Maternal engineered nanomaterial exposure and fetal microvascular function: does the Barker hypothesis apply?

Abstract

Objective-The continued development and use of engineered nanomaterials (ENM) has given rise to concerns over the potential for human health effects. While the understanding of cardiovascular ENM toxicity is improving, one of the most complex and acutely demanding "special" circulations is the enhanced maternal system to support fetal development. The "Barker Hypothesis" proposes that fetal development within a hostile gestational environment may predispose/program future sensitivity. Therefore, the objective of this study was two-fold: 1) to determine if maternal ENM exposure alters uterine and/or fetal microvascular function and 2) test the Barker Hypothesis at the microvascular level. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.The author(s) report(s) no conflict of interest.An abstract has been accepted to present this work at the 52 nd Annual Meeting of the Society of Toxicology, San Antonio TX, to be held March 10-14, 2013. NIH Public Access Author ManuscriptAm J Obstet Gynecol. Author manuscript; available in PMC 2014 September 01. NIH-PA Author ManuscriptStudy Design-Pregnant (gestation day 10) Sprague-Dawley rats were exposed to nanotitanium dioxide aerosols (11.3±0.039 (mg/m 3 )*hour, 5 hours/day, 8.2±0.85 days) to evaluate the maternal and fetal microvascular consequences of maternal exposure. Microvascular tissue isolation (gestation day 20) and arteriolar reactivity studies (<150μm passive diameter) of the uterine premyometrial and fetal tail arteries were conducted.Results-ENM exposures led to significant maternal and fetal microvascular dysfunction which presented as robustly compromised endothelium-dependent and -independent reactivity to pharmacologic and mechanical stimuli. Isolated maternal uterine arteriolar reactivity was consistent with a metabolically impaired profile and hostile gestational environment, impacting fetal weight. The fetal microvessels isolated from exposed dams demonstrate significant impairments to signals of vasodilation specific to mechanistic signaling and shear stress.Conclusion-To our knowledge, this is the first report providing evidence that maternal ENM inhalation is capable of influencing fetal health, thereby supporting that the Barker Hypothesis is applicable at the microvascular level.

PVP formulated fullerene (C60) increases Rho-kinase dependent vascular tissue contractility in pregnant Sprague Dawley rats

“…The Sumner et al study also reported differences in the distribution pattern of radiolabelled C60 between pregnant and non-pregnant life stages [22], which is presumed to be due to changes in vascular reactivity of various vascular beds during pregnancy. The distribution kinetics of nanoparticles can influence both maternal and fetal vascular function [25], embryogenesis, cellular signalling, inflammation, cell cycle, lipid metabolism [26] fetal growth and malformations [23]. The effects of C60 exposure on maternal/fetal vascular reactivity have not been extensively investigated despite the possibility of occupational, general environmental and therapeutic/diagnostic exposures during pregnancy.…”

Vascular Tissue Contractility Changes Following Late Gestational Exposure to Multi-Walled Carbon Nanotubes or their Dispersing Vehicle in Sprague Dawley Rats

“…Additionally, fetal microvessel dysfunction following exposure to engineered nanomaterials which was recently proposed by Stapleton et al [11] may be a possible underlying explanation for our observations of reduced fetal weight despite the absence of augmented contractile responses in umbilical circulation. Stapleton et al [11] used the fetal tail artery as a representative vessel from the fetal microcirculation and reported decreased responses in both endothelium dependent and independent relaxation [60]. Their findings suggests the applicability of the Barker Hypothesis ( i.e.…”

“…Their findings suggests the applicability of the Barker Hypothesis ( i.e. the relation between retarded growth in early life and risk of adult disease is due to long term effects on physiology and metabolism imposed by an adverse environment during critical periods of development) to explain the changes observed in the fetus following maternal nanoparticle exposure [60,61]. This hypothesis may also hold true for our MWCNT exposure scenario, suggesting that the differences in the fetal weight gain may be a reflection of limited blood supply due to increased contraction observed in the uterine vascular segments.…”

A perspective on the developmental toxicity of inhaled nanoparticles

“…Together with a lack of response to nitric oxide, these findings indicate that exposure compromised the normal microvascular dilation in fetal vasculature [141]. Further studies demonstrated that microvascular dysfunction coincided with a reduction in the maximal mitochondrial respiration in both cardiac and uterine tissues [142].…”