Microvascular and mitochondrial dysfunction in the female F1 generation after gestational TiO₂nanoparticle exposure

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.

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]. These results indicate that prenatal NM exposure impairs microvascular function in the offspring and may persist through multiple developmental stages.…”

Xenobiotic pulmonary exposure and systemic cardiovascular response via neurological links

“…This may be related to preferential accumulation of PM within the mitochondria (96) and dysregulation of the respiratory chain complexes I and III in rat brain tissue, leading to an increased generation of ROS (38). These mitochondrial alterations may be long lasting with generational consequences (114).…”

“…Evidence exists of DNA damage, including single-and double-strand breaks and DNA-protein crosslinks (72); altered overall DNA content (11); as well as mitochondrial DNA methylation (18), following exposure to xenobiotic particles. Furthermore, xenobiotic particles may penetrate to the endoplasmic reticulum and trigger the unfolded protein response, a signaling cascade initiated by the intracellular accumulation of misfolded proteins, as well as oxidative stress (129), a response that may also involve the mitochondria (49,78,107,114) (Fig. 3C).…”

Effects of Maternal Exposure to Cadmium Oxide Nanoparticles During Pregnancy on Maternal and Offspring Kidney Injury Markers Using a Murine Model

“…However, few studies have examined such outcomes following exposure to NP. An investigation that examined the effects of titanium dioxide exposure during pregnancy in rats revealed microvascular impairments in the maternal uterine arterioles that resulted in cardiac mitochondrial insufficiency in the offspring that persisted through adulthood (Stapleton et al, 2013, 2014). In our previous studies, pregnant mice were exposed by inhalation to CdO NP, and while Cd was not measurable in the fetus, there were effects on neonatal growth (Blum et al, 2012) and sex-dependent dyslipidemia in adult offspring fed a high-fat diet (report in preparation).…”