Influence of carbon nanomaterial exposure on pro-constrictor mechanisms during pregnancy

Abstract

Engineered carbon based nanoparticles (CNP) such as fullerenes and multiwalled carbon nanotubes (MWCNTs) are increasingly used in industries and in nanomedicine as a platform for drug delivery. Following environmental/occupational exposure through inhalation CNP are translocated to extra-pulmonary sites, raising concerns on their potential effects on vasculature particularly in vulnerable life-stages such as pregnancy. Distribution of intravenously delivered C60 in maternal organs varies between pregnant and non-pregnant life-stages, presumed to be associated with changes in reactivity of various vascular beds during pregnancy. The overall goal of this dissertation was to describe and elucidate intracellular mediators driving changes in contractility of vascular segments from three distinct vascular beds following exposure to CNP during pregnancy. In vitro experiments on aortic endothelial cells and wire myographic studies on vessel segments from Sprague Dawley rats exposed to C60/PVP (polyvinylpyrorrolidone formulated C60) or MWCNTs were used to identify changes in vascular tissue contractility and to determine the contribution of Rho-kinase pathway. Intravenous administration of C60/PVP increased contraction in the uterine artery, aorta and umbilical vein while pulmonary exposure to MWCNTs increased contraction in the uterine artery. These changes were confined to pregnancy, suggesting a higher susceptibility of the uterine vasculature to CNP mediated changes during pregnancy. Both in vitro and wire myographic studies suggested an increase in Rho-kinase activity with C60/PVP exposure (but not with MWCNT exposure), suggesting that C60/PVP mediated increase in contractility may be driven by a common pathway involving Rho-kinase via activation of endothelium and/or altering signaling within smooth muscle. MWCNT exposure induced contractions may be mediated by inflammatory mechanisms as suggested by the increased inflammatory endothelial markers. Our comparisons with naïve rats and untreated endothelial cells indicated a critical role played by the dispersion medium used for CNP delivery in determining contractile effects. These CNP exposures may be detrimental to fetal growth resulting in the observed reduction of fetal weight gain following acute exposure to both CNP. The conclusions drawn from this work contribute to both nanomedicine and nanotoxicology, focusing on safe applications of nanotechnology. It also widens our understanding on the life-stage related changes in susceptibility to environmental insults.