A bibenzimidazole-containing ruthenium(II) complex acting as a cation-driven molecular switch.
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Journal Article↗
Biomedical subjects
J G Vos
Publications and source records attributed to J G Vos.
Site-specific methylation of coordinated 1,2,4-triazoles: a novel route to sterically hindered Ru(bpy)2 complexes.
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Journal Article↗
Contaminant-induced immunosuppression and mass mortalities among harbor seals.
Virus-associated mass mortalities among seals inhabiting northwestern Europe have generated an interest in immunotoxicology in this species. A morbillivirus has been isolated from victims, but a contribution of immunotoxic contaminants to the severity of the outbreaks could not be ruled out. Fish-eating seals occupy high trophic levels in the aquatic food chain, and accumulate high levels of contaminants including polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs). Such chemicals have been found to be immunotoxic at low doses in studies of laboratory animals. We carried out an immunotoxicological study, in which captive harbor seals (Phoca vitulina) were fed herring from either relatively uncontaminated sites of the Atlantic Ocean, or from the highly contaminated Baltic Sea. In this report we summarize the contaminant-related immunosuppression observed in the captive group of seals fed herring from the Baltic Sea. In addition, we describe two parallel studies, in which laboratory rats are exposed as adults or perinatally to the contaminants in the Baltic Sea herring, exhibiting immunotoxicity. On the basis of these studies we conclude that complex mixtures of environmental contaminants including PCBs, PCDFs, and PCDDs may represent a real immunotoxic risk to free-ranging seals.
Animals↗
Toxicology of environmental chemicals in the flounder (Platichthys flesus) with emphasis on the immune system: field, semi-field (mesocosm) and laboratory studies.
European flounder (Platichthys flesus) has shown an increased prevalence of liver tumors and lymphocystis disease (a viral infection) that correlated with pollution in field research in Dutch coastal and estuarine waters. Semi-field or mesocosm experiments confirmed the supposed causality. Although these types of research are highly relevant for the feral population, laboratory experiments are necessary to establish causal relationships between specific chemical pollutants and disease. Therefore, the effects on flounder of some of the potentially causative chemicals such as benzo[a]pyrene (BaP), dimethyl-benz[a]anthracene (DMBA), 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5 pentachlorobiphenyl (PCB-126), and bis(tri-n-butyltin)oxide (TBTO) were examined in several laboratory experiments. These effects were evaluated using general toxicological parameters and histopathology. For immune function assessment, attempts to develop an infection model with the lymphocystis virus were made, but appeared unsuccessful and immune function tests are not fully operational at the moment. Flounder has been successfully maintained and exposed to toxic substances in captivity in our laboratory. Short-term aqueous exposure to high levels of BaP or DMBA did not induce marked effects under our experimental conditions. Results of oral exposure of flounder to low levels of TCDD, PCB-126 or harbor sludge extract show significant induction of cytochrome P4501A (CYP1A) in hepatocytes. Oral exposure to high levels of TCDD or PCB-126 also significantly induced CYP1A immunoreactivity in epithelium in mesonephros and digestive tract and in endothelium in several organs. Remarkable was the induction of CYP1A in a distinct population of mononuclear cells in the mesonephros. Moreover, oral exposure to TCDD resulted in an increased mitotic activity and an increase of the hepatosomatic index in the 20 and 500 microgram TCDD/kg group respectively. Therefore, exposure to TCDD and related substances may promote the development of liver tumors in the field. Exposure to PCB-126 also significantly reduced the relative thymus volume, but other results indicate that flounder is relatively insensitive to this type of chemicals. Short-term aqueous exposure of flounder to TBTO, in concentrations that were in the same order of magnitude as upper TBT levels measured in the field, caused mortality after 7-12 days associated with gill lesions, and induced reduction of the non-specific resistance and decrease of the relative thymus volume. From these results we therefore conclude that TBTO might play a causal role in, for instance, increased prevalence of lymphocystis virus infections in the field
Animals↗
Health effects of endocrine-disrupting chemicals on wildlife, with special reference to the European situation.
Many wildlife species may be exposed to biologically active concentrations of endocrine-disrupting chemicals. There is strong evidence obtained from laboratory studies showing the potential of several environmental chemicals to cause endocrine disruption at environmentally realistic exposure levels. In wildlife populations, associations have been reported between reproductive and developmental effects and endocrine-disrupting chemicals. In the aquatic environment, effects have been observed in mammals, birds, reptiles, fish, and mollusks from Europe, North America, and other areas. The observed abnormalities vary from subtle changes to permanent alterations, including disturbed sex differentiation with feminized or masculinized sex organs, changed sexual behavior, and altered immune function. For most reported effects in wildlife, however, the evidence for a causal link with endocrine disruption is weak or nonexisting. Crucial in establishing causal evidence for chemical-induced wildlife effects appeared semifield or laboratory studies using the wildlife species of concern. Impaired reproduction and development causally linked to endocrine-disrupting chemicals are well documented in a number of species and have resulted in local or regional population changes. These include: Masculinization (imposex) in female marine snails by tributyltin, a biocide used in antifouling paints, is probably the clearest case of endocrine disruption caused by an environmental chemical. The dogwhelk is particularly sensitive, and imposex has resulted in decline or extinction of local populations worldwide, including coastal areas all over Europe and the open North Sea. DDE-induced egg-shell thinning in birds has caused severe population declines in a number of raptor species in Europe and North America. Endocrine-disrupting chemicals have adversely affected a variety of fish species. In the vicinity of certain sources (e.g., effluents of water treatment plants) and in the most contaminated areas is this exposure causally linked with the effects on reproductive organs that could have implications for fish populations. However, there is also a more widespread occurrence of endocrine disruption in fish in the U.K., where estrogenic effects have been demonstrated in freshwater systems, in estuaries, and in coastal areas. In mammals, the best evidence comes from the-field studies on Baltic gray and ringed seals, and from the Dutch semifield studies on harbor seals, where both reproduction and immune functions have been impaired by PCBs in the food chain. Reproduction effects resulted in population declines, whereas impaired immune function has likely contributed to the mass mortalities due to morbillivirus infections. Distorted sex organ development and function in alligators has been related to a major pesticide spill into a lake in Florida, U.S.A. The observed estrogenic/antiandrogenic effects in this reptile have been causally linked in experimental studies with alligator eggs to the DDT complex. Although most observed effects currently reported concern heavily polluted areas, endocrine disruption is a potential global problem. This is exemplified by the widespread occurrence of imposex in marine snails and the recent findings of high levels of persistent potential endocrine-disrupting chemicals in several marine mammalian species inhabiting oceanic waters.
Animals↗
Health effects of hexachlorobenzene and the TEF approach.
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Animals↗
The role of thymus-dependent T cells in hexachlorobenzene-induced inflammatory skin and lung lesions.
The involvement of thymus-dependent T cells in the inflammatory skin and lung lesions and spleen effects induced by hexachlorobenzene (HCB) was investigated by using genetically athymic and euthymic WAG/Rij rats and Brown Norway (BN) rats with or without depletion of T cells by adult thymectomy, lethal irradiation, and bone marrow reconstitution. Rats were exposed to diets with no supplementation or diets supplemented with 150 or 450 mg HCB per kg diet for 4 (BN) or 6 (WAG/Rij) weeks. Skin lesion development and body weight gains were assessed during exposure and spleen and liver weights as well as histopathologic changes in skin, lung, and spleen were assessed after exposure. Oral HCB exposure of athymic and euthymic rats of both rat strains resulted in a dose-dependent increase of relative liver weight at doses of 150 and 450 mg/kg HCB and increased relative spleen weights at a dose of 450 mg/kg. HCB exposure of both strains further resulted in inflammatory changes in skin, lungs, and splenic red pulp independent of the T cell status except for skin lesions in the BN strain. HCB-exposed T cell-competent BN rats showed faster skin lesion development than the T cell-depleted rats, although qualitatively and quantitatively similar skin pathology was observed at the end of the 4-week exposure in both groups. In the WAG/Rij strain skin lesions could not be comparatively assessed due to preexistent inflammatory skin pathology in the nude rats. This study showed that thymus-derived T cells are not required for the induction of skin and lung pathology and splenic changes by HCB and therefore it is suggested that HCB acts differently from many allergenic and autoimmunogenic low molecular weight compounds that trigger pathology via thymus-dependent mechanisms. A role for mononuclear phagocytes and, in BN rats, eosinophilic granulocytes, in the HCB-induced pathology is suggested since these cells were prominently present in the HCB-induced lesions.
Animals↗
The effect of air pollution on exhaled nitric oxide of atopic and nonatopic subjects.
Levels of exhaled nitric oxide (NO) were determined in well-characterized atopic and nonatopic subjects on 4 days with a different level of outdoor air pollution. The two groups matched well regarding spirometric values, i.e., no difference with regard to FEV(1), FVC, and peak flow. On the 4 test days asymptomatic atopic subjects exhaled 1.5- to 2.4-fold higher levels of NO compared with nonatopic subjects. In both groups the increase in exhaled NO in response to air pollution was similar (2.5 times maximal increase, P < 0.01). In conclusion, atopic subjects exhale higher levels of NO compared with nonatopic subjects, but respond to a similar degree to increased levels of air pollution.
Adult↗
Increased exhaled nitric oxide on days with high outdoor air pollution is of endogenous origin.
The aim of this study was to assess the effect of outdoor air pollution on exhaled levels of endogenously released nitric oxide. To exclude bias from exogenous NO in the recovered exhaled air (residual NO or NO in dead volume) an experimental design was used that sampled NO of endogenous origin only. The validity of the presented experimental design was established in experiments where subjects were exposed to high levels of exogenous NO (cigarette smoke or 480 microg x m(-3) synthetic NO). Subsequent 1 min breathing and a final inhalation of NO-free air proved to be sufficient to attain pre-exposure values. Using the presented method detecting only endogenous NO in exhaled air, 18 subjects were sampled on 4 separate days with different levels of outdoor air pollution (read as an ambient NO level of 4, 30, 138 and 246 microg x m(-3)). On the 2 days with highest outdoor air pollution, exhaled NO was significantly (p<0.001) increased (67-78%) above the mean baseline value assessed on 4 days with virtually no outdoor air pollution. In conclusion, the level of endogenous nitric oxide in exhaled air is increased on days with high outdoor air pollution. The physiological implications of this findings need to be investigated further.
Adult↗
Environmental and lifestyle factors may act in concert to increase the prevalence of respiratory allergy including asthma.
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Animals↗
A pollen model in the rat for testing adjuvant activity of air pollution components.
During the last decades, the prevalence of allergy has increased worldwide. Allergic rhinitis ("hay fever") and asthma are two of the most common allergic diseases. A possible cause for increased allergy to pollen is air pollution. The increase of industrialization and the number of diesel engines associated with diesel exhaust particles (DEP) in the air parallel the increase in allergic airway diseases. To investigate the adjuvant effect of DEP in pollen allergy, Brown Norway (BN) rats were sensitized intranasally or intratracheally with timothy grass pollen (Phleum pratense) with or without DEP (3 mg/ml). Intranasal sensitization (200 microl, 10 mg/ml) was performed daily for 5 consecutive days and intratracheal sensitization (200 microl, 10 mg/ml) was performed once. Challenge with pollen was performed at day 21 similarly to the sensitization protocol. Blood samples were taken at day 28 after the first sensitization. The binding of DEP to pollen grains was studied by scanning electron microscopy and the inflammatory response in the lung was studied by light microscopy. Immunoglobulin E (IgE) and IgG(1) responses against pollen grains were measured by digoxigenin (DIG) enzyme-linked immunosorbent assay (ELISA). Scanning electron microscopy revealed a mixture of free DEP and DEP associated with pollen grains. Both intranasal and intratracheal routes of administration of pollen grains induced inflammatory reactions in the lung with an influx of macrophages, eosinophilic granulocytes, and granuloma formation. Pollen grains were localized in the alveoli after both intranasal and intratracheal administration and were surrounded by macrophages. The number and localization of pollen grains were similar for both routes of administration. After coexposure with DEP, DEP-loaded macrophages were found around the pollen. Localization, inflammatory reaction, and integrity of pollen were similar to those seen without DEP. At day 28, specific IgE and IgG(1) antibodies were found in serum of rats immunized intranasally or intratracheally. IgE antibody response was higher in rats immunized with pollen grains and DEP than in rats immunized with pollen only (dilution mean +/- SEM: 59.4 +/- 4.6 vs. 27 +/- 5.1). The IgG(1) antibody response was much higher compared to the IgE response (factor of 10(4)), but the level of IgG(1) antibodies was only slightly increased by DEP (dilution mean +/- SEM: 24.2 +/- 2.0 x 10(4) vs. 16.1 +/- 2.1 x 10(4)). In conclusion, the intranasal application of pollen in the BN rat is a suitable and elegant method to evoke inflammatory reactions in the lung and pollen-specific IgE responses measured by DIG ELISA. Finally, this model gives similar results on adjuvant activity of DEP found in the ovalbumin models presented previously.
Adjuvants, Immunologic↗
Detection of immunotoxicity of benzo[a]pyrene in a subacute toxicity study after oral exposure in rats.
In an extended OECD 407 study protocol, including immune parameters, male Riv:Tox Wistar SPF rats were treated for 35 days with benzo[a]pyrene (B[a]p) (3, 10, 30, or 90 mg/kg body weight) by gavage. Oral administration of B[a]p in rats resulted not only in general toxicity, as indicated by the effects on body weight, but also in immunotoxicity, as indicated by the effects on bone marrow, thymus, spleen, and lymph nodes. Oral B[a]p induced a dose-related decrease in thymus weight (at 10, 30, and 90-mg/kg). Lymph node weights (popliteal, mandibular, and mesenteric) were decreased in the 90-mg/kg rats only. Histologically, indications for cortical atrophy were noted in the thymuses of the 30- and 90-mg/kg dose groups, which was confirmed by morphometric analysis. Nucleated spleen and bone marrow cell counts were decreased in the 90-mg/kg group. Both the absolute number (90 mg/kg) and relative number (10, 30, and 90 mg/kg) of B cells in the spleen were decreased. Red blood cell (RBC) and white blood cell (WBC) counts were significantly decreased; for the WBC at 90 mg/kg, and for the RBC at 10, 30, and 90 mg/kg. The absolute number of lymphocytes and eosinophilic granulocytes was decreased in the 90-mg/kg group, while the absolute number of monocytes was increased in the 10- and 30-mg/kg dose groups. Serum immunoglobulin levels showed a decrease of IgM and IgA after treatment of the animals with 30 and 90 mg/kg, respectively. The highest dose of B[a]p treatment (90 mg/kg) resulted in a significant decrease of natural killer (NK)-cell activity in the spleen. Most toxic effects were only observed in the highest-dose group (90 mg/kg), but compared to the general toxicity, some parameters indicating immunotoxic effects were also affected at lower doses (10 and 30 mg/kg). In conclusion, immunotoxicity of B[a]p can be detected using parameters of the immune system such as described in the recently updated OECD 407 guideline. In the present study thymus weight changed and spleen B-cell populations were affected at a dose of 10 mg/kg, a level where no overt general toxicity was noted.
Animals↗
A new rat model of otitis media caused by Streptococcus pneumoniae: conditions and application in immunization protocols.
Streptococcus pneumoniae (pneumococcus [Pn]) can be cultured from up to 50% of acute otitis media (AOM) effusions, and these bacteria are the most common cause of AOM-related complications. With the recent advent of antibiotic-resistant Pn strains, treatment of Pn infections may meet with serious difficulties. Prevention through vaccination, notably for the four most common occurring Pn serotypes in humans (i.e., Pn 6B, Pn 14, Pn 19F, and Pn 23F), is a helpful alternative. Testing of vaccine efficacy should occur in an appropriate animal AOM model, which is presented here. The four involved Pn serotypes are not pathogenic to the rat, which was chosen as the experimental animal for practical reasons. To induce a natural infection (i.e., ascending through the eustachian tube), the mucociliary clearance of the eustachian tube was impaired by infusing histamine into the tympanic cavity on 2 consecutive days before intranasal inoculation of the bacteria. With this simple protocol, high and reproducible infection rates, as determined with bacterial cultures, of Pn-induced AOM (approximately 70%) with the two major Pn serotypes 14 and 19F (Pn 14 and Pn 19F) were obtained, whereas lower infection rates (25 to 50%) with Pn 6B and Pn 23F were obtained. In this model, intranasal priming with pneumococci, as well as subcutaneous vaccination with Pn 14 tetanus toxoid-conjugated polysaccharide, induced a protective effect against the induction of otitis media with these bacteria. This shows that immunity to Pn 14 AOM can be induced by both mucosal and systemic presentations of antigen. In conclusion, we have developed an animal model for Pn-induced AOM, which is suitable for the evaluation of the protecting effect of immunization.
Animals↗
The role of the immune system in hexachlorobenzene-induced toxicity.
Hexachlorobenzene (HCB) is a persistent environmental pollutant. The toxicity of HCB has been extensively studied after an accidental human poisoning in Turkey and more recently it has been shown that HCB has immunotoxic properties in laboratory animals and probably also in man. Oral exposure of rats to HCB showed stimulatory effects on spleen and lymph node weights and histology, increased serum IgM levels, and an enhancement of several parameters of immune function. Moreover, more recent studies indicate that HCB-induced effects in the rat may be related to autoimmunity. In Wistar rats exposed to HCB, IgM antibodies against several autoantigens were elevated; in the Lewis rat, HCB differently modulated two experimental models of autoimmune disease. Oral exposure of rats to HCB induces skin and lung pathology in the rat. Recently several studies have been conducted to investigate whether these skin and lung lesions can be related to HCB-induced immunomodulation, and these studies will be discussed in this review. HCB-induced skin and lung lesions probably have a different etiology; pronounced strain differences and correlation of skin lesions with immune parameters suggest a specific involvement of the immune system in HCB-induced skin lesions. The induction of lung lesions by HCB was thymus independent. Thymus-dependent T cells were not likely to be required for the induction of skin lesions, although T cells enhanced the rate of induction and the progression of the skin lesions. No deposition of autoantibodies was observed in nonlesional or lesional skin of HCB-treated rats. Therefore, we concluded that it is unlikely that the mechanism by which most allergic or autoimmunogenic chemicals work, i.e., by binding to macromolecules of the body and subsequent T- and B-cell activation, is involved in the HCB-induced immunopathology in the rat. Such a thymus-independent immunopathology is remarkable, as HCB strongly modulates T-cell-mediated immune parameters. This points at a very complex mechanism and possible involvement of multiple factors in the immunopathology of HCB.
Adjuvants, Immunologic↗
Risk assessment and immunotoxicology.
In general toxicity testing, maximal acceptable concentrations are derived from no-observed adverse effect levels (NOAEL) in rodents. Risk assessment then considers safety factors for the interspecies difference, and intraspecies variability. This approach can be used for assessing maximal acceptable concentrations for chemicals inducing direct immunotoxicity, resulting in e.g. reduced resistance to infections. As for predictive testing of chemicals in terms of sensitization, laboratory animal data are mostly used for risk assessment as well. Generally, the assessment of risk for chemicals that induce contact sensitivity is limited to hazard identification, and risk management is restricted to labeling. An alternative type of evaluation of the risk of adverse effects due to exposure to immunotoxic chemicals may be the so called parallellogram approach. In this parallellogram there are four cornerstones, one of which is the health effect of exposure to a chemical, assessed as an endpoint (e.g. infection model) in experimental animals, and another the quantitative prediction of this endpoint in humans. The other cornerstones are assays of parameters that are relevant to the mechanism of the adverse effect in experimental animals and humans, and are used for species comparison. Species comparisons between the animal species used for hazard identification and humans are crucial for extrapolation of animal data to the human situation. This approach can be used to provide relevant information on the dose-response relationship in humans. In concert with information on actual exposure, such data can then be used for the characterization of risk for adverse health effects in humans. Such approaches have been used for chemicals that exert direct immunotoxic activity (bis(tri-n-butyltin)oxide (TBTO)), and may hold promise for the risk evaluation of chemicals that exert skin sensitizing properties.
Animals↗
Experimental studies on immunosuppression: how do they predict for man?
The ultimate goal of any animal model in immunotoxicity testing is that it be a sensitive predictor of xenobiotic-induced immune dysfunction in humans. Such models should be capable of identifying the target(s) within the immune system affected by the xenobiotic. In particular the tier testing models have been successfully used to identify and characterize a variety of different immunotoxicants in animals as it pertains to immunosuppression and reduced resistance to infectious diseases. These tier models in mice and rats have been validated in interlaboratory studies. Although these protocols were designed for studies of rats and mice, some have been applied successfully for studying immunotoxicity in other animal species, including non-human primates. A great amount of data has been generated by the application of these models, which demonstrate that xenobiotics alter the immune system of animals. In man, the database on chemical-induced immunosuppression is limited, as the use of markers of immunotoxicity has received little attention in clinical and epidemiological studies. Such studies have not been performed frequently, and their interpretation often does not permit unequivocal conclusions to be drawn, due for instance to the presence of confounding factors and the uncontrolled nature of exposure. Also, testing possibilities in humans are limited and immune function changes by chemical exposure are often subtle. In humans, a number of agents have been shown to have immunosuppressive properties (including PCBs, PCDDs, PCDFs, oxidant gases, and ultraviolet radiation), but the strongest evidence stems from the clinical use of immunosuppressant drugs in transplant patients. These human data do in general terms confirm the data gained with experimental animals. Immunotoxicity assessment in rodents therefore adequately forms the basis for human risk assessment. Knowledge on the predictability of these animal models and immune assays can be further improved by comparison of the human and animal data obtained in the development of drugs.
Animals↗
Hexachlorobenzene-induced immunomodulation and skin and lung lesions: a comparison between brown Norway, Lewis, and Wistar rats.
Strain dependence of the induction of skin and lung lesions by hexachlorobenzene (HCB) in the rat was studied to further the insight into the etiology of the lesions. To this end, 3- to 4-week-old female Brown Norway (BN), Lewis, and Wistar rats received diets supplemented with 150 mg (BN and Lewis), 450 mg (BN, Lewis, and Wistar) or 900 mg (BN and Wistar) HCB per kilogram diet for 4 weeks. Gross skin lesion development during exposure as well as pathologic changes in skin and lungs and various parameters of immunomodulation after exposure were assessed. General toxicity as judged by a slight increase in body weight gain and induction of liver cell hypertrophy was similar in BN and Lewis rats exposed to 450 mg/kg HCB and in Wistar rats exposed to 900 mg/kg HCB. Skin lesions ranged from redness to large exudating sores with crusts. With regard to dose, time of onset, incidence, and severity, skin lesions were very severe in BN, moderate in Lewis, and negligible in Wistar. Porphyrins could not be detected in the skin, whereas porphyrins in the liver were seen only in Lewis rats. Histology showed epidermal hyperplasia, deep dermal venules with activated endothelium, and deep dermal inflammatory infiltrates mainly consisting of eosinophilic granulocytes in BN and of mononuclear cells in Lewis and Wistar. Nonlesional skin of HCB-exposed rats showed very similar, though less prominent, changes. Lung pathology appeared negligibly strain-dependent; histology showed venules with an activated endothelium surrounded by a perivascular infiltrate as well as focal alveolar macrophage accumulations in all strains. Parameters of immunomodulation showed moderate strain dependence; relative spleen weights were dose-dependently increased in BN and Wistar and in the 450 mg/kg group in Lewis rats. BN rats showed a more marked splenomegaly than the other strains. Relative popliteal lymph node weights were increased significantly in BN and Lewis rats exposed to 450 mg/kg HCB. In all strains, HCB increased lymph node HEVs. Serum IgE and IgG levels were increased significantly in a dose-dependent way in BN rats only. Total serum IgM levels were elevated significantly in BN, Lewis, and Wistar rats that received 450 mg/kg and in Wistar rats that received 900 mg/kg HCB. Serum IgM levels against ssDNA were dose-dependently increased in all strains, being more marked in BN and Lewis than in Wistar rats. It is concluded that the HCB-induced inflammatory skin and lung pathologies have different etiology. Pronounced strain differences in the skin lesions suggest a specific involvement of the immune system. Skin lesions correlated significantly with all assessed parameters of immunomodulation in BN, with some in Lewis and with none in Wistar rats. No correlation was observed between the parameters of immunomodulation and lung lesions.
Animals↗
Impaired cellular immune response in rats exposed perinatally to Baltic Sea herring oil or 2,3,7,8-TCDD.
While the immunotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been well established, the effects of complex environmental mixtures of polyhalogenated aromatic hydrocarbons (PHAHs) are poorly understood. Many PHAHs, including the polychlorinated-biphenyls (PCBs), -dibenzofurans (PCDFs), and dibenzo-p-dioxins (PCDDs), possess 'dioxin-like' activities, and accumulate in the aquatic food chain. Organisms occupying high trophic levels may therefore be exposed to concentrations which may present an immunotoxic risk. In this study, pregnant PVG rats were administered a daily oral dose of 1 ml of the following during pregnancy and lactation: (1) oil extracted from herring caught in the relatively uncontaminated Atlantic Ocean; (2) oil extracted from herring caught in the contaminated Blastic Sea; or (3) the Atlantic herring oil extract spiked with 2,3,7,8-TCDD. The daily intakes of aryl hydrocarbon (Ah)-receptor dependent toxic equivalents (TEQ) for mothers were 0.3 in the Atlantic group, 2.1 in the Baltic group, and 134 ng/kg body wt. in the 2,3,7,8-TCDD positive control group. Immune function and host resistance to rat cytomegalovirus (RCMV) were assessed in offspring aged 11, 25, 46 or 59 days. Rat pups in the positive control TCDD-spiked group exhibited immunosuppression characterized by reduced thymus weight and cellularity, reduced thymocyte and splenocyte proliferative responses to T-dependent mitogens in vitro, reduced virus-associated natural killer (NK) cell and specific antibody responses. While less pronounced, a similar pattern of effects was observed in the rat pups exposed only to the Baltic Sea herring oil. These immunotoxic effects were transient in both exposure groups, with a time-related recovery in immune function possibly due to the half-life of TCDD in rats and the waning exposure levels in the rapidly growing pups. We previously demonstrated that the same Baltic Sea herring led to impaired natural killer cell and T-lymphocyte function in harbour seals during the course of a long-term captive feeding study. The collective results of these studies in rats and seals indicate the immunotoxic potential of environmental mixtures at current levels in the aquatic environment, and suggest that the developing immune system of young mammals may be at particular risk.
Animals↗