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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.

Background 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. Objective 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. Methods 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. Results 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. Conclusions 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.

Recent studies in experimental animals found that oral exposure to micro- and nano-plastics (MNPs) during pregnancy had multiple adverse effects on outcomes and progeny, although no study has yet identified the translocation of ingested MNPs to the placenta or fetal tissues, which might account for those effects. We therefore assessed the placental and fetal translocation of ingested nanoscale polystyrene MNPs in pregnant rats. Sprague Dawley rats (N = 5) were gavaged on gestational day 19 with 10 mL/kg of 250 µg/mL 25 nm carboxylated polystyrene spheres (PS25C) and sacrificed after 24 h. Hyperspectral imaging of harvested placental and fetal tissues identified abundant PS25C within the placenta and in all fetal tissues examined, including liver, kidney, heart, lung and brain, where they appeared in 10–25 µm clusters. These findings demonstrate that ingested nanoscale polystyrene MNPs can breach the intestinal barrier and subsequently the maternal–fetal barrier of the placenta to access the fetal circulation and all fetal tissues. Further studies are needed to assess the mechanisms of MNP translocation across the intestinal and placental barriers, the effects of MNP polymer, size and other physicochemical properties on translocation, as well as the potential adverse effects of MNP translocation on the developing fetus.

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 2 ) 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 2 aerosols (~ 10 mg/m 3 , 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 2 aerosols during gestation may promote the development of coronary disease in adult offspring.

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.

Plastics are ubiquitous in all trophic environments. Human exposures primarily occur via ingestion, inhalation, and/or injection routes. However, laboratory models of micro- and nanoplastic (MNP) particle exposures replicating the human condition remain inconsistent and uncharacterized, thus limiting study strength and compromising the reliability of results. The purpose of this study was to thoroughly optimize and characterize an established methodology for MNP rodent inhalation exposures, and to model particle respiratory deposition to estimate theoretical in silico exposures in rats and humans for the assessment of MNP health effects. Using our whole-body rodent inhalation facility, we generated MNP aerosols after thorough material characterization of a commercially available food-grade polyamide-12 (PA-12) bulk microparticle powder. PA-12 particulate was thoroughly assessed via pyrolysis–gas chromatography–mass spectrometry (PY-GC-MS), attenuated total reflectance-Fourier-transform infrared (ATR-FTIR) spectroscopy, and helium ion microscopy (HIM) to confirm material chemistry, size, and surface shape. Representative MNP were established and measured at three mass concentrations, low (1.01 mg/m 3  ± 0.17), mid- (5.05 mg/m 3  ± 0.5), and high (9.98 mg/m 3  ± 3.14) levels, representative of environmental and occupational exposure. The aerosol micro- and nanoparticle size distributions were measured and monitored in real-time with a scanning mobility particle sizer (SMPS), an aerodynamic particle sizer (APS), and a high-resolution electrical low-pressure impactor (HR-ELPI+) over a size range of 10 nm − 20 µm. Multi-day studies were conducted to assess intra- and inter-day variability in terms of several size distribution summary statistics. The merged data revealed a bi- and tri- modal distribution of particles with geometric mean diameters within the nano- and micro- size ranges for all concentrations. While commercial characterization reported an average size of 5 µm ±1, aerosol characterization in-house revealed MNP well within the nano-range, with average geometric mean of less than 200 nm and aerodynamic size peak mode values less than 100 nm at all concentrations. These data were entered into multiple-path particle dosimetry (MPPD © ) model software to predict pulmonary anatomical deposition, which identified no significant differences between Sprague-Dawley rats and humans. Overall, we provide a thoroughly characterized methodology for controlled laboratory-based assessments to evaluate MNP toxicity and risk over a range of environmental and occupational doses. MPPD modeling of these exposures identifies pulmonary tract deposition within the human and rodent model, with no physiological differences between the low and high dose. This study provides a foundational methodology to assess the toxicological implications of MNP inhalation. Using our whole-body rodent inhalation facility, we generated MNP aerosols after thorough material characterization of a commercially available food-grade polyamide-12 (PA-12) bulk microparticle powder. PA-12 particulate was thoroughly assessed via pyrolysis–gas chromatography–mass spectrometry (PY-GC-MS), attenuated total reflectance–Fourier-transform infrared (ATR-FTIR) spectroscopy, and helium ion microscopy (HIM) to confirm material chemistry, size, and surface shape. Representative MNP were established and measured at three mass concentrations, low (1.01 mg/m 3 ± 0.17), mid- (5.05 mg/m 3 ± 0.5), and high (9.98 mg/m 3 ± 3.14) levels, representative of environmental and occupational exposure. The aerosol micro- and nanoparticle size distributions were measured and monitored in real-time with a scanning mobility particle sizer (SMPS), an aerodynamic particle sizer (APS), and a high-resolution electrical low-pressure impactor (HR-ELPI+) over a size range of 10 nm – 20 µm. Multi-day studies were conducted to assess intra- and inter-day variability in terms of several size distribution summary statistics. The merged data revealed a bi- and tri- modal distribution of particles with geometric mean diameters within the nano- and micro- size ranges for all concentrations. While commercial characterization reported an average size of 5 µm ± 1, aerosol characterization in-house revealed MNP well within the nano-range, with average geometric mean of less than 200 nm and aerodynamic size peak mode values less than 100nm at all concentrations. These data were entered into multiple-path particle dosimetry (MPPD © ) model software to predict pulmonary anatomical deposition, which identified no significant differences between Sprague-Dawley rats and humans. Overall, we provide a thoroughly characterized methodology for controlled laboratory-based assessments to evaluate MNP toxicity and risk over a range of environmental and occupational doses. MPPD modeling of these exposures identifies pulmonary tract deposition within the human and rodent model, with no physiological differences between the low and high dose. This study provides a foundational methodology to assess the toxicological implications of MNP inhalation.

Hypercholesterolemia is defined as excessively high plasma cholesterol levels, and is a strong risk factor for many negative cardiovascular events. Total cholesterol levels above 200 mg/dl have repeatedly been correlated as an independent risk factor for development of peripheral vascular (PVD) and coronary artery disease (CAD), and considerable attention has been directed toward evaluating mechanisms by which hypercholesterolemia may impact vascular outcomes; these include both results of direct cholesterol lowering therapies and alternative interventions for improving vascular function. With specific relevance to the microcirculation, it has been clearly demonstrated that evolution of hypercholesterolemia is associated with endothelial cell dysfunction, a near-complete abrogation in vascular nitric oxide bioavailability, elevated oxidant stress, and the creation of a strongly pro-inflammatory condition; symptoms which can culminate in profound impairments/alterations to vascular reactivity. Effective interventional treatments can be challenging as certain genetic risk factors simply cannot be ignored. However, some hypercholesterolemia treatment options that have become widely used, including pharmaceutical therapies which can decrease circulating cholesterol by preventing either its formation in the liver or its absorption in the intestine, also have pleiotropic effects with can directly improve peripheral vascular outcomes. While physical activity is known to decrease PVD/CAD risk factors, including obesity, psychological stress, impaired glycemic control, and hypertension, this will also increase circulating levels of high density lipoprotein and improving both cardiac and vascular function. This review will provide an overview of the mechanistic consequences of the predominant pharmaceutical interventions and chronic exercise to treat hypercholesterolemia through their impacts on chronic sub-acute inflammation, oxidative stress, and microvascular structure/function relationships.

A growing body of research links engineered nanomaterial (ENM) exposure to adverse cardiovascular endpoints. The purpose of this study was to evaluate the impact of ENM exposure on vascular reactivity in discrete segments so that we may determine the most sensitive levels of the vasculature where these negative cardiovascular effects are manifest. We hypothesized that acute nano-TiO exposure differentially affects reactivity with a more robust impairment in the microcirculation. Sprague-Dawley rats (8-10 weeks) were exposed to nano-TiO intratracheal instillation (20, 100, or 200 µg suspended per 250 µL of vehicle) 24 h prior to vascular assessments. A serial assessment across distinct compartments of the vascular tree was then conducted. Wire myography was used to evaluate macrovascular active tension generation specifically in the thoracic aorta, the femoral artery, and third-order mesenteric arterioles. Pressure myography was used to determine vascular reactivity in fourth- and fifth-order mesenteric arterioles. Vessels were treated with phenylephrine, acetylcholine (ACh), and sodium nitroprusside. Nano-TiO exposure decreased endothelium-dependent relaxation in the thoracic aorta and femoral arteries assessed ACh by 53.96 ± 11.6 and 25.08 ± 6.36%, respectively. Relaxation of third-order mesenteric arterioles was impaired by 100 and 20 µg nano-TiO exposures with mean reductions of 50.12 ± 8.7 and 68.28 ± 8.7%. Cholinergic reactivity of fourth- and fifth-order mesenteric arterioles was negatively affected by nano-TiO with diminished dilations of 82.86 ± 12.6% after exposure to 200 µg nano-TiO , 42.6 ± 12.6% after 100 µg nano-TiO , and 49.4 ± 12.6% after 20 µg nano-TiO . Endothelium-independent relaxation was impaired in the thoracic aorta by 34.05 ± 25% induced by exposure to 200 µg nano-TiO and a reduction in response of 49.31 ± 25% caused by 100 µg nano-TiO . Femoral artery response was reduced by 18 ± 5%, while third-order mesenteric arterioles were negatively affected by 20 µg nano-TiO with a mean decrease in response of 38.37 ± 10%. This is the first study to directly compare the differential effect of ENM exposure on discrete anatomical segments of the vascular tree. Pulmonary ENM exposure produced macrovascular and microvascular dysfunction resulting in impaired responses to endothelium-dependent, endothelium-independent, and adrenergic agonists with a more robust dysfunction at the microvascular level. These results provide additional evidence of an endothelium-dependent and endothelium-independent impairment in vascular reactivity.

Cerium dioxide nanoparticles (CeO 2 NPs) are an engineered nanomaterial (ENM) that possesses unique catalytic, oxidative, and reductive properties. Currently, CeO 2 NPs are being used as a fuel catalyst but these properties are also utilized in the development of potential drug treatments for radiation and stroke protection. These uses of CeO 2 NPs present a risk for human exposure; however, to date, no studies have investigated the effects of CeO 2 NPs on the microcirculation following pulmonary exposure. Previous studies in our laboratory with other nanomaterials have shown impairments in normal microvascular function after pulmonary exposures. Therefore, we predicted that CeO 2 NP exposure would cause microvascular dysfunction that is dependent on the tissue bed and dose. Twenty-four-hour post-exposure to CeO 2 NPs (0–400 μg), mesenteric, and coronary arterioles was isolated and microvascular function was assessed. Our results provided evidence that pulmonary CeO 2 NP exposure impairs endothelium-dependent and endothelium-independent arteriolar dilation in a dose-dependent manner. The CeO 2 NP exposure dose which causes a 50 % impairment in arteriolar function (EC 50 ) was calculated and ranged from 15 to 100 μg depending on the chemical agonist and microvascular bed. Microvascular assessments with acetylcholine revealed a 33–75 % reduction in function following exposure. Additionally, there was a greater sensitivity to CeO 2 NP exposure in the mesenteric microvasculature due to the 40 % decrease in the calculated EC 50 compared to the coronary microvasculature EC 50 . CeO 2 NP exposure increased mean arterial pressure in some groups. Taken together, these observed microvascular changes may likely have detrimental effects on local blood flow regulation and contribute to cardiovascular dysfunction associated with particle exposure.