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. Although 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 2-fold: (1) to determine whether maternal ENM exposure alters uterine and/or fetal microvascular function and (2) test the Barker hypothesis at the microvascular level.

Study design: Pregnant (gestation day 10) Sprague-Dawley rats were exposed to nano-titanium dioxide aerosols (11.3 ± 0.039 mg/m(3)/hr, 5 hr/d, 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 (<150 μm passive diameter) of the uterine premyometrial and fetal tail arteries were conducted.

Results: ENM exposures led to significant maternal and fetal microvascular dysfunction, which was seen 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 that impacted fetal weight. The fetal microvessels that were isolated from exposed dams demonstrated significant impairments to signals of vasodilation specific to mechanistic signaling and shear stress.

Conclusion: To our knowledge, this is the first report to provide evidence that maternal ENM inhalation is capable of influencing fetal health and that the Barker hypothesis is applicable at the microvascular level.

Keywords: Barker hypothesis; engineered nanomaterials (ENM); microvascular.

Figure 1

ENM aerosol generation and characterization. Aerosol size distribution and characterization is determined and confirmed using two methods: A) ELPI, which characterizes the mass-based aerodynamic diameter, with a mean of 149 nm ± 3.9.and B) SMPS, which describes the particle geometric size distribution, with a median of 167 nm. C) A representative image of the daily concentration distribution over the 5-hour exposure, portraying a maintained plateau at 11.2 mg/m³ ± 0.05 for the exposure on Jan 23, 2012.

Figure 1

ENM aerosol generation and characterization. Aerosol size distribution and characterization is determined and confirmed using two methods: A) ELPI, which characterizes the mass-based aerodynamic diameter, with a mean of 149 nm ± 3.9.and B) SMPS, which describes the particle geometric size distribution, with a median of 167 nm. C) A representative image of the daily concentration distribution over the 5-hour exposure, portraying a maintained plateau at 11.2 mg/m³ ± 0.05 for the exposure on Jan 23, 2012.

Figure 1

ENM aerosol generation and characterization. Aerosol size distribution and characterization is determined and confirmed using two methods: A) ELPI, which characterizes the mass-based aerodynamic diameter, with a mean of 149 nm ± 3.9.and B) SMPS, which describes the particle geometric size distribution, with a median of 167 nm. C) A representative image of the daily concentration distribution over the 5-hour exposure, portraying a maintained plateau at 11.2 mg/m³ ± 0.05 for the exposure on Jan 23, 2012.

Figure 2

Acetylcholine dose response curve for A) uterine arterioles (n=9-16 vessels). Values are mean ± S.E. * P≤ 0.05 sham vs. exposed repeated measures ANOVA. B) fetal tail arteries (n=7-11 vessels) after maternal engineered nanomaterial exposure. * P≤ 0.05 sham regression line vs. exposed regression line. ENM exposure during pregnancy impairs endothelium-dependent dilation of the uterus and fetus.

Figure 2

Acetylcholine dose response curve for A) uterine arterioles (n=9-16 vessels). Values are mean ± S.E. * P≤ 0.05 sham vs. exposed repeated measures ANOVA. B) fetal tail arteries (n=7-11 vessels) after maternal engineered nanomaterial exposure. * P≤ 0.05 sham regression line vs. exposed regression line. ENM exposure during pregnancy impairs endothelium-dependent dilation of the uterus and fetus.

Figure 3

Spermine-NONOate dose response curve for A) uterine arterioles (n=9-16 vessels) B) fetal tail arteries (n=7-12 vessels) after maternal engineered nanomaterial exposure. Values are mean ± S.E. * P≤ 0.05 sham regression line vs. exposed regression line. Maternal ENM inhalation impairs maternal and fetal microvascular reactivity to smooth muscle NO signaling.

Figure 3

Spermine-NONOate dose response curve for A) uterine arterioles (n=9-16 vessels) B) fetal tail arteries (n=7-12 vessels) after maternal engineered nanomaterial exposure. Values are mean ± S.E. * P≤ 0.05 sham regression line vs. exposed regression line. Maternal ENM inhalation impairs maternal and fetal microvascular reactivity to smooth muscle NO signaling.

Figure 4

Phenylephrine dose response curve for A) uterine arterioles (n=8-16 vessels) B) fetal tail arteries (n=6-10 vessels) after maternal engineered nanomaterial exposure. Values are mean ± S.E. * P≤ 0.05 sham regression line vs. exposed regression line. α-Adrenergic responsiveness was enhanced in uterine vessels, but unchanged in fetal arteries after maternal ENM inhalation.

Figure 4

Phenylephrine dose response curve for A) uterine arterioles (n=8-16 vessels) B) fetal tail arteries (n=6-10 vessels) after maternal engineered nanomaterial exposure. Values are mean ± S.E. * P≤ 0.05 sham regression line vs. exposed regression line. α-Adrenergic responsiveness was enhanced in uterine vessels, but unchanged in fetal arteries after maternal ENM inhalation.

Figure 5

Uterine arteriolar responsiveness to flow and shear stress after maternal engineered nanomaterial exposure. A) increased intraluminal flow (5-30 μL/min) (4-7 vessels). B) shear stress as a function of flow. C) increased relaxation as a function of increased shear. Values are mean ± S.E. * P≤ 0.05 sham regression line vs. exposed regression line. Uterine responsiveness to alterations in flow and shear stress is impaired.

Figure 5

Uterine arteriolar responsiveness to flow and shear stress after maternal engineered nanomaterial exposure. A) increased intraluminal flow (5-30 μL/min) (4-7 vessels). B) shear stress as a function of flow. C) increased relaxation as a function of increased shear. Values are mean ± S.E. * P≤ 0.05 sham regression line vs. exposed regression line. Uterine responsiveness to alterations in flow and shear stress is impaired.

Figure 5

Uterine arteriolar responsiveness to flow and shear stress after maternal engineered nanomaterial exposure. A) increased intraluminal flow (5-30 μL/min) (4-7 vessels). B) shear stress as a function of flow. C) increased relaxation as a function of increased shear. Values are mean ± S.E. * P≤ 0.05 sham regression line vs. exposed regression line. Uterine responsiveness to alterations in flow and shear stress is impaired.

Figure 6

Fetal tail artery responsiveness to flow and shear stress after maternal engineered nanomaterial exposure. A) increased intraluminal flow (5-30 μL/min) (3-7 vessels). B) shear stress as a function of flow. C) increased relaxation as a function of increased shear.

Figure 6

Fetal tail artery responsiveness to flow and shear stress after maternal engineered nanomaterial exposure. A) increased intraluminal flow (5-30 μL/min) (3-7 vessels). B) shear stress as a function of flow. C) increased relaxation as a function of increased shear.

Figure 6

Fetal tail artery responsiveness to flow and shear stress after maternal engineered nanomaterial exposure. A) increased intraluminal flow (5-30 μL/min) (3-7 vessels). B) shear stress as a function of flow. C) increased relaxation as a function of increased shear.