Pregnancy is a vulnerable life stage for the mother and developing fetus. Because of this dual concern, approved therapeutic options for pre-existing conditions or pregnancy-induced pathologies, ...placental deformities, or fetal concerns are extremely limited. These cases often leave patients and clinicians having to choose between maternal health and fetal development. Recent advancements in nanomedicine and nanotherapeutic devices have made the development of perinatal therapeutics an attractive objective. However, perinatal medicine requires a multifaceted approach given the interactions between maternal, placental, and fetal physiology. Maternal-fetal interactions are centralized to the placenta, a specialized transient barrier organ, to allow for nutrient and waste exchange. Perinatal nanotherapeutics must be designed for placental avoidance or uptake. In this review, pregnancy-related conditions, experimental models, and modes of drug delivery during pregnancy are discussed.
Abstract
Background
Plastic is everywhere. It is used in food packaging, storage containers, electronics, furniture, clothing, and common single-use disposable items. Microplastic and nanoplastic ...particulates are formed from bulk fragmentation and disintegration of plastic pollution. Plastic particulates have recently been detected in indoor air and remote atmospheric fallout. Due to their small size, microplastic and nanoplastic particulate in the atmosphere can be inhaled and may pose a risk for human health, specifically in susceptible populations. When inhaled, nanosized particles have been shown to translocate across pulmonary cell barriers to secondary organs, including the placenta. However, the potential for maternal-to-fetal translocation of nanosized-plastic particles and the impact of nanoplastic deposition or accumulation on fetal health remain unknown. In this study we investigated whether nanopolystyrene particles can cross the placental barrier and deposit in fetal tissues after maternal pulmonary exposure.
Results
Pregnant Sprague Dawley rats were exposed to 20 nm rhodamine-labeled nanopolystyrene beads (2.64 × 10
14
particles) via intratracheal instillation on gestational day (GD) 19. Twenty-four hours later on GD 20, maternal and fetal tissues were evaluated using fluorescent optical imaging. Fetal tissues were fixed for particle visualization with hyperspectral microscopy. Using isolated placental perfusion, a known concentration of nanopolystyrene was injected into the uterine artery. Maternal and fetal effluents were collected for 180 min and assessed for polystyrene particle concentration. Twenty-four hours after maternal exposure, fetal and placental weights were significantly lower (7 and 8%, respectively) compared with controls. Nanopolystyrene particles were detected in the maternal lung, heart, and spleen. Polystyrene nanoparticles were also observed in the placenta, fetal liver, lungs, heart, kidney, and brain suggesting maternal lung-to-fetal tissue nanoparticle translocation in late stage pregnancy.
Conclusion
These studies confirm that maternal pulmonary exposure to nanopolystyrene results in the translocation of plastic particles to placental and fetal tissues and renders the fetoplacental unit vulnerable to adverse effects. These data are vital to the understanding of plastic particulate toxicology and the developmental origins of health and disease.
Adverse cardiovascular and inflammatory outcomes after airborne particulate matter (PM) inhalation have long been a topic of epidemiological studies. Previous studies have identified, the ...microcirculation as particularly vulnerable to this insult. However, the mechanisms of microvascular dysfunction are complex and vary with each specific aerosol. Variations in neurohormonal and inflammatory status contribute to the complexity of defining mechanisms of microvascular dysfunction caused by aerosols. Given the recent identification and toxicological concerns surrounding micro‐ and nanoplastic exposures, we aimed to evaluate microvascular reactivity after acute plastic particle inhalation in this study. Virgin female Sprague Dawley rats in estrus were exposed to filtered air or aerosolized polyamide (i.e., nylon) particles in a whole‐body inhalation chamber. We hypothesized the uterine microvascular reactivity would achieve a vasoconstrictive state due to plastic particle inhalation. Exposure only during estrus served to control for neurohormonal differences within groups. 24h later, the radial arteriole of the uterus was selected as a representative vessel for the microcirculation. Ex vivouterine radial arteriole reactivity was assessed using pressure myography Living Systems Instrumentation, St. Albans, VT). Vascular reactivity was assessed based on responses to endothelium‐dependent (methacholine, MCh, 10‐9‐10‐4 M), –independent (sodium nitroprusside, SNP, 10‐9‐10‐4 M), and smooth muscle contractility (phenylephrine, PE, 10‐9‐10‐4 M). Inflammatory cytokines (IL‐4, IL‐6, MCP‐1, CXCL1; Sigma, St. Louis, MO and IL 5; Abcam, Cambridge, UK) were quantified in plasma with ELISA. Acute inhalation exposure to polyamide MNPs led to significantly impaired vascular reactivity through endothelium‐dependent and vascular smooth muscle mechanisms. Percent maximum dilation in response to 10‐9 M MCh was significantly reduced in exposed animals when compared to controls (‐9.44% ± 3.65 vs. 7.26% ± 4.61). Smooth muscle contraction was also impaired with percent maximum dilation in response to 10‐8 M PE being significantly increased in exposed animals compared to controls (‐9.56%±7.28 vs. ‐59.7±17.4). The levels of IL‐6 were not significant between groups which suggests systemic inflammation may not be a key component of plastic aerosol induced vascular dysfunction. In summary, exposure to polyamide MNPs resulted in less vascular reactivity to pharmacologic stimuli during estrus. However, the mechanisms attributing to disrupted microvascular function remain elusive. An important consideration for future studies will be the proper time point in which various cytokines can be assessed and the reproductive ramifications of these findings. Future studies should examine the impact of plastic particulate inhalation on endothelial inflammatory activation, metabolism, or apoptotic mechanisms. Altogether this information may give insight into how plastic particle inhalation could impair distal tissue health, including endometrial perfusion and ability to sustain pregnancy.
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/m3 /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.
Maternal exposure to environmental contaminants during pregnancy can profoundly influence the risk of developing cardiovascular disease in adult offspring. Our previous studies have demonstrated ...impaired cardiovascular health, microvascular reactivity, and cardiac function in fetal and young adult progeny after maternal inhalation of nano-sized titanium dioxide (nano-TiO
) aerosols during gestation. The present study was designed to evaluate the development of cardiovascular and metabolic diseases later in adulthood. Pregnant Sprague-Dawley rats were exposed to nano-TiO
aerosols (~ 10 mg/m
, 134 nm median diameter) for 4 h per day, 5 days per week, beginning on gestational day (GD) 4 and ending on GD 19. Progeny were delivered in-house. Body weight was recorded weekly after birth. After 47 weeks, the body weight of exposed progeny was 9.4% greater compared with controls. Heart weight, mean arterial pressure, and plasma biomarkers of inflammation, dyslipidemia, and glycemic control were recorded at 3, 9 and 12 months of age, with no significant adaptations. While no clinical risk factors (i.e., hypertension, dyslipidemia, or systemic inflammation) emerged pertaining to the development of cardiovascular disease, we identified impaired endothelium-dependent and -independent arteriolar dysfunction and cardiac morphological alterations consistent with myocardial inflammation, degeneration, and necrosis in exposed progeny at 12 months. In conclusion, maternal inhalation of nano-TiO
aerosols during gestation may promote the development of coronary disease in adult offspring.
Exposure to micro- and nanoplastic particles (MNPs) in humans is being identified in both the indoor and outdoor environment. Detection of these materials in the air has made inhalation exposure to ...MNPs a major cause for concern. One type of plastic polymer found in indoor and outdoor settings is polyamide, often referred to as nylon. Inhalation of combustion-derived, metallic, and carbonaceous aerosols generate pulmonary inflammation, cardiovascular dysfunction, and systemic inflammation. Additionally, due to the additives present in plastics, MNPs may act as endocrine disruptors. Currently there is limited knowledge on potential health effects caused by polyamide or general MNP inhalation.
The purpose of this study is to assess the toxicological consequences of a single inhalation exposure of female rats to polyamide MNP during estrus by means of aerosolization of MNP.
Bulk polyamide powder (i.e., nylon) served as a representative MNP. Polyamide aerosolization was characterized using particle sizers, cascade impactors, and aerosol samplers. Multiple-Path Particle Dosimetry (MPPD) modeling was used to evaluate pulmonary deposition of MNPs. Pulmonary inflammation was assessed by bronchoalveolar lavage (BAL) cell content and H&E-stained tissue sections. Mean arterial pressure (MAP), wire myography of the aorta and uterine artery, and pressure myography of the radial artery was used to assess cardiovascular function. Systemic inflammation and endocrine disruption were quantified by measurement of proinflammatory cytokines and reproductive hormones.
Our aerosolization exposure platform was found to generate particles within the micro- and nano-size ranges (thereby constituting MNPs). Inhaled particles were predicted to deposit in all regions of the lung; no overt pulmonary inflammation was observed. Conversely, increased blood pressure and impaired dilation in the uterine vasculature was noted while aortic vascular reactivity was unaffected. Inhalation of MNPs resulted in systemic inflammation as measured by increased plasma levels of IL-6. Decreased levels of 17β-estradiol were also observed suggesting that MNPs have endocrine disrupting activity.
These data demonstrate aerosolization of MNPs in our inhalation exposure platform. Inhaled MNP aerosols were found to alter inflammatory, cardiovascular, and endocrine activity. These novel findings will contribute to a better understanding of inhaled plastic particle toxicity.
The Barker Hypothesis states change to the maternal environment may have significant impacts on fetal development, setting the stage for adult disease to occur. The development of the maternofetal ...vasculature during implantation and maintenance during pregnancy is extremely precise, yet dynamic. Delays or dysfunction in the orchestration of anatomical remodeling, maintenance of blood pressure, or responsiveness to metabolic demand may have severe consequences to the developing fetus. While these intermissions may not be fatal to the developing fetus, an interruption, reduction, or an inability to meet fetal demand of blood flow during crucial stages of development may predispose young to disease later in life. Maternal inability to meet fetal demand can be attributed to improper placental development and vascular support through morphological change or physiological function will significantly limit nutrient delivery and waste exchange to the developing fetus. Therefore, we present an overview of the uteroplacental vascular network, maternal cardiovascular adaptations that occur during pregnancy, placental blood flow, and common maternal comorbidities and/or exposures that may perturb maternal homeostasis and affect fetal development. Overall, we examine uterine microvasculature pathophysiology contributing to a hostile gestational environment and fetal predisposition to disease as it relates to the Barker Hypothesis.
Vascular distribution of nanomaterials Stapleton, Phoebe A.; Nurkiewicz, Timothy R.
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology,
July/August 2014, Letnik:
6, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Once considered primarily occupational, novel nanotechnology innovations, and applications have led to widespread domestic use and intentional biomedical exposures. With these exciting advances, the ...breadth and depth of toxicological considerations must also be expanded. The vascular system interacts with every tissue in the body, striving to maintain homeostasis. Engineered nanomaterials (ENM) have been reported to distribute in many different tissues and organs. However, these observations have tended to use approaches requiring tissue homogenization and/or gross organ analyses. These techniques, while effective in establishing presence, preclude an exact determination of where ENM are deposited within a tissue. If nanotechnology is to achieve its full potential, it is necessary to identify this exact distribution and deposition of ENM throughout the cardiovascular system, with respect to vascular hemodynamics and in vivo ENM modifications taken into account. Distinct levels of the vasculature will first be described as individual compartments. Then the vasculature will be considered as a whole. These unique compartments and biophysical conditions will be discussed in terms of their propensity to favor ENM deposition. Understanding levels of the vasculature will also be discussed. Ultimately, future studies must verify the mechanisms speculated on and presented herein.
This article is categorized under:
Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease
Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Engineered nanomaterials have been developed for widespread applications due to many highly unique and desirable characteristics. The purpose of this study was to assess pulmonary inflammation and ...subepicardial arteriolar reactivity in response to multi-walled carbon nanotube (MWCNT) inhalation and evaluate the time course of vascular alterations. Rats were exposed to MWCNT aerosols producing pulmonary deposition. Pulmonary inflammation via bronchoalveolar lavage and MWCNT translocation from the lungs to systemic organs was evident 24 h post-inhalation. Coronary arterioles were evaluated 24-168 h post-exposure to determine microvascular response to changes in transmural pressure, endothelium-dependent and -independent reactivity. Myogenic responsiveness, vascular smooth muscle reactivity to nitric oxide, and α-adrenergic responses all remained intact. However, a severe impact on endothelium-dependent dilation was observed within 24 h after MWCNT inhalation, a condition which improved, but did not fully return to control after 168 h. In conclusion, results indicate that MWCNT inhalation not only leads to pulmonary inflammation and cytotoxicity at low lung burdens, but also a low level of particle translocation to systemic organs. MWCNT inhalation also leads to impairments of endothelium-dependent dilation in the coronary microcirculation within 24 h, a condition which does not fully dissipate within 168 h. The innovations within the field of nanotechnology, while exciting and novel, can only reach their full potential if toxicity is first properly assessed.
Phthalates are ubiquitous compounds known to leach from the plastic products that contain them. Due to their endocrine-disrupting properties, a wide range of studies have elucidated their effects on ...reproduction, metabolism, neurodevelopment, and growth. Additionally, their impacts during pregnancy and on the developing fetus have been extensively studied. Most recently, there has been interest in the impacts of phthalates on the placenta, a transient major endocrine organ critical to maintenance of the uterine environment and fetal development. Phthalate-induced changes in placental structure and function may have significant impacts on the course of pregnancy and ultimately, child health. Prior reviews have described the literature on phthalates and placental health; however to date, there has been no comprehensive, systematic review on this topic. Here, we review 35 papers (24 human and 11 animal studies) and summarize phthalate exposures in relation to an extensive set of placental measures. Phthalate-related alterations were reported for placental morphology, hormone production, vascularization, histopathology, and gene/protein expression. The most consistent changes were observed in vascular and morphologic endpoints, including cell composition. These changes have implications for pregnancy complications such as preterm birth and intrauterine growth restriction as well as potential ramifications for children's health. This comprehensive review of the literature, including common sources of bias, will inform the future work in this rapidly expanding field.
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