2 will identify the mechanisms through which maternal ENM exposures influence fetal microvascular function. The hypothesis is that because the fetal circulation is governed largely by the same principles as other organs, then maternal ENM exposure leads to fetal microvascular dysfunction that stems from similar mechanisms. However, because the fetal circulation is not fully active and/or integrated at the end of gestation, the prevalence and intensity of these alterations on microvascular reactivity should be augmented.
Aim 3 will determine if maternal ENM exposure alters the fetal transcriptome and/or epigenome, and sensitizes the adult microcirculation to subsequent ENM exposures. The hypothesis is that ENM exposure during pregnancy creates a hostile gestational environment that alters the fetal genome. These genetic components should also correlate with mechanisms of microvascular dysfunction, or pathology, and may contribute to the basis of adult disease and/or ENM sensitivity. This research is conceptually innovative because it tests the "Barker Hypothesis" from a microvascular perspective, which is the principal level of the vasculature for a host of physiological parameters and pathologies. This proposal is technically innovative because it focuses unique and powerful methodologies on an unstudied area of critical need. This research is directly responsive to the National Nanotechnology Initiative and is significant to human health because it fills two major knowledge gaps by identifying the uterine microvascular consequences of ENM inhalation, and also determining the fetal consequences of gestational exposures. The proposed research is mechanistically significant because the roots of these microvascular consequences will be elucidated;and correlated with an epigenetic component that may be used to prevent and/or diminish negative health outcomes associated with ENM exposures.

Public Health Relevance

The proposed research is relevant to public health because the effects of maternal nanomaterial inhalation on fetal health are unknown. This project will identify maternal nanomaterial exposure outcomes in terms of maternal and fetal microvascular health;and it will be the first formal transcriptomic and epigenetic assessment of these consequences. This project is directly relative to the NIEHS mission because it will determine if environmental nanomaterial exposure creates a hostile gestational environment that forms the basis of adult disease and/or sensitivity.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Nadadur, Srikanth
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West Virginia University
Schools of Medicine
United States
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Stapleton, Phoebe A; Nurkiewicz, Timothy R (2014) Maternal nanomaterial exposure: a double threat to maternal uterine health and fetal development? Nanomedicine (Lond) 9:929-31
Stapleton, Phoebe A; Nurkiewicz, Timothy R (2014) Vascular distribution of nanomaterials. Wiley Interdiscip Rev Nanomed Nanobiotechnol 6:338-48
Stapleton, Phoebe A; Minarchick, Valerie C; Yi, Jinghai et al. (2013) Maternal engineered nanomaterial exposure and fetal microvascular function: does the Barker hypothesis apply? Am J Obstet Gynecol 209:227.e1-11
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Knuckles, Travis L; Stapleton, Phoebe A; Minarchick, Valerie C et al. (2013) Air pollution particulate matter collected from an Appalachian mountaintop mining site induces microvascular dysfunction. Microcirculation 20:158-69
Kang, Lori S; Nurkiewicz, Timothy R; Wu, Guoyao et al. (2012) Changes in eNOS phosphorylation contribute to increased arteriolar NO release during juvenile growth. Am J Physiol Heart Circ Physiol 302:H560-6
Stapleton, Phoebe A; Minarchick, Valerie C; McCawley, Michael et al. (2012) Xenobiotic particle exposure and microvascular endpoints: a call to arms. Microcirculation 19:126-42
Hubbs, Ann F; Mercer, Robert R; Benkovic, Stanley A et al. (2011) Nanotoxicology--a pathologist's perspective. Toxicol Pathol 39:301-24

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