Maternal Nanomaterial Exposures: Fetal Microvascular Endpoints and Programming

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DESCRIPTION (provided by applicant): 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.