Flash-, somatosensory-, and peripheral nerve-evoked potentials in rats perinatally exposed to Aroclor 1254

Pregnant Long–Evans rats were exposed to 0, 1 or 6 mg/kg/day of Aroclor 1254 (A1254; Lot no. 124-191), a commercial mixture of polychlorinated biphenyls (PCBs), from gestation day (GD) 6 through postnatal day (PND) 21. At 128–140 days of age, male and female offspring were tested for visual-, somatosensory- and peripheral nerve-evoked potentials. The evoked responses increased in amplitude with larger stimulus intensities, and gender differences were detected for some endpoints. In contrast, developmental exposure to A1254 failed to significantly affect the electrophysiological measures. A subset of the animals were tested for low-frequency hearing dysfunction using reflex modification audiometry (RMA). An elevated threshold for a 1-kHz tone was observed, replicating previous findings of A1254-induced auditory deficits [Hear. Res. 144 (2000) 196; Toxicol. Sci. 45(1) (1998) 94; Toxicol. Appl. Pharmacol. 135(1) (1995) 77.]. These findings indicate no statistically significant changes in visual-, somatosensory- or peripheral nerve-evoked potentials following developmental exposure to doses of A1254 that produce behavioral hearing deficits. However, subtle changes in the function of the visual or somatosensory systems cannot be disproved.     

Differential and non-uniform tissue and brain distribution of two distinct 14C-hexachlorobiphenyls in weanling rats.

Excretion and tissue retention of a coplanar and a non-coplanar hexachlorobiphenyl (HxCB) were determined 48 h after a single intraperitoneal (ip) dose of 8 mg/kg radiolabeled [14C]-HxCBs to weanling male and female Long-Evans rats. The objective was to understand the involvement of initial target organs of chlorobiphenyl (CB) accumulation following acute exposure in immature animals. During the short interval, both HxCBs remained sequestered predominantly in mesenteric fat (compared to subcutaneous fat) and less than 1% of the doses were excreted. Excretion was 4- to 8-fold lower than adult rats. Coplanar CB 169 (3,3',4,4',5,5'-HxCB) did not accumulate appreciably in the brain, but was retained at 3-fold higher levels in the liver than was non-coplanar CB 153 (2,2',4,4',5,5'-HxCB). Accumulation of 14C-CB 153 in brains was 4- to 9-fold higher than that of 14C-CB 169 and was adequate to detect non-uniform distribution in serial cryostat sections by phosphor imaging autoradiography. The autoradiographs showed a higher CB 153-derived radioactivity associated with fiber tracts throughout the brain. Specifically, the corpus callosum, internal and external capsules, medial lemniscus, tegmentum of the mesencephalon and metencephalon, and cerebellar peduncles showed significantly higher 14C-CB 153 than the other structures. The 14C-CB 153 was not found in the ventricular system and vascular spaces. These results suggest for the first time that an ortho-substituted PCB congener accumulated preferentially in brain in a structure-specific manner when compared to a non-ortho-substituted PCB congener.     

Cardiopulmonary responses of Wistar Kyoto, spontaneously hypertensive, and stroke-prone spontaneously hypertensive rats to particulate matter (PM) exposure

Humans with underlying cardiovascular disease, including stroke, are more susceptible to ambient particulate matter (PM)-induced morbidity and mortality. We hypothesized that stroke-prone spontaneously hypertensive rats (SHRSP) would be more susceptible than healthy Wistar Kyoto (WKY) rats to PM-induced cardiac oxidative stress and pulmonary injury. We further postulated that PM-induced injury would be greater in SHRSP than in spontaneously hypertensive rats (SHR) based on the greater disease severity in SHRSP than SHR. First, male WKY and SHRSP were intratracheally (IT) instilled with saline or 1.11, 3.33, or 8.33 mg/kg of oil combustion PM and responses were analyzed 4 or 24 h later. Second, SHR and SHRSP were IT instilled with saline or 3.33 or 8.33 mg/kg of the same PM and responses were analyzed 24 h later. Pulmonary injury and inflammation were assessed in bronchoalveolar lavage fluid (BALF) and cardiac markers in cytosolic and mitochondrial fractions. BALF neutrophilic inflammatory response was induced similarly in all strains following PM exposure. BALF protein leakage, gamma-glutamyl transferase, and N-acetylglucosaminidase activities, but not lactate dehydrogenase activity, were exacerbated in SHRSP compared to WKY or SHR. Pulmonary cytosolic and cardiac mitochondrial ferritin levels decreased, and cardiac cytosolic superoxide dismutase (SOD) activity increased in SHRSP only. Pulmonary SOD activity decreased in WKY and SHRSP. Cardiac mitochondrial isocitrate dehydrogenase (ICDH) activity decreased in PM-exposed WKY and SHR; control levels were lower in SHRSP than SHR or WKY. In summary, strain-related differences exist in pulmonary protein leakage and oxidative stress markers. PM-induced changes in cardiac oxidative stress sensitive enzymes are small, and appear only slightly exacerbated in SHRSP compared to WKY or SHR. Multiple biological markers may be differentially affected by PM in genetic models of cardiovascular diseases. Preexisting cardiovascular disease may influence susceptibility to PM pulmonary and cardiac health effects in a disease-specific manner.     

Consistent pulmonary and systemic responses from inhalation of fine concentrated ambient particles: roles of rat strains used and physicochemical properties

Several studies have reported health effects of concentrated ambient particles (CAP) in rodents and humans; however, toxicity end points in rodents have provided inconsistent results. In 2000 we conducted six 1-day exposure studies where spontaneously hypertensive (SH) rats were exposed to filtered air or CAPs (< or = 2.5 microm, 1,138-1,765 microg/m3) for 4 hr (analyzed 1-3 hr afterward). In seven 2-day exposure studies in 2001, SH and Wistar Kyoto (WKY) rats were exposed to filtered air or CAP (< or = 2.5 microm, 144-2,758 microg/m3) for 4 hr/day times 2 days (analyzed 1 day afterward). Despite consistent and high CAP concentrations in the 1-day exposure studies, no biologic effects were noted. The exposure concentrations varied among the seven 2-day exposure studies. Except in the first study when CAP concentration was highest, lavageable total cells and macrophages decreased and neutrophils increased in WKY rats. SH rats demonstrated a consistent increase of lavage fluid gamma-glutamyltransferase activity and plasma fibrinogen. Inspiratory and expiratory times increased in SH but not in WKY rats. Significant correlations were found between CAP mass (microgram per cubic meter) and sulfate, organic carbon, or zinc. No biologic effects correlated with CAP mass. Despite low chamber mass in the last six of seven 2-day exposure studies, the levels of zinc, copper, and aluminum were enriched severalfold, and organic carbon was increased to some extent when expressed per milligram of CAP. Biologic effects were evident in those six studies. These studies demonstrate a pattern of rat strain-specific pulmonary and systemic effects that are not linked to high mass but appear to be dependent on CAP chemical composition.     

Neurotoxicity of persistent organic pollutants: possible mode(s) of action and further considerations

Persistent organic pollutants (POPs) are long-lived toxic organic compounds and are of major concern for human and ecosystem health. Although the use of most POPs is banned in most countries, some organochlorine pesticides are still being used in several parts of the world. Although environmental levels of some POPs such as polychlorinated biphenyls (PCBs) have declined, newly emerging POPs such as polybrominated diphenyl ethers (PBDEs) have been increasing considerably. Exposure to POPs has been associated with a wide spectrum of effects including reproductive, developmental, immunologic, carcinogenic, and neurotoxic effects. It is of particular concern that neurotoxic effects of some POPs have been observed in humans at low environmental concentrations. This review focuses on PCBs as a representative chemical class of POPs and discusses the possible mode(s) of action for the neurotoxic effects with emphasis on comparing dose-response and structure-activity relationships (SAR) with other structurally related chemicals. There is sufficient epidemiological and experimental evidence showing that PCB exposure is associated with motor and cognitive deficits in humans and animal models. Although several potential mode(s) of actions were postulated for PCB-induced neurotoxic effects, changes in neurotransmitter systems, altered intracellular signalling processes, and thyroid hormone imbalance are predominant ones. These three potential mechanisms are discussed in detail in vitro and in vivo. In addition, SAR was conducted on other structurally similar chemicals to see if they have a common mode(s) of action. Relative potency factors for several of these POPs were calculated based on their effects on intracellular signalling processes. This is a comprehensive review comparing molecular effects at the cellular level to the neurotoxic effects seen in the whole animal for environmentally relevant POPs.     

The spontaneously hypertensive rat: an experimental model of sulfur dioxide-induced airways disease.

Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction, inflammation, and mucus hypersecretion, features that are common in bronchitis, emphysema, and often asthma. However, current rodent models do not reflect this human disease. Because genetically predisposed spontaneously hypertensive (SH) rats display phenotypes such as systemic inflammation, hypercoagulation, oxidative stress, and suppressed immune function that are also apparent in COPD patients, we hypothesized that SH rat may offer a better model of experimental bronchitis. We, therefore, exposed SH and commonly used Sprague Dawley (SD) rats (male, 13- to 15-weeks old) to 0, 250, or 350 ppm sulfur dioxide (SO(2)), 5 h/day for 4 consecutive days to induce airway injury. SO(2) caused dose-dependent changes in breathing parameters in both strains with SH rats being slightly more affected than SD rats. Increases in bronchoalveolar lavage fluid (BALF) total cells and neutrophilic inflammation were dose dependent and significantly greater in SH than in SD rats. The recovery was incomplete at 4 days following SO(2) exposure in SH rats. Pulmonary protein leakage was modest in either strain, but lactate dehydrogenase and N-acetyl glucosaminidase activity were increased in BALF of SH rats. Airway pathology and morphometric evaluation of mucin demonstrated significantly greater impact of SO(2) in SH than in SD rats. Baseline differences in lung gene expression pattern suggested marked immune dysregulation, oxidative stress, impairment of cell signaling, and fatty acid metabolism in SH rats. SO(2) effects on these genes were more pronounced in SH than in SD rats. Thus, SO(2) exposure in SH rats may yield a relevant experimental model of bronchitis.     

Systemic vascular disease in male B6C3F1 mice exposed to particulate matter by inhalation: studies conducted by the National Toxicology Program

Epidemiological studies suggest an association between ambient particulate matter and cardiopulmonary diseases in humans. The mechanisms underlying these health effects are poorly understood. To better understand the potential relationship between particulate-matter-induced inflammation and vascular disease, a 2-phase retrospective study was conducted. Phase one included the review of heart, lung, and kidney tissues from high-dose and control male B6C3F1 mice exposed by inhalation to 9 particulate compounds for a 2-year period. The results showed that high-dose males developed significantly increased incidences of coronary and renal arteritis over controls in 2 of the 9 studies (indium phosphide and cobalt sulfate heptahydrate), while marginal increases in arteritis incidence was detected in 2 additional studies (vanadium pentoxide and gallium arsenide). In contrast, arteritis of the muscular arteries of the lung was not observed. Morphological features of arteritis in these studies included an influx of mixed inflammatory cells including neutrophils, lymphocytes, and macrophages. Partial and complete effacement of the normal vascular wall architecture, often with extension of the inflammatory process into the periarterial connective tissue, was observed. Phase 2 evaluated the heart, lung, kidney, and mesentery of male and female B6C3F1 mice from the 90-day studies of the 4 compounds demonstrating arteritis after a 2-year period. The results showed arteritis did not develop in the 90-day studies, suggesting that long-term chronic exposure to lower-dose metallic particulate matter may be necessary to induce or exacerbate arteritis.     

Altered gene expression profiles of rat lung in response to an emission particulate and its metal constituents

Comprehensive and systematic approaches are needed to understand the molecular basis for the health effects of particulate matter (PM) reported in epidemiological studies. Due to the complex nature of the pollutant and the altered physiological conditions of predisposed populations, it has been difficult to establish a direct cause and effect relationship. A high-throughput technology such as gene expression profiling may be useful in identifying molecular networks implicated in the health effects of PM and its causative constituents. Differential gene expression profiles derived for rat lungs exposed to PM and its constituent metals using a custom rat cardiopulmonary cDNA array are presented here. This array consists of 84 cardiopulmonary-related genes representing various biological functions such as lung injury/inflammation, repair/remodeling, structural and matrix alterations, and vascular contractility, as well as six expressed sequence tags (ESTs). The cDNA array was hybridized with (32)P-labeled cDNA generated from rat lung RNA. Total lung RNA was isolated from male Sprague-Dawley rats at 3 and 24 h following intratracheal instillation of either saline, residual oil fly ash (ROFA; 3.3 mg/kg), or its most toxic metallic constituents, nickel (NiSO(4); 3.3 mmol/kg) and vanadium (VSO(4); 5.7 mmol/kg). Metal concentrations reflected the levels present in one ROFA instillate. Densitometric scans of the array blots indicated ROFA- and metal-specific increased expression (1.5 to 3-fold) of stress response, inflammatory, and repair-related genes, and also genes involved in vascular contractility and thrombogenic activity. Expression of multiple cytokines in ROFA exposed rat lung compared to Ni and V suggest the role and importance of understanding constituent interactions in PM toxicity. Expression profiling using genomic approaches will aid in our understanding of toxicant-specific altered molecular pathways in lung injury and pathogenesis.