Microvascular and mitochondrial dysfunction in the female F1 generation after gestational TiO2 nanoparticle exposure

Phoebe A Stapleton,Cody E Nichols,Jinghai Yi,Carroll R Mcbride,Valerie C Minarchick,Danielle L Shepherd,John M Hollander,Timothy R Nurkiewicz

doi:10.3109/17435390.2014.984251

Abstract

Due to the ongoing evolution of nanotechnology, there is a growing need to assess the toxicological outcomes in under-studied populations in order to properly consider the potential of engineered nanomaterials (ENM) and fully enhance their safety. Recently, we and others have explored the vascular consequences associated with gestational nanomaterial exposure, reporting microvascular dysfunction within the uterine circulation of pregnant dams and the tail artery of fetal pups. It has been proposed (via work derived by the Barker Hypothesis) that mitochondrial dysfunction and subsequent oxidative stress mechanisms as a possible link between a hostile gestational environment and adult disease. Therefore, in this study, we exposed pregnant Sprague-Dawley rats to nanosized titanium dioxide aerosols after implantation (gestational day 6). Pups were delivered, and the progeny grew into adulthood. Microvascular reactivity, mitochondrial respiration and hydrogen peroxide production of the coronary and uterine circulations of the female offspring were evaluated. While there were no significant differences within the maternal or litter characteristics, endothelium-dependent dilation and active mechanotransduction in both coronary and uterine arterioles were significantly impaired. In addition, there was a significant reduction in maximal mitochondrial respiration (state 3) in the left ventricle and uterus. These studies demonstrate microvascular dysfunction and coincide with mitochondrial inefficiencies in both the cardiac and uterine tissues, which may represent initial evidence that prenatal ENM exposure produces microvascular impairments that persist throughout multiple developmental stages.

Highlights

Maternal health status and lifestyle during pregnancy have been hypothesized as the fetal basis of adult disease (Capra et al, 2013) and is commonly termed the ‘‘Barker Hypothesis’’ (Fall et al, 1995; Hales & Barker, 1992)
Models representing fetal programming through the Barker Hypothesis mechanistically link the presentation of adult disease, with mitochondrial abnormalities (mitochondrial dysfunction and development of reactive oxygen species (ROS)) that stem from fetal development in a hostile gestational environment (Andreux et al, 2013)
Mitochondrial dysfunction and inefficiencies leading to ROS production and subsequent nitric oxide (NO) quenching has been hypothesized as a major disrupter of normal microvascular reactivity (Mann et al, 2012; Nurkiewicz et al, 2009; Stapleton et al, 2012b)

Summary

Introduction

Maternal health status and lifestyle during pregnancy have been hypothesized as the fetal basis of adult disease (Capra et al, 2013) and is commonly termed the ‘‘Barker Hypothesis’’ (Fall et al, 1995; Hales & Barker, 1992). The National Institute of Environmental Health and Safety announced an initiative to evaluate fetal toxicity, teratology and the genetic basis of adult disease (National Institute of Environmental Health Sciences, 2012). This has lead to a handful of initial studies to address this call (Hougaard et al, 2010, 2013; Jo et al, 2013; Stapleton et al, 2013; Yamashita et al, 2011). We focus our current studies on exposure after a sufficient time has been allowed for embryonic implantation

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