Cardiovascular and Thermoregulatory Toxicity of an Emission Source Particulate in Healthy and Compromised Rats

Recent epidemiological studies have demonstrated a positive association between concentrations of ambient particulate matter (PM) and cardiopulmonary morbidity and mortality; however, there are limited toxicological data to support these findings. In rodents, exposure to certain xenobiotics causes an acute hypothermic response, characterized by decreases in body core temperature (Tco), heart rate (HR), and oxygen consumption. This study investigates the cardiovascular toxicity of PM and its potential relationship to the hypothermic response following intratracheal instillation of residual oil fly ash (ROFA), an emission source pollutant, in conscious, unrestrained male Sprague-Dawley rats. Four phases of this study were conducted to examine the effects of ROFA (0.0, 0.25, 1.0, or2.5mg/rat) in normal rats and in three models of compromised animals: 1) cold exposed rats, 2) rats with pulmonary inflammation, and 3) rats with pulmonary inflammation and hypertension. HR, T[co], and electrocardiographic (ECG) data were monitored continuously in these rats via aradiotelemetric data acquisition system for 96 hours following instillation. T[co] and HR decreased in a dose dependent manner in normal subjects following ROFA instillation. ECG data showed rate-related changes as well as increases in frequency and severity of arrhythmias, particularly atrioventricular nodal block and premature beats. Responses were exacerbated in all compromised animal models compared to those seen in healthy animals. Lethality was observed only in animals with concurrent pulmonary hypertension and inflammation and was preceded by severe decreases in HR and T[co]. These data demonstrate increased toxicity of emission source particulates in animals with cardiopulmonary disease and support epidemiological studies that report positive correlations between increased PM concentrations and excess mortality in cardiopulmonary-compromised patients.Master of Science in Public Healt

Gestational Vulnerability to Ozone Air Pollution - A Placental Story

About 99% of the global population resides in areas with air pollution surpassing World Health Organization standards. Air pollution is associated with adverse neonatal health outcomes such as low fetal birth weight and an increased risk for maternal pre-eclampsia. A particularly reactive air pollutant is ozone, which forms reactive oxygen species that induce cellular damage. Research exists on the dispersion of reactive oxygen species through the bloodstream leading to fetal vulnerability during pregnancy, specifically via the placenta. Yet, placental and fetal development is a temporal process with varied susceptibility to negative gestational outcomes. To addressing this gap, our laboratory utilized non-targeted proteomic analysis of amniotic fluid collected at term after either gestational day (GD) 10 or GD20 ozone exposure. Results provided a comprehensive list of proteins that indicated distinct outcome phenotypes. The acute GD20 exposure resulted in a potent acute-phase increase in antioxidant factors while the subacute GD10 exposure had a greater influence of growth factors. In follow-up, selected markers of these phenotypes will be assessed within matched placentas. Relevant to the antioxidant GD20 response, we will assess superoxide dismutase 1 (SOD1) and catalase, which catalyze superoxide and hydrogen peroxide, respectively. Per the GD10 subacute response, connective tissue growth factor (CTGF) is produced by cells involved with structure and stabilization of the ECM and affects cellular growth, migration, adhesion, and vascularization. Together with CTGF, collagen T1A2 plays a vital role in the extracellular matrix (ECM) and has been linked to pregnancy complications such as miscarriage, gestational diabetes, and preeclampsia. To assess differential impacts on the placental vasculature, we will be investigating vascular endothelial cell adhesion molecule 1 (VCAM-1) and vascular endothelial cadherin (VE-Cadherin), which have both been identified as biomarkers of preeclampsia. In our experiments, pregnant Sprague-Dawley rats were exposed once to 0.3 ppm of ozone (O3) or filtered air (FA) via whole-body inhalation at GD10 or GD20 while control animals received a sham filtered air exposure at both times. Placentas were collected and snap-frozen at GD21 followed by thin-sectioning using a frozen microtome and formaldehyde fixation. Primary antibodies to our protein targets are incubated overnight at 4C followed by secondary alexa-fluor conjugated antibodies to allow for multi-channel immunofluorescence detection. Images are generated on a Zeiss Axio Imager.M2 microscope at 200x magnification. Ongoing experiments are set at optimizing primary antibody concentrations. The experimental design involves creating three wells of two sample placental tissues per slide that are prepared and marked with primary and then secondary antibodies specific to the protein of interest. Each well contains a different dilution of the antibody that yields different fluorescence. Densitometric analysis is used to determine the concentration with the greatest signal-to-noise ratio. Once optimized, antibodies will be co-imaged on placenta tissues across five replicate animal exposure per experimental group. Quantification of mean fluorescence intensity will then be tabulated across decidual, labyrinth and chorionic placental lamina. Results will be assessed using analysis of variance with post-hoc testing for group differences. Expected outcomes will demonstrate the relationship between prior amniotic fluid proteomic findings and effects within the placenta while differentiating placental vulnerability across windows of gestation. These findings will prove significant in understanding outcomes at term for both the mother and fetus when exposed to ozone pollution.https://scholarscompass.vcu.edu/uresposters/1432/thumbnail.jp

Aging, longevity, and the role of environmental stressors: a focus on wildfire smoke and air quality

Aging is a complex biological process involving multiple interacting mechanisms and is being increasingly linked to environmental exposures such as wildfire smoke. In this review, we detail the hallmarks of aging, emphasizing the role of telomere attrition, cellular senescence, epigenetic alterations, proteostasis, genomic instability, and mitochondrial dysfunction, while also exploring integrative hallmarks - altered intercellular communication and stem cell exhaustion. Within each hallmark of aging, our review explores how environmental disasters like wildfires, and their resultant inhaled toxicants, interact with these aging mechanisms. The intersection between aging and environmental exposures, especially high-concentration insults from wildfires, remains under-studied. Preliminary evidence, from our group and others, suggests that inhaled wildfire smoke can accelerate markers of neurological aging and reduce learning capabilities. This is likely mediated by the augmentation of circulatory factors that compromise vascular and blood-brain barrier integrity, induce chronic neuroinflammation, and promote age-associated proteinopathy-related outcomes. Moreover, wildfire smoke may induce a reduced metabolic, senescent cellular phenotype. Future interventions could potentially leverage combined anti-inflammatory and NAD + boosting compounds to counter these effects. This review underscores the critical need to study the intricate interplay between environmental factors and the biological mechanisms of aging to pave the way for effective interventions

Engine-Operating Load Influences Diesel Exhaust Composition and Cardiopulmonary and Immune Responses

Background: The composition of diesel engine exhaust (DEE) varies by engine type and condition, fuel, engine operation, and exhaust after treatment such as particle traps. DEE has been shown to increase inflammation, susceptibility to infection, and cardiovascular responses in experimentally exposed rodents and humans. Engines used in these studies have been operated at idle, at different steady-state loads, or on variable-load cycles, but exposures are often reported only as the mass concentration of particulate matter (PM), and the effects of different engine loads and the resulting differences in DEE composition are unknown

Vascular and Cardiac Impairments in Rats Inhaling Ozone and Diesel Exhaust Particles

BackgroundMechanisms of cardiovascular injuries from exposure to gas and particulate air pollutants are unknown.ObjectiveWe sought to determine whether episodic exposure of rats to ozone or diesel exhaust particles (DEP) causes differential cardiovascular impairments that are exacerbated by ozone plus DEP.Methods and resultsMale Wistar Kyoto rats (10–12 weeks of age) were exposed to air, ozone (0.4 ppm), DEP (2.1 mg/m3), or ozone (0.38 ppm) + DEP (2.2 mg/m3) for 5 hr/day, 1 day/week for 16 weeks, or to air, ozone (0.51 or 1.0 ppm), or DEP (1.9 mg/m3) for 5 hr/day for 2 days. At the end of each exposure period, we examined pulmonary and cardiovascular biomarkers of injury. In the 16-week study, we observed mild pulmonary pathology in the ozone, DEP, and ozone + DEP exposure groups, a slight decrease in circulating lymphocytes in the ozone and DEP groups, and decreased platelets in the DEP group. After 16 weeks of exposure, mRNA biomarkers of oxidative stress (hemeoxygenase-1), thrombosis (tissue factor, plasminogen activator inhibitor-1, tissue plasminogen activator, and von Willebrand factor), vasoconstriction (endothelin-1, endothelin receptors A and B, endothelial NO synthase) and proteolysis [matrix metalloprotease (MMP)-2, MMP-3, and tissue inhibitor of matrix metalloprotease-2] were increased by DEP and/or ozone in the aorta, but not in the heart. Aortic LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) mRNA and protein increased after ozone exposure, and LOX-1 protein increased after exposure to ozone + DEP. RAGE (receptor for advanced glycation end products) mRNA increased in the ozone + DEP group. Exposure to ozone or DEP depleted cardiac mitochondrial phospholipid fatty acids (DEP > ozone). The combined effect of ozone and DEP exposure was less pronounced than exposure to either pollutant alone. Exposure to ozone or DEP for 2 days (acute) caused mild changes in the aorta.ConclusionsIn animals exposed to ozone or DEP alone for 16 weeks, we observed elevated biomarkers of vascular impairments in the aorta, with the loss of phospholipid fatty acids in myocardial mitochondria. We conclude that there is a possible role of oxidized lipids and protein through LOX-1 and/or RAGE signaling

Muscle RING Finger-1 Promotes a Maladaptive Phenotype in Chronic Hypoxia-Induced Right Ventricular Remodeling

Exposure to chronic hypoxia (CH) induces elevated pulmonary artery pressure/resistance, leading to an eventual maladaptive right ventricular hypertrophy (RVH). Muscle RING finger-1 (MuRF1) is a muscle-specific ubiquitin ligase that mediates myocyte atrophy and has been shown to play a role in left ventricular hypertrophy and altered cardiac bioenergetics in pressure overloaded hearts. However, little is known about the contribution of MuRF1 impacting RVH in the setting of CH. Therefore, we hypothesized that MuRF1 deletion would enhance RVH compared to their wild-type littermates, while cardiac-specific overexpression would reduce hypertrophy following CH-induced pulmonary hypertension. We assessed right ventricular systolic pressure (RVSP), right ventricle to left ventricle plus septal weight ratio (RV/LV+S) and hematocrit (Hct) following a 3-wk isobaric CH exposure. Additionally, we conducted dual-isotope SPECT/CT imaging with cardiac function agent 201Tl-chloride and cell death agent 99mTc-annexin V. Predictably, CH induced pulmonary hypertension, measured by increased RVSP, RV/LV+S and Hct in WT mice compared to normoxic WT mice. Normoxic WT and MuRF1-null mice exhibited no significant differences in RVSP, RV/LV+S or Hct. CH-induced increases in RVSP were also similar between WT and MuRF1-null mice; however, RV/LV+S and Hct were significantly elevated in CH-exposed MuRF1-null mice compared to WT. In cardiac-specific MuRF1 overexpressing mice, RV/LV+S increased significantly due to CH exposure, even greater than in WT mice. This remodeling appeared eccentric, maladaptive and led to reduced systemic perfusion. In conclusion, these results are consistent with an atrophic role for MuRF1 regulating the magnitude of right ventricular hypertrophy following CH-induction of pulmonary hypertension

Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence:Supporting the next generation of autophagy researchers and fostering international collaborations

Recently, NIH has funded a center for autophagy research named the Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence, located at the University of New Mexico Health Science Center (UNM HSC), with aspirations to promote autophagy research locally, nationally, and internationally. The center has 3 major missions: (i) to support junior faculty in their endeavors to develop investigations in this area and obtain independent funding; (ii) to develop and provide technological platforms to advance autophagy research with emphasis on cellular approaches for high quality reproducible research; and (iii) to foster international collaborations through the formation of an International Council of Affiliate Members and through hosting national and international workshops and symposia. Scientifically, the AIM center is focused on autophagy and its intersections with other processes, with emphasis on both fundamental discoveries and applied translational research.</p