Biomedical subjects

David O Carpenter

Publications and source records attributed to David O Carpenter.

At least 37 records · Page 2Linked to original sources

PubMed2005

Hospitalization rates for coronary heart disease in relation to residence near areas contaminated with persistent organic pollutants and other pollutants.

Exposure to environmental pollutants may contribute to the development of coronary heart disease (CHD). We determined the ZIP codes containing or abutting each of the approximately 900 hazardous waste sites in New York and identified the major contaminants in each. Three categories of ZIP codes were then distinguished: those containing or abutting sites contaminated with persistent organic pollutants (POPs), those containing only other types of wastes ("other waste"), and those not containing any identified hazardous waste site ("clean"). Effects of residence in each of these ZIP codes on CHD and acute myocardial infarction (AMI) hospital discharge rates were assessed with a negative binomial model, adjusting for age, sex, race, income, and health insurance coverage. Patients living in ZIP codes contaminated with POPs had a statistically significant 15.0% elevation in CHD hospital discharge rates and a 20.0% elevation in AMI discharge rates compared with clean ZIP codes. In neither of the comparisons were rates in other-waste sites significantly greater than in clean sites. In a subset of POP ZIP codes along the Hudson River, where average income is higher and there is less smoking, better diet, and more exercise, the rate of hospitalization for CHD was 35.8% greater and for AMI 39.1% greater than in clean sites. Although the cross-sectional design of the study prevents definite conclusions on causal inference, the results indirectly support the hypothesis that living near a POP-contaminated site constitutes a risk of exposure and of development of CHD and AMI.

Adult↗

PubMed2005

Risk-based consumption advice for farmed Atlantic and wild Pacific salmon contaminated with dioxins and dioxin-like compounds.

We reported recently that several organic contaminants occurred at elevated concentrations in farmed Atlantic salmon compared with concentrations of the same contaminants in wild Pacific salmon [Hites et al. Science 303: 226-229 (2004)]. We also found that polychlorinated biphenyls (PCBs), toxaphene, dieldrin, dioxins, and polybrominated diphenyl ethers occurred at higher concentrations in European farm-raised salmon than in farmed salmon from North and South America. Health risks (based on a quantitative cancer risk assessment) associated with consumption of farmed salmon contaminated with PCBs, toxaphene, and dieldrin were higher than risks associated with exposure to the same contaminants in wild salmon. Here we present information on cancer and noncancer health risks of exposure to dioxins in farmed and wild salmon. The analysis is based on a tolerable intake level for dioxin-like compounds established by the World Health Organization and on risk estimates for human exposure to dioxins developed by the U.S. Environmental Protection Agency. Consumption of farmed salmon at relatively low frequencies results in elevated exposure to dioxins and dioxin-like compounds with commensurate elevation in estimates of health risk.

Animals↗

PubMed2005

Polychlorinated biphenyls in serum of the Siberian Yupik people from St. Lawrence Island, Alaska.

OBJECTIVES: To determine serum levels of polychlorinated biphenyls (PCBs) in Siberian Yupik adults from St. Lawrence Island, Alaska, and to determine the relative contribution of atmospheric transport of PCBs and local contamination to body burdens. STUDY DESIGN: Siberian Yupiks of various ages were recruited from three populations: residents of the village of Gambell, residents of the village of Savoonga who did not have family hunting camps near the Northeast Cape (NEC), a Formerly Used Defense Site (FUDS) known to be contaminated with PCBs, and residents of Savoonga whose families had a hunting camp at the NEC. METHODS: Levels of PCBs were measured in serum samples from 130 people, ages 19-76. These Alaska Natives follow a traditional diet high in marine mammals and fish, which bioconcentrate organochlorine compounds that migrate to the Arctic via global air transport and ocean currents. RESULTS: The lipid-adjusted serum PCB levels of those members of families with hunting camps at the NEC had a mean lipid-adjusted PCB concentration of 1,143 ppb, whereas other residents of Savoonga had values of 847 ppb and residents of Gambell had values of 785 ppb. CONCLUSIONS: Our observations suggest that atmospheric transport of PCBs contributes to levels in the Yupik people, but that the abandoned military site at the NEC may also contribute to the human body burden in those individuals who have either spent substantial time or consumed food from there.

Adult↗

PubMed2004

Use of bipolar parallel electrodes for well-controlled microstimulation in a mouse hippocampal brain slice.

In a hippocampal brain slice two types of stimulating electrodes [single (SE) or monopolar and parallel bipolar (PE)] were used to determine the optimal protocol for single pulse microstimulation. We show that even for a constant-current power source the amplitude of stimulating current (SC) is not constant, especially for short pulse widths (PW) (<200 micros). Recording the stimulating current and computing the amount of electric charge that is passed through the microelectrode gives the best estimate of the strength of electrical stimulation. For SE the evoked response is obstructed for a time interval larger than three times the PW. The stimulus artifact (SA) substantially decreases when a PE is used. The orientation of the stimulating current relative to the position of the targeted fibers (Schaffer collaterals) was controlled when using a PE. The use of PEs allowed the accurate recording of the physiological response that contains three clearly defined peaks. Stimulation can be elicited at PW as short as 30 micros when the main current is capacitive. The charge needed to elicit physiological responses was in the range of 1-40 nC (the lower values for the PE) suggesting that use of PEs is most advantageous for well-controlled microstimulation studies in brain slices.

Action Potentials↗

PubMed2004

Rodent lymphocytes express functionally active glutamate receptors.

RT-PCR demonstrated that ionotropic (iGluR NR1) and metabotropic (mGluR Group III) glutamate receptors are expressed in rodent lymphocytes. Flow cytometry showed that activation of iGluR NR1 by N-methyl-D-aspartate (NMDA) increased intracellular free calcium and reactive oxygen species (ROS) levels and activated caspase-3. The latter effect was attenuated by the NMDA antagonist, 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), by the antioxidant N-acetylcysteine and by cyclosporin A. Treatment with L-2-amino-4-phosphonobutyric acid (L-AP4), an mGluR Group III agonist, increased lymphocyte ROS levels but to a lower extent than did NMDA. Activation of lymphocytes with both NMDA and L-AP4 caused a synergistic increase in ROS levels and induced necrotic cellular death without elevating the caspase-3 activation observed in the presence of NMDA alone. These results show that lymphocyte iGluR NR1 and mGluR Group III receptors may be involved in controlling rodent lymphocyte functions and longevity as they regulate events in cell proliferation, maturation, and death.

Aminobutyrates↗

PubMed2004

Global assessment of polybrominated diphenyl ethers in farmed and wild salmon.

We have shown recently that levels of persistent, bioaccumulative contaminants (polychlorinated biphenyls, dioxins, and several chlorinated pesticides) are significantly higher in farmed than in wild salmon and that European farm-raised salmon have significantly greater toxic contaminant loads than those raised in North and South America. In this paper, we extend these results to polybrominated diphenyl ethers (PBDEs) and show that farm-raised salmon have higher levels of these compounds than wild salmon. We also show that farm-raised salmon from Europe have higher PBDE levels than those raised in North America and that both European and North American farm-raised salmon have higher PBDE levels than those farm-raised in Chile. Among the species of wild salmon, chinook had significantly elevated PBDE levels relative to the other wild species. These elevated PBDE levels may be related to chinook's feeding behavior and trophic level. Among all of the wild species we studied, chinook tend to feed higher in the food web throughout their adult life and grow to be larger individuals.

Animals↗

PubMed2004

Comparative effects of technical toxaphene, 2,5-dichloro-3-biphenylol and octabromodiphenylether on cell viability, [Ca2+]i levels and membrane fluidity in mouse thymocytes.

Flow cytometric studies of mouse thymocytes show that technical toxaphene (10-20 ppm) and 2,5-dichloro-3-biphenylol (PCB 9-OH) (5-10 ppm) kill cells and cause an increase in intracellular calcium concentration, [Ca2+]i, whereas commercial octabromodiphenylether (OBDE) has no effect. The cell death is not a result of the rise of [Ca2+]i, since the divalent cation ionophore, ionomycin, causes a large elevation in [Ca2+]i without cell death. We have studied effects of these compounds on membrane fluorescence polarization, a measure of membrane fluidity, using 1,6-diphenyl-1,3,5-hexatriene (DPH). We find that toxaphene causes a decrease in membrane fluidity in the concentration range associated with cell death, whereas PCB 9-OH causes an increase in fluidity and OBDE has no effect. These observations suggest that alterations of membrane fluidity of thymocytes, whether it be an increase or decrease, can cause cytotoxicity.

Animals↗

PubMed2004

Ortho-substituted but not coplanar PCBs rapidly kill cerebellar granule cells.

Several PCB congeners were assessed for their cytotoxicity on cerebellar granule cells in an attempt to compare their structure-activity relationship as potential neurotoxicants and to assess the mechanisms associated with their toxicity. Flow cytometry was used to monitor the changes of a number of biochemical endpoints: membrane integrity, intracellular free calcium concentration ([Ca(2+)](i)), reactive oxygen species (ROS) production, mitochondrial membrane potential (Delta psi(m)), and cell size. The non-coplanar, ortho-substituted congeners, PCB 8 (2,4'-dichlorobiphenyl), PCB 28 (2,4,4'-trichlorobiphenyl), PCB 47 (2,4,2',4'-tetrachlorobiphenyl), and PCB 52 (2,5,2',5'-tetrachlorobiphenyl) (10 microM) killed neurons to different degrees within 30 min. Loss of viability was accompanied by increased [Ca(2+)](i) and decreased Delta psi(m). No significant changes of ROS level were observed during exposure. The coplanar congeners, PCB 77 (3,4,3',4'-tetrachlorobiphenyl), PCB 80 (3,5,3',5'-tetrachlorobiphenyl), and PCB 81 (3,4,5,4'-tetrachlorobiphenyl) (10 microM), had no effects on membrane integrity, [Ca(2+)](i) or Delta psi(m) in this time period of exposure. In Ca(2+)-free Tyrode's medium, there was no [Ca(2+)](i) increase after exposure to the ortho-substituted congeners, but also no reduction in loss of membrane integrity, suggesting Ca(2+) influx was not the cause of viability loss. The mitochondrial uncoupler, carbonyl cyanide m-chlorophenyl hydrazone (CCCP) (1-2 microM), caused a large decrease of Delta psi(m), but only a slight loss of viability, which suggested that Delta psi(m) is not the primary cause of PCB 52-induced cell death. These studies show that ortho-substituted PCBs are toxic to cerebellar granule cells; however, their toxic action is not secondary to elevation of intracellular calcium, a change in mitochondrial membrane potential, or free radical generation.

Animals↗

PubMed2004

Ortho-substituted PCBs kill cells by altering membrane structure.

Our previous studies have demonstrated that ortho-substituted PCBs cause a rapid cell death in both thymocytes and cerebellar granule cell neurons, whereas coplanar congeners are without effect at comparable concentrations and exposure times. We have demonstrated that multiple membrane components are altered by these exposures, including the plasma membrane, mitochondria, and endoplasmic reticulum. The present experiments were designed to test the hypothesis that because of their stereochemistry, ortho-substituted congeners cause a greater disruption of membrane integrity than do coplanar congeners, and that this membrane disruption results in altered cellular function and to cell death. To test this hypothesis we have measured fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) in thymocytes, cerebellar granule cells, and lipid bilayer vesicles upon exposure to an ortho-substituted PCB congener (PCB 52) and a coplanar congener (PCB 77), and compared results obtained in these studies to those from flow cytometric studies of plasma membrane permeability to large molecules and elevations of intracellular calcium in living cells. The fluorescence polarization of the DPH probe, which inserts into the lipid bilayer, reflects changes in membrane fluidity. In all three preparations we found that whereas fluorescence polarization was unchanged upon exposure to PCB 77, it was reduced significantly by PCB 52, reflecting an increase in membrane fluidity. These observations are consistent with the hypothesis that ortho-substituted PCBs disrupt membrane structure, which alters the function of membrane proteins. In the two cell types we have studied, the disruption is sufficient to cause death of the cell within a brief time.

Animals↗

PubMed2004

Global assessment of organic contaminants in farmed salmon.

The annual global production of farmed salmon has increased by a factor of 40 during the past two decades. Salmon from farms in northern Europe, North America, and Chile are now available widely year-round at relatively low prices. Salmon farms have been criticized for their ecological effects, but the potential human health risks of farmed salmon consumption have not been examined rigorously. Having analyzed over 2 metric tons of farmed and wild salmon from around the world for organochlorine contaminants, we show that concentrations of these contaminants are significantly higher in farmed salmon than in wild. European-raised salmon have significantly greater contaminant loads than those raised in North and South America, indicating the need for further investigation into the sources of contamination. Risk analysis indicates that consumption of farmed Atlantic salmon may pose health risks that detract from the beneficial effects of fish consumption.

Analysis of Variance↗

PubMed2004

An ecosystem approach to the health effects of mercury in the Great Lakes basin ecosystem.

New concerns about the global presence and human health significance of mercury have arisen as a result of recent epidemiological data demonstrating subtle neurological effects from consumption of mercury-contaminated fish. In the Great Lakes Basin, the complexity of the diverse sources, pools, and sinks of mercury and of the pathways of distribution, fate, and biotransformation requires an ecosystem approach to the assessment of exposures of Great Lakes' human populations. Further epidemiological research is needed to verify preliminary indications of harmful effects in people living near the Great Lakes. Great Lakes fish are valuable resources for subsistence nutrition, recreation, and commerce, but the benefits of fish consumption must be balanced by concern for the hazards from the contaminants that they may contain. The efficacy of fish consumption advisories in reducing exposures should continue to be evaluated while planning continues for remedial actions on contaminated sediments from historic industrial activities and for regulatory action to control sources.

Animals↗

PubMed2004

Hippocampal long-term potentiation (LTP) is reduced by a coplanar PCB congener.

Neurotoxicity of polychlorinated biphenyls (PCBs) is usually ascribed to the ortho-substituted congeners. We have examined the effects of acute perfusion of 3,3',4,4'-tetrachlorobiphenyl (PCB 77), a coplanar, dioxin-like congener, on long-term potentiation (LTP) in the Schaffer collateral-CA1 and the mossy fiber-CA3 pathways in mouse hippocampus. LTP in both pathways was blocked by PCB 77, with a threshold effect at a concentration of 1 microM. LTP is a useful model of learning and memory function in which a patterned stimulation of an afferent pathway produces a persistent increase in the efficacy of synaptic transmission. LTP is reduced by PCB mixtures and ortho-substituted congeners at concentrations comparable to those studied here. These observations provide evidence in support of the hypothesis that dioxin-like and non-dioxin-like PCB congeners are equally potent in causing the cognitive decrements seen in children exposed prenatally to PCBs.

Animals↗

PubMed2004

TCDD and PCBs inhibit breast cancer cell proliferation in vitro.

The effects on cell proliferation of arylhydrocarbon receptor (AhR) agonists in estrogen-responsive T47D and ZR-75-1 cells were investigated. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the non-ortho-substituted polychlorinated biphenyl (PCB) congeners, PCB 77, PCB 81, PCB 126, and PCB 169 each inhibited 17beta-estradiol (E(2))-stimulated cell proliferation in a dose-responsive manner. In the absence of added E(2), TCDD, PCB 77, PCB 81, and PCB 169 had no significant effect on cell proliferation, while PCB 126 at high concentrations caused slight elevations. The order of effective inhibition of E(2)-stimulated cell proliferation by the PCB congeners was: PCB 81>PCB 126 approximately = PCB 169>PCB 77. In the comparative literature, mammalian TEFs for these congeners toxic potency are in the order: PCB 126>PCB 169>PCB 81 approximately = PCB 77 [Organohalogen Compd. 34 (1997) 237]. Our results thus show an unexpected different pattern for the inhibitory effects of PCBs congeners on E(2)-mediated cell proliferation.

Breast Neoplasms↗

PubMed2004

A survey of metals in tissues of farmed Atlantic and wild Pacific salmon.

Contamination of fish tissues with organic and inorganic contaminants has been a pervasive environmental and public health problem. The present study reports the concentrations of nine metals in tissues of farmed Atlantic salmon (Salmo salar) and two species of wild-caught salmon (chum [Oncorhynchus keta] and coho [O. kisutch]) analyzed as part of a global survey of contaminants in these fish. Of the nine metals, organic arsenic was significantly higher in farmed than in wild salmon, whereas cobalt, copper, and cadmium were significantly higher in wild salmon. None of the contaminants exceeded federal standards or guidance levels.

Animals↗

PubMed2004

Amyloid-beta induced cell death is independent of free radicals.

Acutely dissociated rat cerebellar granule cell neurons were incubated with amyloid-beta (1-42) and studied by flow cytometry. Amyloid-beta caused a dose-dependent loss of viability, as determined by intracellular accumulation of propidium iodide (PI),and that was not accompanied by significant elevation of intracellular calcium, measured by Fluo-3 or reactive oxygen species (ROS), measured by 2',7'-dihydro-dichlorfluorescein diacetate (DCF). Carnosine, a ROS scavenger and an inhibitor of non-enzymatic glycosylation, partially reduced cell death caused by amyloid-beta. We conclude that amyloid-beta causes a relatively acute loss of cell viability in cerebellar granule cell neurons, which does not result from either elevation of intracellular calcium concentration or generation of ROS.

Alzheimer Disease↗

PubMed2003

The effects of protein kinase C activity on synaptic transmission in two areas of rat hippocampus.

The effects of three protein kinase C (PKC) agonists (phorbol ester, ingenol and indolactam-V) and two PKC antagonists (D-erythro-sphingosine and chelerythrine) on input-output (I-O) relations in the Schaffer collateral pathway to CA1 (SC-CA1) and mossy fiber pathway to CA3 (MF-CA3) were determined in rat hippocampus brain slices. In the SC-CA1 pathway, phorbol esters and indolactam-V had only small effects on field excitatory post-synaptic potentials (fEPSP) in slices from 60-day animals, although ingenol, an activator of novel PKC isozymes, caused a significant decrease of the field excitatory post-synaptic potentials amplitude in 60-day animals, but not in 30-day animals. In contrast, in the MF-CA3 pathway, PKC agonists induced a significant increase in the field excitatory post-synaptic potentials. PKC antagonists depressed the field excitatory post-synaptic potentials in the SC-CA1 pathway, but had no significant effect in the MF-CA3 pathway. In the MF-CA3 pathway, paired-pulse facilitation was abolished by PKC agonists and unaffected by antagonists. In SC-CA1, it was depressed by agonists to levels below control, whereas it was significantly increased by chelerythine. We conclude that PKC plays important but different roles in both regions. In the SC-CA1 pathway, PKC is almost maximally active under control circumstances, and PKC antagonists significantly reduce synaptic responses. In contrast, in the MF-CA3 pathway, there is no apparent activation under resting circumstances, but significant potentiation of synaptic transmission is induced when PKC is activated. There are developmental changes in the pattern of PKC isozymes, and both pre- and post-synaptic actions are important.

Alkaloids↗

PubMed2003

Ortho-substituted PCBs kill thymocytes.

The effects of exposure of acutely dissociated rat thymocytes to various polychlorinated biphenyl (PCB) congeners were examined using flow cytometry. Non-planar, ortho-substituted congeners caused a rapid cell death at low micromolar concentrations, while coplanar, dioxin-like congeners at the same concentration were without significant effect. The most potent of the congeners studied was PCB 52 (2,2',5,5'-tetrachlorobiphenyl), which had an IC50 of 3.96 microM at 20 min. Prior to loss of viability there was a decrease in mitochondrial membrane potential Delta Psi m, an accumulation of intracellular calcium, and a progressive leakiness of the plasma membrane. Application of PCB 52 in calcium-free medium reduced the calcium accumulation, but did not reduce cell death. Agents that depolarized mitochondria also did not induce the same degree of cell death caused by PCB 52. Cyclosporin A, which prevents opening of the mitochondria permeability transition channel, protected against cell death but did not protect against mitochondrial depolarization or calcium accumulation. Rapamycin and FK 506 at high concentration provided partial protection against cell death. These observations indicate that the ortho-substituted PCB 52 disrupts plasma, mitochondrial and endoplasmic reticulum membranes. We hypothesize that PCB 52 incorporates into lipid bilayers and with its bulky, three-dimensional ortho-substituted congener structure disrupts membrane function to a greater degree than coplanar congeners.

Animals↗

PubMed2003

PbCl2-induced hyperpolarization of rat thymocytes: involvement of charybdotoxin-sensitive K+ channels.

The effect of PbCl2 on membrane potential and intracellular divalent metal cation concentrations of rat thymocytes was examined by flow cytometry. PbCl2 at concentrations of 0.3 microM or higher (up to 10 microM) produced persistent, dose-dependent hyperpolarization (decrease in the intensity of di-BA-C4 fluorescence). Removal of external Ca2+ did not significantly affect the PbCl2-induced hyperpolarization. Charybdotoxin, a specific antagonist of Ca(2+)-dependent K+ conductance, greatly attenuated the PbCl2-induced hyperpolarization. PbCl2 increased the intensity of fluo-3 fluorescence under both normal Ca2+ and nominally Ca(2+)-free conditions. These results suggest that Pb2+ enters thymocytes, causing an increase in fluo-3 fluorescence, and activates Ca(2+)-dependent K+ channels, resulting in hyperpolarization. The persistent activation of K+ channels by Pb2+, leading to persistent hyperpolarization, may be one mechanism whereby Pb2+ alters immune function, as membrane potential changes influence physiological functions of lymphocytes.

Animals↗