Cardiomyopathy confers susceptibility to particulate matter-induced oxidative stress,vagal dominance,arrhythmia and pulmonary inflammation in heart failure-prone rats

Abstract

Acute exposure to ambient fine particulate matter (PM_2.5) is tied to cardiovascular morbidity and mortality, especially among those with prior cardiac injury. The mechanisms and pathophysiological events precipitating these outcomes remain poorly understood but may involve inflammation, oxidative stress, arrhythmia and autonomic nervous system imbalance. Cardiomyopathy results from cardiac injury, is the leading cause of heart failure, and can be induced in heart failure-prone rats through sub-chronic infusion of isoproterenol (ISO). To test whether cardiomyopathy confers susceptibility to inhaled PM_2.5 and can elucidate potential mechanisms, we investigated the cardiophysiologic, ventilatory, inflammatory and oxidative effects of a single nose-only inhalation of a metal-rich PM_2.5 (580?µg/m³, 4?h) in ISO-pretreated (35 days?×?1.0?mg/kg/day sc) rats. During the 5 days post-treatment, ISO-treated rats had decreased HR and BP and increased pre-ejection period (PEP, an inverse correlate of contractility) relative to saline-treated rats. Before inhalation exposure, ISO-pretreated rats had increased PR and ventricular repolarization time (QT) and heterogeneity (Tp-Te). Relative to clean air, PM_2.5 further prolonged PR-interval and decreased systolic BP during inhalation exposure; increased tidal volume, expiratory time, heart rate variability (HRV) parameters of parasympathetic tone and atrioventricular block arrhythmias over the hours post-exposure; increased pulmonary neutrophils, macrophages and total antioxidant status one day post-exposure; and decreased pulmonary glutathione peroxidase 8 weeks after exposure, with all effects occurring exclusively in ISO-pretreated rats but not saline-pretreated rats. Ultimately, our findings indicate that cardiomyopathy confers susceptibility to the oxidative, inflammatory, ventilatory, autonomic and arrhythmogenic effects of acute PM_2.5 inhalation.     

Ambient air pollution alters heart rate regulation in aged mice

Context:?Heart rate alterations associated with exposure to particulate matter (PM) and gaseous pollutants have been observed in epidemiological studies and animal experiments. Nevertheless, the time-lag of these associations is still unclear.

Objective:?Determine the association at different time-lags between the complex mixture of ambient concentrations of PM, carbon monoxide (CO), and nitrogen dioxide (NO₂), and markers of cardiac function in a model of aged mice.

Materials and methods:?AKR/J inbred mice were exposed to ambient air, 6?h daily for 40 weekdays. During this period, the animals’ electrocardiogram (ECG), deep body temperature (Tdb), and body weight (BW) were registered, and concentrations of PM, CO, NO₂, as well as air temperature and relative humidity (RH) were measured. Data analysis included random effects models with lagged covariate methods.

Results:?CO was significantly associated with declines in heart rate (HR) and heart rate variability (HRV), PM was significantly associated with declines in HRV and BW, and NO₂ was significantly associated with declines in HR. Some significant associations occurred in the same day (PM and HRV, PM and BW, CO and HR), whereas others were delayed by 1 to 3 days (CO and HR, CO and HRV, NO₂ and HR, PM and HRV).

Discussion and conclusion:?Finding significant declines in heart function in aged mice associated with the combined effects of air pollutants at ambient concentrations and at different time-lags is of great importance to public health. These results further implicate the potential short term and delayed effects of air pollution on HR alterations.     

Effects of repeated exposure to isoproterenol in vivo and in vitro on amylase release from rat parotid tissue

Effects of repeated exposure to isoproterenol (ISO), in vivo and in vitro, were investigated on amylase release from rat parotid slices responding to secretagogues. Responses to ISO and dibutyryl cyclic AMP (DBcAMP) were reduced in the tissue from ISO-treated rats (3 mg/kg, 3 times daily for 3 days), but not in the tissue from propranolol plus ISO-treated rats. Administration of inhibitors of protein synthesis with ISO resulted in a protective effect with regard to development of decreased responses to ISO, DBcAMP and carbachol. A decreased response to ISO (10(-5) M) was caused by repeated exposure to ISO in vitro and could not be prevented by pretreatment with inhibitors of protein synthesis. Although the basal level of cyclic AMP in parotid tissue was lower in ISO-pretreated rats than in control rats, after incubation with ISO, the level of cyclic AMP did not differ between ISO-pretreated and control rats. These results suggest that the decreased response (amylase release) to ISO in the parotid tissue from ISO-pretreated rats may have been due to an impairment of common secretory process(es) involving various secretagogues and that the development of the impairment may be closely connected to the de novo synthesis of proteins induced by ISO, but not the impairment of the beta-adrenoceptor-adenylate cyclase system.     

Whole and particle-free diesel exhausts differentially affect cardiac electrophysiology, blood pressure, and autonomic balance in heart failure-prone rats

Epidemiological studies strongly link short-term exposures to vehicular traffic and particulate matter (PM) air pollution with adverse cardiovascular (CV) events, especially in those with preexisting CV disease. Diesel engine exhaust is a key contributor to urban ambient PM and gaseous pollutants. To determine the role of gaseous and particulate components in diesel exhaust (DE) cardiotoxicity, we examined the effects of a 4-h inhalation of whole DE (wDE) (target PM concentration: 500 μg/m(3)) or particle-free filtered DE (fDE) on CV physiology and a range of markers of cardiopulmonary injury in hypertensive heart failure-prone rats. Arterial blood pressure (BP), electrocardiography, and heart rate variability (HRV), an index of autonomic balance, were monitored. Both fDE and wDE decreased BP and prolonged PR interval during exposure, with more effects from fDE, which additionally increased HRV triangular index and decreased T-wave amplitude. fDE increased QTc interval immediately after exposure, increased atrioventricular (AV) block Mobitz II arrhythmias shortly thereafter, and increased serum high-density lipoprotein 1 day later. wDE increased BP and decreased HRV root mean square of successive differences immediately postexposure. fDE and wDE decreased heart rate during the 4th hour of postexposure. Thus, DE gases slowed AV conduction and ventricular repolarization, decreased BP, increased HRV, and subsequently provoked arrhythmias, collectively suggesting parasympathetic activation; conversely, brief BP and HRV changes after exposure to particle-containing DE indicated a transient sympathetic excitation. Our findings suggest that whole- and particle-free DE differentially alter CV and autonomic physiology and may potentially increase risk through divergent pathways.     

Elevated blood pressure and heart rate in rats exposed to a coal-derived complex organic mixture

The susceptibility of the cardiovascular system to exposure to a high-boiling coal liquid (heavy distillate, HD) was studied in the rat using an isoproterenol (ISO) myocardial infarction model. Male Fischer rats were exposed to HD by inhalation (0.7 mg/l), 6 h/day, 5 days/week, for 6 weeks. After a 10-day recovery period, sham-exposed and HD-exposed rats were injected subcutaneously with 0, 20, 40 or 60 mg ISO/kg body weight. Blood pressure, heart rate, electrocardiogram and 99mTc uptake by the heart were measured 1 day later. A dose-related increase was observed in the uptake of 99mTc by the hearts of both sham-exposed and HD-exposed animals after ISO injection; however, uptake by the sham-exposed group was significantly greater than that of exposed groups. The most striking observation was a 20% elevation in arterial blood pressure of HD-exposed rats over that of sham-exposed animals when no ISO was injected. These results suggest that the cardiovascular system could be detrimentally affected by exposure to coal-derived complex mixtures and, possibly, to other complex organic mixtures.     

Particle deposition in spontaneously hypertensive rats exposed via whole-body inhalation: measured and estimated dose.

A plethora of epidemiological studies have shown that exposure to elevated levels of ambient particulate matter (PM) can lead to adverse health outcomes, including cardiopulmonary-related mortality. Subsequent animal toxicological studies have attempted to mimic these cardiovascular and respiratory responses, in order to better understand underlying mechanisms. However, it is difficult to quantitate the amount of PM deposited in rodent lungs following inhalation exposure, thus making fundamental dose-to-effect assessment and linkages to human responses problematic. To address this need, spontaneously hypertensive rats were exposed to an oil combustion-derived PM (HP12) via inhalation while being maintained in whole-body plethysmograph chambers. Rats were exposed 6 h/day to 13 mg/m(3) of HP12 for 1 or 4 days. Immediately following the last exposure, rats were sacrificed and their tracheas and lung lobes harvested and separated for neutron activation analysis. Total lower respiratory tract deposition ranged from 20-60 microg to 89-139 microg for 1- and 4-day exposures, respectively. Deposition data were compared to default and rat-specific estimates provided by the Multiple Path Particle Deposition (MPPD) model, yielding model predictions that were < 33% of the measured dose. This study suggests that HP12 exposure decreased particle clearance, as the mass of HP12 in the lungs following a 4-day protocol was nearly four times that observed after a 1-day exposure. This work should improve the ability of risk assessors to extrapolate rat-to-human exposure concentrations on the basis of lung burdens and, thus, better relate inhaled doses and resultant toxicological effects.     

Comparative electrocardiographic,autonomic and systemic inflammatory responses to soy biodiesel and petroleum diesel emissions in rats

Abstract

Context: Biodiesel fuel represents an alternative to high particulate matter (PM)-emitting petroleum-based diesel fuels, yet uncertainty remains regarding potential biodiesel combustion emission health impacts.

Objective: The purpose of this study was to compare cardiovascular responses to pure and blended biodiesel fuel emissions relative to petroleum diesel exhaust (DE).

Materials and methods: Spontaneously hypertensive rats were exposed for 4?h per day for four days via whole body inhalation to combustion emissions (based on PM concentrations 50, 150 or 500?μg/m³ or filtered air) from pure (B100) or blended (B20) soy biodiesel, or to pure petroleum DE (B0). Electrocardiogram (ECG) and heart rate variability (HRV, an index of autonomic balance) were monitored before, during and after exposure while pulmonary and systemic inflammation were assessed one day after the final exposure. ECG and HRV data and inflammatory data were statistically analyzed using a linear mixed model for repeated measures and an analysis of variance, respectively.

Results: B100 and B0, but not B20, increased HRV during all exposure days at the highest concentration indicating increased parasympathetic tone. Electrocardiographic data were mixed. B100 and B0, but not B20, caused significant changes in one or more of the following: serum C-reactive protein, total protein, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, and blood urea nitrogen (BUN) and plasma angiotensin converting enzyme (ACE) and fibrinogen.

Discussion and conclusions: Although responses to emissions from all fuels were mixed and relatively mild, some findings point to a reduced cardiovascular impact of blended biodiesel fuel emissions.     

Cardiovascular and thermoregulatory effects of inhaled PM-associated transition metals: a potential interaction between nickel and vanadium sulfate.

Recent epidemiological studies have shown an association between daily morbidity and mortality and ambient particulate matter (PM) air pollution. It has been proposed that bioavailable metal constituents of PM are responsible for many of the reported adverse health effects. Studies of instilled residual oil fly ash (ROFA) demonstrated immediate and delayed responses, consisting of bradycardia, hypothermia, and arrhythmogenesis in conscious, unrestrained rats. Further investigation of instilled ROFA-associated transition metals showed that vanadium (V) induced the immediate responses, while nickel (Ni) was responsible for the delayed effects. Furthermore, Ni potentiated the immediate effects caused by V when administered concomitantly. The present study examined the responses to these metals in a whole-body inhalation exposure. To ensure valid dosimetric comparisons with instillation studies, 4 target exposure concentrations ranging from 0.3-2.4 mg/m(3) were used to incorporate estimates of total inhalation dose derived using different ventilatory parameters. Rats were implanted with radiotelemetry transmitters to continuously acquire heart rate (HR), core temperature (T(CO)), and electrocardiographic data throughout the exposure. Animals were exposed to aerosolized Ni, V, or Ni + V for 6 h per day x 4 days, after which serum and bronchoalveolar lavage samples were taken. Even at the highest concentration, V failed to induce any significant change in HR or T(CO). Ni caused delayed bradycardia, hypothermia, and arrhythmogenesis at concentrations > 1.2 mg/m(3). When combined, Ni and V produced observable delayed effects at 0.5 mg/m(3) and potentiated responses at 1.3 mg/m(3), greater than were produced by the highest concentration of Ni (2.1 mg/m(3)) alone. These results indicate a possible synergistic relationship between inhaled Ni and V, and provide insight into potential interactions regarding the toxicity of PM-associated metals.     

Ultrafine carbon black disturbs heart rate variability in mice

Previous epidemiological and toxicological studies have reported the associations between ambient particulate matter (PM) exposure and changes in heart rate variability (HRV), a marker of cardiac autonomic nervous system (ANS) function. However, both the responsible components in PM and their mechanisms affecting HRV remain uncertain. We propose that carbon black (CB), one of the main components in PM, may affect HRV through mechanisms independent of cardio-pulmonary and systemic inflammation and/or injury. Male C57BL/6 mice were exposed by intra-tracheal instillation to ultrafine CB (once every two days for three times) at doses of 0, 0.05, 0.15 and 0.6 mg/kg. HRV indices, standard deviation of all normal R-R intervals (SDNN) and the square root of mean of sum of squares of differences between adjacent normal R-R intervals (RMSSD), showed significant decreases in 0.15 and 0.6 mg/kg CB exposed groups. Slight pulmonary inflammation and myocardial injury were only observed in 0.6 mg/kg CB exposed group. We conclude that CB can disturb cardiac ANS function in mice, indicated by the withdrawal of parasympathetic modulation, through mechanisms independent of apparent myocardial and pulmonary injury.     

Pharmacokinetics of inhaled manganese phosphate in male Sprague-Dawley rats following subacute (14-day) exposure

Methylcyclopentadienyl manganese tricarbonyl (MMT) is used as a gasoline octane enhancer. Manganese phosphate is the primary respirable (PM(2.5)) MMT-combustion product emitted from the automobile tailpipe. The goal of this study was to determine the exposure-response relationship for inhaled manganese phosphate in adult male CD rats. Rats were exposed 6-h/day for either 5 days/week (10 exposures) or 7 days/week (14 exposures) to manganese phosphate at 0, 0.03, 0.3, or 3 mg Mn/m(3) (MMAD congruent with 1.5 micrometer). The following tissues collected at the end of the 2-week exposure: plasma, erythrocytes, olfactory bulb, striatum, cerebellum, lung, liver, femur, and skeletal muscle (n = 6 rats/exposure group) were analyzed for manganese content by neutron activation analysis. Intravenous (54)MnCl(2) tracer studies were also conducted following the 14th exposure (n = 6 rats/concentration), and whole-body gamma spectrometry was performed immediately after injection and at 1, 2, 4, 8, 12, and 16 weeks after (54)MnCl(2) administration. Increased manganese concentrations were observed in olfactory bulb, lung, femur, and skeletal muscle following exposure to 3 mg Mn/m(3) (10 or 14 exposures). Increased manganese concentrations were also observed in olfactory bulb, striatum, and lung following exposure to 0.3 mg Mn/m(3) (14 exposures only). Red blood cell and plasma manganese concentrations were increased only in rats exposed to 3 mg Mn/m(3) (10 exposures). Rats exposed to 3 mg Mn/m(3) also had an increased whole-body manganese clearance rate when compared to air-exposed control animals. Our results suggest that the rat olfactory bulb may accumulate more manganese than other brain regions following inhalation exposure.     

Interactions between toluene and alcohol

Weanling male Fischer-344 rats were exposed by inhalation to air or 2000 ppm toluene for 8 hours each day for 2 weeks. Subgroups had access to water or 6% alcohol as their only fluid sources, respectively. Rats exposed to both toluene and alcohol subsequently showed a marked preference for 6% alcohol in two-bottle choice tests that persisted for up to 20 days for some rats. Rats exposed to toluene without access to alcohol and control rats (exposed to air and water) showed a marked aversion to the alcohol solution, and only 2 of 12 rats forced to drink alcohol without exposure to toluene preferred alcohol in the preference tests. Exposure to both toluene and alcohol also caused greater inhibition of weight gain than exposure to either substance alone, accompanied by greater signs of organ toxicity as indicated by clinical blood chemistries. Exposure to toluene caused marked hearing loss as assessed by a behavioral technique (conditioned avoidance), and there was a trend toward enhancement of this ototoxic effect by forced consumption of alcohol.     

Clinical and pathological manifestations of cardiovascular disease in rat models: the influence of acute ozone exposure

Abstract

Rodent models of cardiovascular diseases (CVD) and metabolic disorders are used for examining susceptibility variations to environmental exposures. However, cross-model organ pathologies and clinical manifestations are often not compared. We hypothesized that genetic CVD rat models will exhibit baseline pathologies and will thus express varied lung response to acute ozone exposure. Male 12–14-week-old healthy Wistar Kyoto (WKY), Wistar (WIS), and Sprague–Dawley (SD) rats and CVD-compromised spontaneously hypertensive (SH), fawn-hooded hypertensive (FHH), stroke-prone SH (SHSP), obese SH heart-failure (SHHF), obese diabetic JCR (JCR) rats were exposed to 0.0, 0.25, 0.5, or 1.0?ppm ozone for 4?h and clinical biomarkers, and lung, heart and kidney pathologies were compared immediately following (0–h) or 20-h later. Strain differences were observed between air-exposed CVD-prone and WKY rats in clinical biomarkers and in kidney and heart pathology. Serum cholesterol was higher in air-exposed obese SHHF and JCR compared to other air-exposed strains. Ozone did not produce lesions in the heart or kidney. CVD-prone and SD rats demonstrated glomerulopathy and kidney inflammation (WKY?=?WIS?=?SH?<?SD?=?SHSP?<?SHHF?<?JCR?=?FHH) regardless of ozone. Cardiac myofiber degeneration was evident in SH, SHHF, and JCR, while only JCR tends to have inflammation in coronaries. Lung pathology in air-exposed rats was minimal in all strains except JCR. Ozone induced variable alveolar histiocytosis and bronchiolar inflammation; JCR and SHHF were less affected. This study provides a comparative account of the clinical manifestations of disease and early-life organ pathologies in several rat models of CVD and their differential susceptibility to lung injury from air pollutant exposure.     

Effects of Instilled Combustion-Derived Particles in Spontaneously Hypertensive Rats. Part II: Pulmonary Responses

A consistent association between exposure to high concentrations of ambient particulate matter (PM) and excess cardiopulmonary-related morbidity and mortality has been observed in numerous epidemiological studies, across many different geographical locations. To elicit a similar response in a controlled laboratory setting, spontaneously hypertensive rats were exposed to an oil combustion-derived PM (HP-12) and monitored for changes in pulmonary function and indices of pulmonary injury. Rats were implanted with radiotelemeters to monitor electrocardiogram, heart rate, systemic arterial blood pressure, core temperature, and activity. Animals were divided into four groups and exposed via intratracheal instillation (IT) to suspensions of HP-12 (0.0, 0.83, 3.33, and 8.33 mg/kg; control, low, mid, and high dose, respectively) in saline vehicle. Telemetered rats were monitored continuously for 4–7 days post-IT and pulmonary function was examined using a whole-body plethysmograph system for 6 h/day on post-IT days 1–7. At 24, 96, and 192 h post-IT, bronchoalveolar lavage fluid (BALF) was obtained from subsets of nontelemetered animals in order to assess the impact of HP-12 on biochemical indices of pulmonary inflammation and injury. Immediate dose-related changes in pulmonary function were observed after HP-12 exposure, consisting of decreases in tidal volume (↓12–41%) and increases in breathing frequency (↑52–103%), minute ventilation (↑12–25%), and enhanced pause (↑113–187%). These functional effects were resolved by 7 days post-IT, although some average BALF constituents remained elevated through day 7 for mid- and high-dose groups when compared to those of the saline-treated control group. This study demonstrates significant deficits in pulmonary function, along with significant increases in BALF indices of pulmonary inflammation and injury in SH rats after IT exposure to HP-12.     

Biopersistence of potassium hexatitanate in inhalation and intratracheal instillation studies

An inhalation study and an intratracheal instillation study were conducted to evaluate the biological effects of the new chemical, potassium hexatitanate (PH). For the inhalation study, Wistar male rats were exposed to PH for 6?h a day, 5 days a week for a period of 3 months. The mass median aerodynamic diameter of PH in the exposure chamber was 4.9?μm (1.8) and the mean concentration during the exposure was 2.3?±?0.1?mg/m(3). After the 3-month inhalation period, rats were dissected at 3 days, 1 month, 3 months, 6 months, and 12 months. The initial PH burden was 0.17?±?0.03?mg/lung, and this decreased exponentially up to 6 months after inhalation. After 6 months, the rate at which the burden decreased slowed. The biological halftime up to 6 months after exposure was 2.3 months. No difference was found in the dimension of PH fibers in the lung during the observation period and the histopathological examination found no remarkable inflammation or fibrosis. For the intratracheal instillation study, the rats were given a single 2-mg dose of PH suspended in a 0.4?ml saline solution. The geometric mean diameter was 4.3?μm (2.3). After instillation, the rats were dissected at 3 days to 12 months. The PH burden in the lungs decreased exponentially and the biological halftime was 3.1 months. The results of the dimension of PH and histopathological findings were the same as those for the inhalation study. These data suggest that the toxicity of PH in the lung is low in these doses.     

Synergistic effects of exposure to concentrated ambient fine pollution particles and nitrogen dioxide in humans

Context: Exposure to single pollutants e.g. particulate matter (PM) is associated with adverse health effects, but it does not represent a real world scenario that usually involves multiple pollutants.

Objectives: Determine if simultaneous exposure to PM and NO₂ results in synergistic interactions.

Materials and methods: Healthy young volunteers were exposed to clean air, nitrogen dioxide (NO₂, 0.5 ppm), concentrated fine particles from Chapel Hill air (PM_2.5CAPs, 89.5?±?10.7 µg/m³), or NO₂+PM_2.5CAPs for 2?h. Each subject performed intermittent exercise during the exposure. Parameters of heart rate variability (HRV), changes in repolarization, peripheral blood endpoints and lung function were measured before and 1 and 18?h after exposure. Bronchoalveolar lavage (BAL) was performed 18?h after exposure.

Results: NO₂ exposure alone increased cholesterol and HDL 18?h after exposure, decreased high frequency component of HRV one and 18?h after exposure, decreased QT variability index 1?h after exposure, and increased LDH in BAL fluid. The only significant change with PM_2.5CAPs was an increase in HDL 1?h after exposure, likely due to the low concentrations of PM_2.5CAPs in the exposure chamber. Exposure to both NO₂ and PM_2.5CAPs increased BAL α1-antitrypsin, mean t wave amplitude, the low frequency components of HRV and the LF/HF ratio. These changes were not observed following exposure to NO₂ or PM_2.5CAPs alone, suggesting possible interactions between the two pollutants.

Discussion and conclusions: NO₂ exposure may produce and enhance acute cardiovascular effects of PM_2.5CAPs. Assessment of health effects by ambient PM should consider its interactions with gaseous copollutants.     

PM2.5-induced changes in cardiac function of hypertensive rats depend on wind direction and specific sources in Steubenville, Ohio

BACKGROUND: Increases in particulate matter less than 2.5 μm (PM(2.5)) in ambient air is linked to acute cardiovascular morbidity and mortality. Specific components and potential emission sources of PM(2.5) responsible for adverse health effects of cardiovascular function are unclear. Methods: Spontaneously hypertensive rats were implemented with radiotelemeters to record ECG responses during inhalation exposure to concentrated ambient particles (CAPs) for 13 consecutive days in Steubenville, OH. Changes in heart rate (HR) and its variability (HRV) were compared to PM(2.5) trace elements in 30-min time frames to capture acute physiological responses with real-time fluctuations in PM(2.5) composition. Using positive matrix factorization, six major source factors were identified: (i) coal/secondary, (ii) mobile sources, (iii) metal coating/processing, (iv) iron/steel manufacturing, (v) lead and (vi) incineration. Results: Exposure-related changes in HR and HRV were dependant on winds predominately from either the northeast (NE) or southwest (SW). During SW winds, the metal processing factor was associated with increased HR, whereas factors of incineration, lead and iron/steel with NE winds were associated with decreased HR. Decreased SDNN was dominated during NE winds by the incinerator factor, and with SW winds by the metal factor. Metals and mobile source factors also had minor impacts on decreased SDNN with NE winds. Individual elemental components loaded onto these factors generally showed significant associations, although there were some discrepancies. Conclusions: Acute cardiovascular changes in response to ambient PM(2.5) exposure can be attributed to specific PM constituents and sources linked with incineration, metal processing, and iron/steel production.     

Differential cardiotoxicity in response to chronic doxorubicin treatment in male spontaneous hypertension-heart failure (SHHF), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats

Life threatening complications from chemotherapy occur frequently in cancer survivors, however little is known about genetic risk factors. We treated male normotensive rats (WKY) and strains with hypertension (SHR) and hypertension with cardiomyopathy (SHHF) with 8 weekly doses of doxorubicin (DOX) followed by 12 weeks of observation to test the hypothesis that genetic cardiovascular disease would worsen delayed cardiotoxicity. Compared with WKY, SHR demonstrated weight loss, decreased systolic blood pressure, increased kidney weights, greater cardiac and renal histopathologic lesions and greater mortality. SHHF showed growth restriction, increased kidney weights and renal histopathology but no effect on systolic blood pressure or mortality. SHHF had less severe cardiac lesions than SHR. We evaluated cardiac soluble epoxide hydrolase (sEH) content and arachidonic acid metabolites after acute DOX exposure as potential mediators of genetic risk. Before DOX, SHHF and SHR had significantly greater cardiac sEH and decreased epoxyeicosatrienoic acid (EET) (4 of 4 isomers in SHHF and 2 of 4 isomers in SHR) than WKY. After DOX, sEH was unchanged in all strains, but SHHF and SHR rats increased EETs to a level similar to WKY. Leukotriene D4 increased after treatment in SHR. Genetic predisposition to heart failure superimposed on genetic hypertension failed to generate greater toxicity compared with hypertension alone. The relative resistance of DOX-treated SHHF males to the cardiotoxic effects of DOX in the delayed phase despite progression of genetic disease was unexpected and a key finding. Strain differences in arachidonic acid metabolism may contribute to variation in response to DOX toxicity.     

Inhalation toxicity of adiponitrile in rats

Adiponitrile, a chemical intermediate used in the manufacture of hexamethylenediamine, has moderate acute toxicity both orally and dermally. The acute inhalation toxicity was determined by exposing groups of young adult male ChR-CD rats for single 4-hr periods. The LC50 was 1.71 mg/liter. Male rats were exposed to either 0 (control), 0.03, 0.1, or 0.3 mg vaporized adiponitrile/liter for ten 6-hr periods (5 exposure days, 2 rest days, 5 exposure days). Clinical signs during exposure included irregular respiration and mild salivation. Rats exposed to 0.3 mg/liter showed weight loss during the first 5 exposures followed by a normal rate of weight gain. After 10 exposures, rats in this group had the following clinical pathologic changes: increased blood glucose, urea nitrogen, creatinine, and urine glucose; decreased erythrocyte count, hemoglobin, leukocyte count, relative number of eosinophils, and urine osmolality. Rats exposed to 0.1 mg/liter had increased urea nitrogen and lymphocytes and decreased numbers of neutrophils and eosinophils. No changes in clinical pathology parameters were seen in rats exposed to 0.03 mg/liter. Rats from all groups had normal values 14 days following the last exposure. Pathologic examination failed to reveal any compound-related changes.     

PM2.5-induced changes in cardiac function of hypertensive rats depend on wind direction and specific sources in Steubenville,Ohio

Background: Increases in particulate matter less than 2.5?µm (PM_2.5) in ambient air is linked to acute cardiovascular morbidity and mortality. Specific components and potential emission sources of PM_2.5 responsible for adverse health effects of cardiovascular function are unclear.

Methods: Spontaneously hypertensive rats were implemented with radiotelemeters to record ECG responses during inhalation exposure to concentrated ambient particles (CAPs) for 13 consecutive days in Steubenville, OH. Changes in heart rate (HR) and its variability (HRV) were compared to PM_2.5 trace elements in 30-min time frames to capture acute physiological responses with real-time fluctuations in PM_2.5 composition. Using positive matrix factorization, six major source factors were identified: (i) coal/secondary, (ii) mobile sources, (iii) metal coating/processing, (iv) iron/steel manufacturing, (v) lead and (vi) incineration.

Results: Exposure-related changes in HR and HRV were dependant on winds predominately from either the northeast (NE) or southwest (SW). During SW winds, the metal processing factor was associated with increased HR, whereas factors of incineration, lead and iron/steel with NE winds were associated with decreased HR. Decreased SDNN was dominated during NE winds by the incinerator factor, and with SW winds by the metal factor. Metals and mobile source factors also had minor impacts on decreased SDNN with NE winds. Individual elemental components loaded onto these factors generally showed significant associations, although there were some discrepancies.

Conclusions: Acute cardiovascular changes in response to ambient PM_2.5 exposure can be attributed to specific PM constituents and sources linked with incineration, metal processing, and iron/steel production.     

Pulmonary effects and clearance after long-term inhalation of potassium octatitanate whiskers in rats

The pulmonary effects of long-term inhalation of potassium octatitanate whisker (PT1), one of the durable man-made fibers (MMFs), were examined in rats. Male Wistar rats were exposed to PT1 by inhalation for 6 h/day, 5 days/wk for 1 yr. The daily average exposure concentration of PT1 aerosol was 2.2 +/- 0.7 mg/m3 (111 +/- 34 fiber/ml) during the exposure. Rats were sacrificed at 3 days, 6 mo, and 12 mo after 1 yr of inhalation exposure. The amount of deposited PT1 in rat lungs (lung burden) was 2.4 +/- 0.7 mg and the deposition fraction was 7.2% at 3 days after 1 yr. The clearance of inhaled PT1 after 1-yr inhalation was prolonged so that the biological half-life time (BHT) was difficult to estimate. The histopathological findings showed that mild fibrotic changes were observed around the macrophages that had engulfed the PT1 in the 3-day, 6-mo, and 12-mo rat sacrifice groups. As for pulmonary tumors, no malignant tumors were observed, although 2 adenomas at 6 mo and 1 adenoma and 1 squamous metaplasia at 12 mo after the exposure were found in the rat lungs.