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)
Project #
Application #
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Nadadur, Srikanth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
West Virginia University
Schools of Medicine
United States
Zip Code
Ishikawa, Aline A; Salazar, Jesus V; Salinas, Magaly et al. (2016) Self-Assembled Nanospheres for Encapsulation and Aerosolization of Rifampicin. RSC Adv 6:12959-12963
Abukabda, Alaeddin B; Stapleton, Phoebe A; Nurkiewicz, Timothy R (2016) Metal Nanomaterial Toxicity Variations Within the Vascular System. Curr Environ Health Rep 3:379-391
Maurer, Megan M; Donohoe, Gregory C; Maleki, Hossein et al. (2016) Comparative plasma proteomic studies of pulmonary TiO2 nanoparticle exposure in rats using liquid chromatography tandem mass spectrometry. J Proteomics 130:85-93
Engler-Chiurazzi, Elizabeth B; Stapleton, Phoebe A; Stalnaker, Jessica J et al. (2016) Impacts of prenatal nanomaterial exposure on male adult Sprague-Dawley rat behavior and cognition. J Toxicol Environ Health A 79:447-52
Stapleton, P A; McBride, C R; Yi, J et al. (2015) Uterine microvascular sensitivity to nanomaterial inhalation: An in vivo assessment. Toxicol Appl Pharmacol 288:420-8
Stapleton, Phoebe A; Nichols, Cody E; Yi, Jinghai et al. (2015) Microvascular and mitochondrial dysfunction in the female F1 generation after gestational TiO2 nanoparticle exposure. Nanotoxicology 9:941-51
Stapleton, Phoebe A; Abukabda, Alaeddin B; Hardy, Steven L et al. (2015) Xenobiotic pulmonary exposure and systemic cardiovascular response via neurological links. Am J Physiol Heart Circ Physiol 309:H1609-20
Armstead, Andrea L; Minarchick, Valerie C; Porter, Dale W et al. (2015) Acute inflammatory responses of nanoparticles in an intra-tracheal instillation rat model. PLoS One 10:e0118778
Nichols, Cody E; Shepherd, Danielle L; Knuckles, Travis L et al. (2015) Cardiac and mitochondrial dysfunction following acute pulmonary exposure to mountaintop removal mining particulate matter. Am J Physiol Heart Circ Physiol 309:H2017-30
Minarchick, Valerie C; Stapleton, Phoebe A; Fix, Natalie R et al. (2015) Intravenous and gastric cerium dioxide nanoparticle exposure disrupts microvascular smooth muscle signaling. Toxicol Sci 144:77-89

Showing the most recent 10 out of 27 publications